Valentyna Ivanova, MD, Discusses Cardio-Oncology Care at Allegheny Health Network

Rising survival rates in cancer care have come with caveats: Depending on which therapy a patient receives, there is the potential for cardiotoxicity. This can range from elevated blood pressure during treatment to late onset effects months or years later. Cardiotoxicity usually involves anthracyclines, most data show, with newer therapies offering fewer cardiac effects.

However, despite the overall reduced cardiotoxicity profile with immune checkpoint inhibitors (ICIs), some patients can experience myocarditis, and results can be fatal.

A 2018 meta-analysis focused on ICI myocarditis published in JAMA Oncology found fatalities are rare, occurring in 0.6% of cases, but 43% of these cases involved cardiac or neurologic events.¹ Cardiac immune-related adverse events (irAEs) in randomized trials are more common, according to a 2021 meta-analysis published in the European Heart Journal, which found an incidence of 3.1% for ICI monotherapies, 5.8% for dual ICI therapies, and 3.7% (irAEs/AEs) for ICIs plus chemotherapy, compared with 2.5% of patients who reported AEs when treated with chemotherapy only.²

With this in mind, numerous cancer centers and health systems have developed treatment protocols or specialized teams to address cardiotoxicity. Allegheny Health Network (AHN), centered in Pittsburgh and serving the greater western Pennsylvania region, has developed the AHN Cardio-Oncology Clinic for Cardiotoxicity to offer patients specialized

Ivanova

treatments.² Cardiologist Valentyna Ivanova, MD, who is the program director for cardio-oncology at Allegheny General Hospital in Pittsburgh, described the team approach that serves patients at her hospital as well as at Saint Vincent Hospital in Erie and Wexford Health + Wellness Pavilion.

“The health care team altogether consists of the cardiologists who would have a special interest in cardio-oncology and have had any extra training as our program [has] evolved,” she said in an interview with Evidence-Based Oncology (EBO).

The cardio-oncology team includes Indu G. Poornima, MD, who with Ivanova sees patients at both Allegheny General Hospital and Wexford Pavilion, as well as Anita U. Radhakrishnan, MD, and Rachel A. Hughes-Doichev, MD, who see patients at Allegheny General Hospital. In addition, Ivanova said, physicians Jasmin M. Martinez-Castellanos, MD, and Orestis Pappas, MD, treat patients at Saint Vincent Hospital. “That doesn’t mean that we are not extending our care to patients who are not able to come physically to these facilities where we are providing in-person care,” Ivanova said.

This interview has been edited for clarity.

EBO: Can you describe how cardio-oncology services are delivered in Allegheny Health Network?

Ivanova: All patients with cancer who require cardiac care for various reasons are seen and treated in outpatient as well as inpatient facilities in the Allegheny Health Network. We provide face-to-face care for patients in Allegheny General Hospital and in the Wexford Health + Wellness Pavilion, as well as in Saint Vincent Hospital.

We do offer our larger community of patients with cancer video visits at this time, [and] we are in close cooperation with all our oncology colleagues, who are taking care of these patients to determine [which of] these patients are at higher risk for developing any cardiac toxicity from their oncology treatment. There are screening criteria for referral to the cardio-oncology program, which we developed and shared with the oncology care team to assist with preventive cardiology evaluation of higher cardiovascular risk oncology patients. We also work constantly behind the scenes by communicating about patients in specific cases, to make sure we provide the best and timely care for oncology patients in the system.

EBO: Could you describe any special facilities or diagnostic imaging tools that are available in your network that are particularly important for cardio-oncology?

Ivanova: Allegheny Health System provides an array of diagnostic testing, especially imaging, that aids in the diagnosis and creation of treatment plans for patients with cancer. Starting from the ultrasound, which would be transthoracic or transesophageal ultrasound, this includes the 3D volumetric left ventricular (LV) systolic function assessment in both TEE (transesophageal echocardiogram) and TTE (transthoracic echocardiogram) studies, and also the global longitudinal strain technique, which is allowing us to predict a decline in LV systolic function even prior to its occurrence; this allows for early intervention on potential adverse effects of oncology treatments that would result in a decline of LV systolic function.

We also provide a special cardiac MRI, which allows us to determine on a molecular structural level any specific reasons for declining LV systolic function—not only if it’s drug related, but also other underlying conditions that patients might have when they present for cardio-oncology. This is an especially valuable tool to assess for ICI myocarditis…. One of the major criteria for diagnosis of ICI myocarditis is MRI-related findings. We also provide an array of nuclear cardiology imaging, including MUGA (multigated acquisition) scans and also all stress test types, if we need to resort to those to assess for ischemic changes, as certain oncology drugs can cause ischemic complications. When necessary, we offer a stress test with a SPECT (single-photon emission computed tomography) or PET imaging.

We are able to assess for any valvular disease. Certain patients come to cardio-oncology with severe valvular abnormalities, and we have the ability to test and treat them for it, along with their ongoing oncology treatments by offering transcutaneous (least invasive) valve replacements, repairs. Cardiac catheterization is another diagnostic or revascularization treatment test we offer our patients, including transcatheter treatment for pulmonary embolism, which is sometimes an adverse effect of oncology treatment.

EBO: Would you elaborate on the particular points in the patient’s care journey when they should have a cardio-oncology evaluation?

Ivanova: This goes to the core of what the cardio-oncology program is. We are working with our oncology colleagues—not only physicians, but also nurses, pharmacists, physician’s assistants, nurse practitioners, and others who work in close collaboration with oncologists.

We were able to incorporate cardiovascular (CV) screening criteria in all the oncology order sets; this helps oncology providers when they see the patient with an oncology diagnosis to determine: Are these patients at higher risk of developing CV disease or complications? Should they be referred to the cardio-oncology program preventively, instead of waiting and seeing if something happens during the treatment? Those criteria have been very helpful to start the process of risk stratification at the initial oncology visit.

Based on screening parameters, patients who are at higher risk for developing cardiac problems during treatment are referred to the cardio-oncology program for further evaluation and management. Those are 2 types of screening criteria: patient-related risk factors and also treatment-related risk factors. These criteria are pretty well-defined, so it’s easy to follow.

And from there, when a patient is seen in our cardio-oncology program, our job is to make sure we assess the whole situation: overall health, CV health, and the risk of planned oncology treatment from a cardiac standpoint. Then we develop strategies to prevent any cardiac complications, even before the treatment starts.

During the treatment, we require strategies to allow us to effectively monitor for any complications from CV toxicity. We do early intervention if we see the potential for some problem from a cardiac standpoint during treatment, as well as post treatment. When treatment ends, the cardio-oncology program doesn’t stop there, because we need to make sure the patients have an ability to live life to their full potential from a cardiovascular standpoint after treatment.

[Perhaps] the patient didn’t develop any complications while treated, but there are some medications that can cause delayed cardiac effects. We discuss this with the patient, including long-term monitoring strategies. We do not to miss the potential for long-term effects of the treatment they received.

Our main goal is to avoid any dose interruptions for patients and to make sure that oncology concentrates on the cancer treatment process while we concentrate on making sure that patients receive their treatment in full, with minimal or no interruptions.

EBO: What are some real-world barriers to recognizing and managing ICI myocarditis in clinical practice?

Ivanova: Immune checkpoint inhibitors are relatively new medications; they started out as adjuvant therapies, but now they have become neoadjuvant or first-line therapies that are widely used in many cancer treatments. As our oncology colleagues are learning more and more about this group of medications, we also learn together with them what specific adverse cardio-vascular effects these therapies can cause, including very deadly ICI-induced myocarditis. As the time goes by, there are more and more data becoming available regarding ICI cardiac adverse effects. And I think more and more oncologists are becoming aware of the necessity to monitor patients on ICI therapies for major CV side effects with prescreening, and then continuously screening at least through the first 3 to 4 months of therapy. The main challenge we experienced initially was raising awareness for the necessity of screening all patients on ICI for possible CV adverse events.

As we know, ICI myocarditis is extremely rare. There is 0.5% to 1.4% chance of this complication happening compared with other ICI complications. However, the rate of MACE (major adverse cardiovascular events) from ICI myocarditis is 25% to 50%, whereas the MACE rate from any other type of myocarditis is less than 5%, so ICI-induced myocarditis is extremely deadly when it occurs and requires immediate hospitalization and treatment.

At AHN, all patients prior to initiation of ICI receive an electrocardiogram (ECG) and troponin level checked, and ECG and troponin are checked prior to the consequent cycles within first 4 months of treatment. With this screening process in place, oncologists are able to detect subclinical ICI-induced myocarditis, based on ECG changes or an increase of troponin levels greater than 5 times from baseline level. If necessary, patients are urgently referred to the cardio-oncology program. We have developed a system that allows us to see patients very quickly and confirm or rule out the diagnosis of ICI myocarditis by using appropriate testing modalities. Early detection of ICI myocarditis allows for early intervention and saves lives.

EBO: The most recent National Comprehensive Cancer Network (NCCN) Annual Conference discussed new guidelines regarding myocarditis and toxicities with ICIs. How does the work at AHN align with the recent NCCN guidelines updates?

Ivanova: There are multiple guidelines: the most recent guidelines, which came out in 2022, are from NCCN³ and the European Society of Cardiology.⁴ For ICI myocarditis, based on the data collected to date, the main surveillance parameters are: ECG and troponin. Regardless of the troponin assay used by different health systems, the level of suspicion for development of subclinical ICI myocarditis is raised if troponin increases by more than 5 times from the baseline or new conduction abnormalities or arrhythmias are detected on the ECG. The highest ICI myocarditis incidence rate observed within first 4 months of treatment. Also, simultaneous use of 2 ICI agents for treatment is increasing the MACE incidence rate. If troponin and ECG remain normal throughout the first 4 months of treatment, there is no need to continue CV laboratory surveillance, but clinical monitoring should be continued throughout the duration of the whole treatment.
if there is clinical myocarditis, the patients present as very sick, more often than not, requiring cardiac [intensive care unit] care with invasive hemodynamic and telemonitoring and initiated on pulse dose intravenous steroids.

EBO: At this year’s American College of Cardiology conference, there were sessions on cardio-oncology as well as a major clinical trial presented, the STOP-CA trial (NCT02943590).⁵ Results showed that the use of statins reduced heart dysfunction associated with anthracyclines. What did you think of those results? Can they be translated into everyday practice?

Ivanova: That was an interesting trial. Tomas Neilan, MD, MPH, director of the cardio-oncology program at Massachusetts General Hospital in Boston is one of the main investigators. This study enrolled 300 patient with lymphoma undergoing treatment with anthracyclines. Baseline echocardiogram was obtained to determine LV systolic function and then half of the patients were randomized to taking atorvastatin 40mg and another half to taking placebo with first dose before anthracycline use and for total of 12 month The primary end point was defined as decline of LVEF greater than 10% or EF less than 55%. At 12 months the primary end point occurred in 9% of patients in the statin group and 22% in the placebo group.

However, the average mean decline of LVEF was of 4% in statin subgroup and of 5% in placebo subgroup. Very small difference, although was found to be statistically significant. There were certain trials also done with statins and patients with breast cancer, which were not showing any statistically significant results.⁶

This study sends a strong signal that in lymphoma patients treated with anthracyclines, the use of statins is possibly beneficial. However, we cannot widely apply use of statins for the prevention of cardiovascular side effects in all cancer patients. More prospective studies are necessary.

EBO: How do you see cardio-oncology evolving?

Ivanova: Cardio-oncology has become a key part of the oncology team involved in care of cancer patients.

The oncology field evolved very quickly within last 30 years thanks to progress in developing new treatment options. Initially, a cancer diagnosis was a death sentence if it could not be cured by surgery; then the radiation modality came alone as part of curative treatment, followed by chemotherapy, initially with anthracyclines only, but then other chemotherapy agents were developed. Since the 1990s, the targeted therapy concept was introduced, and agents started to come to market one after another, followed by immunotherapy with ICI. The quick advances in treatment options led to more curative results for cancer patients, although we learned this could cause adverse CV side effects that might lead to the need to stop cancer treatment or to change the therapy. That is where cardio-oncology becomes very useful, by allowing oncologist to concentrate on their job of finding the best treatment options while specialized cardiologists work alongside the oncology team to prevent or reverse adverse effects and allow patients to receive necessary treatment in full.

Also, the number of cancer survivors is increasing. We are making sure that cancer survivors live meaningful lives after they beat cancer and do not succumb to long- term side effects of therapies. I think cardio-oncology is one of the areas that will be a permanent fixture in the oncology team, as we provide care prior to, during, and after treatment by oncologists.

References
1. Wang DY, Salem JE, Cohen JV, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 2018;4(12):1721-1728. doi:10.1001/jamaoncol.2018.3923
2. Rubio-Infante N, Ramírez-Flores YA, Castillo EC, Lozano O, García-Rivas G, Torre-Amione G. Cardiotoxicity associated with immune checkpoint inhibitor therapy: a meta-analysis. Eur J Heart Fail. 2021;23(10):1739-1747. doi:10.1002/ejhf.2289
3. Davies M, McPherson J, Thompson JA. Updates on the management of immunotherapy-related toxicities. J Natl Comp Cancer Netw. Published online June 1, 2023. doi:10.6004/jnccn.2023.5005
4. Lyon AR, Dent S, Stanway S, et al. Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society. Eur J Heart Fail. 2020;22(11):1945-1960. doi:10.1002/ejhf.1920
5. Neilan TG, Silva TQ, Onoue T, et al. The STOP-CA Trial: Statins TO Prevent the Cardiotoxicity associated with Anthracyclines. Presented at: 72nd American College of Cardiology Scientific Session & Expo Together With the World College of Cardiology; March 4-6, 2023; New Orleans, LA. Abstract 23-LBCT-19421-ACC.
6. Zhao G, Ji Y, Ye Q, et al. Effects of statin use on risk prognosis of breast cancer: a meta-analysis. Anticancer Drugs. 2022;33(1):e507-e518. doi:10.1097/CAD.0000000000001151