Managing patients with lung cancer in the current era of an increasing array of systemic treatments has become a complex balancing act of trying to improve outcomes and survival from a cancer perspective while taking the necessary treatment and monitoring steps for cardioprotection. With few consensus guidelines and sparse data to support decision-making, this clinical scenario is made even more challenging. This topic was the focus of a presentation at the recent 2024 American College of Cardiology (ACC) course on Advancing the Cardiovascular Care of the Oncology Patient.¹

“For patients with higher-stage lung cancer, risk of cancer mortality really dwarfs the risk of competing, noncancer, cardiopulmonary morbidity and mortality.”

— Lova Sun, MD, MSCE

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“The concept of bidirectional risk between cancer and cardiovascular disease [CVD] is certainly very applicable in lung cancer,” stated Lova Sun, MD, MSCE, Assistant Professor of Medicine, Division of Hematology/Oncology, University of Pennsylvania, Perelman School of Medicine, Philadelphia. There are many shared risk factors, such as smoking, older age, and systemic inflammation, she added, and those with lung cancer have been found to have more than a 60% increased risk of CVD.

A longitudinal study out of the United Kingdom followed almost half a million people who were free of lung cancer at baseline to assess a potential link between CVD and lung cancer.² These investigators found that those who had CVD had about a one and a half times increased risk of developing different types of lung cancer (eg, adenocarcinoma, squamous cell carcinoma) vs those without CVD. Conversely, if you had any type of lung cancer, you had about a two to four times higher risk of developing CVD than if you did not have lung cancer, Dr. Sun explained.

These baseline risk factors are further exacerbated in those with lung cancer by potentially cardiotoxic and complex therapies. Depending on stage, histology, and genetic drivers, many of these individuals receive surgery and radiotherapy for early-stage disease; chemoradiotherapy for locally advanced disease; and chemotherapy, immunotherapy, and targeted therapies for metastatic disease.

For patients with higher-stage lung cancer, “risk of cancer mortality really dwarfs the risk of competing, noncancer, cardiopulmonary morbidity and mortality,” Dr. Sun noted. In comparison, those with earlier-stage lung cancer have a more substantive risk of competing events from noncancer etiologies. However, more recently, increasing survival in those with advanced or metastatic lung cancer suggests “we should care about cardiovascular risk mitigation in lung cancer management” across the board, she stated.

Radiation Therapy and Chemotherapy

Cardiac events occur early in those treated for lung cancer, and they are common (> 10%) at 2 years after treatment, commented Nicolas Palaskas, MD, FACC, Associate Professor of Medicine, Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston. In fact, radiotherapy cardiac dose is considered a modifiable risk factor for major adverse cardiac events and all-cause mortality.³

Nicolas Palaskas, MD, FACC

“We have to be concerned about cardiovascular events early on after radiotherapy for lung cancer,” Dr. Palaskas said. Based on prospective studies, with a follow-up of about 2 years, early cardiovascular disease events after radiotherapy for lung cancer included arrhythmia, heart failure, pericardial disease, and myocardial infarction.

“Preexisting coronary heart disease is a major risk factor for cardiovascular events after radiotherapy,” Dr. Palaskas said. The hazard ratio in a study by Atkins et al³ was 3.6. At 2 years out, there was an 11.7% rate of major cardiovascular events with preexisting coronary heart disease. “And at 5 years out, the incidence in these patients was 20%,” he stated.

As for radiation dose and major cardiovascular events, Atkins et al looked at median heart doses of 10 and < 10 Gy.⁴ They found that preexisting heart disease was a strong risk factor for those receiving higher doses of radiation. However, Dr. Palaskas noted, “maybe mean heart dose is not the best way to assess radiotherapy dose and risk of cardiovascular events.” Many studies are looking now at cardiac substructure dosimetry and major cardiovascular events.⁴ “Left main coronary artery and proximal left anterior descending artery [doses] seem to be better predictors of major adverse cardiovascular events after radiotherapy,” he explained.

Dr. Palaskas outlined steps to prevent cardiotoxicity from radiotherapy. Early referral to cardiology is suggested to optimize cardiovascular risk factors. Next, radiation oncologists should be engaged in dosimetry analysis to minimize doses to the heart, left main coronary artery, and left anterior descending artery. Finally, risk stratification should be performed using cardiac dose and preexisting cardiovascular disease factors.

“Despite the explosion of targeted and immunotherapies, chemotherapy (a platinum doublet) remains a mainstay of therapy for both early-stage and advanced-stage lung cancers,” noted Dr. Sun. Cisplatin, in particular, has been known to cause arrhythmia, electrocardiographic changes, myocardial infarction, myocarditis, cardiomyopathy, and hypertension, and often it may be substituted with carboplatin in patients at higher risk of such cardiac effects. Other chemotherapy agents may cause cardiotoxicity, such as paclitaxel and docetaxel (bradycardia, heart block), vincristine and vinorelbine (hypertension, myocardial infarction), and etoposide (myocardial infarction and angina).

“There are not a lot of guidelines when it comes to cardiovascular toxicity from cancer treatments, specifically for our lung cancer population,” Dr. Sun acknowledged. “So, we tend to fall back on our primary/secondary cardiovascular risk mitigation (eg, lifestyle, medication management, electrolyte monitoring, and possibly the investigative cardiac blood biomarkers).”

Targeted Therapies and Immune Checkpoint Inhibitors

Dr. Sun turned to targeted therapies for lung cancer and focused on the third-generation EGFR tyrosine kinase inhibitor osimertinib. Osimertinib is now standard of care in the first-line management of advanced EGFR-mutated non–small cell lung cancer (NSCLC), based on the FLAURA2 trial results.⁵ According to the study investigators, use of this agent in combination with a platinum agent and pemetrexed achieved statistically significant and clinically meaningful improvement in progression-free survival.

The most common cardiac event in the FLAURA2 trial was QTc prolongation, at a rate of 10%. Higher rates of heart failure, atrial fibrillation, myocardial infarction, and pericardial effusion in some cases with osimertinib compared with earlier-generation EGFR-targeted agents have been seen, noted Dr. Sun. In a real-world analysis out of Stanford University, Franquiz et al⁶ found a left ventricular ejection fraction decline of at least 10% to up to 50% in 17 of 862 patients (about 2%) treated with osimertinib.

Reasonable clinical approaches to monitoring patients receiving osimertinib for lung cancer are based on guidelines from the European Society of Cardiology, published in 2022.⁷ They include electrocardiographic monitoring for QTc prolongation in high-risk patients as well as assessment of left ventricular ejection fraction at baseline and at 3 months in those with cardiac risk factors.

Briefly, Dr. Sun mentioned another class of agents being used to treat lung cancer: the ALK inhibitors. Agents such as alectinib, brigatinib, ceritinib, and lorlatinib have been known to “reliably” cause hypertension, elevations in blood glucose, and hyperlipidemia.

Finally, Dr. Sun mentioned the ever-growing number of immunotherapy approvals in the lung cancer space across both perioperative and advanced-stage disease settings. Along with the benefits they offer in terms of efficacy, immune checkpoint inhibitors have been found to be linked to cardiac immune-related adverse events such as myocarditis, pericardial effusion, and arrhythmia.

Illustrative Case Study: Heart of the Matter

Through the presentation of a case study, Drs. Sun and -Palaskas explored clinical decision-making for a 69-year-old woman with left lobe NSCLC, who moves through most of the treatment options in this disease setting. In addition to lung cancer, she has a history of atypical chest pain, hypertension, and hyperlipidemia, as well as risk factors such as diabetes and smoking.

Given her history and risk factors, the next steps to protect her cardiovascular health before initiating cancer therapy may include referring her to cardiology, using multidisciplinary risk mitigation and comorbidity optimization with radiation oncology and cardiology, and obtaining an ECG. Next, intensity-modulated radiation therapy (IMRT) planning was for 66 Gy in 33 fractions, with carboplatin plus paclitaxel, to reduce the amount of radiation to the left anterior descending artery as much as possible.

Practicing cardiologist Daniel Addison, MD, Associate Professor of Medicine and a member of the panel discussing this case, mentioned the comparison of IMRT vs proton therapy. Dr. -Addison is Director of the OSU Cardio-Oncology Program at The Ohio State University Wexner Medical Center, Columbus.

Daniel Addison, MD

“Data do suggest the risk of major cardiovascular events is decreased with proton therapy vs more traditional IMRT methods,” Dr. Addison stated. According to Dr. Palaskas, it is unclear whether the reduced risk is a matter of protons over photons or a result of the reduced dose with proton therapy. In addition, Dr. Sun suggested, it might be in the way the dose is distributed with proton therapy, with “a lower scatter dose and less effect to surrounding tissues.”

In the case patient, when new liver metastases were seen on magnetic resonance imaging (MRI) after chemoradiotherapy (with a stage IV metastatic lung cancer diagnosis), a regimen of carboplatin, pemetrexed, and the immune checkpoint inhibitor pembrolizumab was selected. Of note, no actionable alterations were found on next-generation sequencing, and PD-L1 expression was 20%. About 10 days after starting this regimen, she developed fatigue, decreased appetite, nausea, and chest pain.

In this clinical scenario, the question arises as to how best to handle such a relatively asymptomatic patient who is suspected of having myocarditis but lacks a definitive diagnosis. “In a patient presenting with hypotension, with recent [immune checkpoint inhibitor] initiation, myocarditis has to be in our differential considerations,” stated Dr. Addison. He suggested considering cardiac MRI (and at an experienced center, perhaps endomyocardial biopsy). Catheterization was added to the additional workup, and this patient had moderate multivessel disease and mild T2 prolongation. In addition, there was evidence of lymphocyte infiltration but no myocyte loss—not technically myocarditis. “In this setting, I am hedging toward treating this patient as potential myocarditis. There is a cost of not treating in this scenario,” according to Dr. Addison.

Dr. Palaskas shared his study findings on whether or not to treat borderline myocarditis in the setting of immune checkpoint inhibitor therapy.⁸ “We defined an [endomyocardial biopsy] grading system for [immune checkpoint inhibitor] myocarditis encompassing a spectrum of histologic findings of inflammatory infiltrates. A subset of low-grade myocardial inflammation patients were able to continue [the immune checkpoint inhibitor] without immunosuppressive therapy. Further studies are needed to identify low-risk patients who can be safely treated with [an immune checkpoint inhibitor].”

This patient was treated with low-dose (1 mg/kg) steroids and tapered over 4 weeks. The immune checkpoint inhibitor was stopped, and she experienced cancer progression, postobstructive pneumonia, and then death. Dr. Palaskas noted that as cardio-oncologists, “we have very complicated patients. We have to look not only to their cardiovascular health but their whole cancer health combined.” 

DISCLOSURE: Dr. Sun has served as a consultant to Sanofi Genzyme, Regeneron, Genmab, Seagen, and Bayer and has received institutional trial funding from Blueprint, Seagen, IO Biotech, Erasca, and Immunocore. Dr. Palaskas has served as a consultant to Kiniksa and Replimune and has received research grants from the Cancer Prevention Research Institute of Texas and the Andrew Sabin Family Foundation. Dr. Addison has received research support from the National Institutes of Health and the American Heart Association–Robert Wood Johnson Foundation.

REFERENCES

1. Palaskas N, Sun L: Spotlight on lung cancer: Case insights into radiation, ICI, and EGFR therapies. 2024 ACC Conference: Advancing the Cardiovascular Care of the Oncology Patient. Presented February 10, 2024.

2. Zhang S, Liu L, Shi S, et al: Bidirectional association between cardiovascular disease and lung cancer in a prospective cohort study. J Thorac Oncol 19:80-93, 2024.

3. Atkins KM, Rawal B, Chaunzwa TL, et al: Cardiac radiation dose, cardiac disease, and mortality in patients with lung cancer. J Am Coll Cardiol 73:2976-2987, 2019.

4. Atkins KM, Chaunzwa TL, Lamba N, et al: Association of left anterior descending coronary artery radiation dose with major adverse cardiac events and mortality in patients with non–small cell lung cancer. JAMA Oncol 7:206-219, 2021.

5. Jänne P, Planchard D, Cheng, et al: Osimertinib with/without platinum-based chemotherapy as first-line treatment in patients with EGFRm advanced NSCLC (FLAURA2). 2023 World Conference on Lung Cancer. Abstract PL03.13. Presented September 11, 2023.

6. Franquiz MJ, Waliany S, Xu AY, et al: Osimertinib-associated cardiomyopathy in patients with non-small cell lung cancer: A case series. JACC CardioOncol 5:839-841, 2023.

7. Lyon AR, López-Fernández T, Couch LS, et al: 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association, the European Society for Therapeutic Radiology and Oncology and the International Cardio-Oncology Society. Eur Heart J 43:4229-4361, 2022.

8. Palaskas NL, Segura A, Lelenwa L, et al: Immune checkpoint inhibitor myocarditis: Elucidating the spectrum of disease through endomyocardial biopsy. Eur J Heart Fail 23:1725-1735, 2021.