In a Danish single-institution study reported in JACC: CardioOncology, Søndergaard et al found a high rate of undetected or inadequately treated preexisting cardiovascular disease prior to the receipt of chemoradiation and a high rate of cardiovascular events during follow-up in patients undergoing curative treatment for esophageal cancer.

Study Details

The study involved 55 consecutive eligible patients with locally advanced, nonmetastatic squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction enrolled at the Department of Cardiology at Aarhus University Hospital between June 2018 and February 2021. Among the 55 patients, 42 received neoadjuvant chemoradiation followed by surgery, and 13 received definitive chemoradiation.

Patients received weekly chemotherapy with carboplatin at AUC 2 and paclitaxel at 50 mg/m² plus concurrent intensity-modulated radiotherapy. The neoadjuvant group received 41.4 Gy in 23 fractions over 5 weeks and the definitive chemoradiation group received 50 Gy in 25 fractions or 50.4 Gy in 28 fractions over 6 weeks. Esophageal resection was performed no earlier than 3 to 4 weeks after completion of neoadjuvant chemoradiation using an open thoracic approach, minimally invasive surgery, or a combination of both.

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Prior to the start of treatment, patients underwent clinical cardiac examination; the date of examination was considered baseline and served as the starting point for the 90-day follow-up period. Cardiovascular events during follow-up were defined as major adverse cardiovascular events (consisting of transient ischemic attack, imaging-verified new stroke, unstable angina, heart failure, or cardiomyopathy) or as Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 arrhythmia, thromboembolic events, or pericardial effusion requiring pericardiocentesis.

Pretreatment Cardiovascular Disease

Patients had a median age of 67 years (range = 50–86 years), and 89% were male. Among the 55 patients, 18 (33%) had cardiovascular disease diagnosed during evaluation (n = 12, 22%) or were not being treated for cardiovascular disease as recommended in current guidelines (n = 6, 11%).

Overall, 47% of patients had hypertension, 29% had dyslipidemia, 11% had ischemic heart disease or heart failure, and 9% had atrial fibrillation. A total of 9 patients (16%) had elevated N-terminal pro–B-type natriuretic peptide (NT-proBNP) at baseline, with 6 having preexisting cardiovascular disease, and 12 (22%) had elevated troponin T, with 4 having preexisting cardiovascular disease.  

Cardiovascular Events During Follow-up

During 90-day follow-up, 13 patients (24%) had a total of 15 predefined cardiovascular events; of the 13 patients, 4 had no preexisting cardiovascular disease or elevated levels of NT-proBNP. The 90-day cardiovascular event-free rate of major adverse cardiovascular events and CTCAE grade ≥ 3 was 76.4% (95% confidence interval [CI] = 62.8%­–85.5%).

Major adverse cardiovascular events consisted of hospitalization for unstable angina (n = 3) and stroke (n = 1), and CTCAE grade ≥ 3 consisted of onset of atrial fibrillation (n = 5), atrioventricular nodal reentry tachycardia (n = 1), pericardial effusion (n = 1), and pulmonary emboli or deep venous thromboembolic events (n = 4). No patients developed heart failure requiring hospitalization. Death occurred in two patients: one due to cancer following a cardiovascular event and one due to an unknown cause.

On univariate analysis, factors significantly associated with increased risk of cardiovascular events were preexisting atrial fibrillation (events in 3 of 5 with vs 10 of 50 patient without; hazard ratio [HR] = 4.35, 95% CI = 1.18–16.1) and dilated left atrium (events in 8 of 20 with left atrial volume index ≥ 34 vs 5 of 35 with < 34 mL/m; HR = 3.59, 95% CI = 1.17–10.9). Ever-smokers (events in 7 of 41) vs never-smokers (events in 6 of 14) had a reduced risk of cardiovascular events (HR = 0.33, 95% CI = 0.11–0.98).

Left-ventricular systolic dysfunction was common among patients with cardiovascular events, with 61.5% having impaired left-ventricular global longitudinal strain (< 18%) and 16% having left-ventricular ejection fraction < 50%. Hazard ratios for these factors were not significant, however (1.74, 95% CI = 0.70–5.34, and 1.76, 95% CI = 0.48–6.40, respectively).

Other factors not significantly associated with cardiovascular event risk included age; sex; body mass index; systolic and diastolic blood pressure; heart rate; total and LDL cholesterol; NT-proBNP level; troponin T level; hypertension; ischemic heart disease; diastolic dysfunction; cardiopulmonary exercise testing measures; tricuspid annular plane systolic excursion; histology; type of treatment; and type of surgery.

The investigators concluded, “A systematic cardiac evaluation prior to chemoradiation in patients with esophageal cancer revealed a high prevalence of undetected cardiovascular disease, inadequately treated preexisting cardiovascular disease, and a high incidence of cardiovascular events after chemoradiation. These findings highlight the need for a systematic baseline cardiac examination in patients with esophageal cancer to optimize cardiovascular disease treatment.”

Mette Marie A. Søndergaard, MD, of the Department of Cardiology, Aarhus University Hospital, is the corresponding author for the JACC:CardioOncology article.

Disclosure: This study was supported by the Danish Cancer Society, Carpenter Jorgen Holm and Wife Elisa F. Hansen’s Memorial Scholarship, and Radiumstationens Research Fund. For full disclosures of the study authors, visit jacc.org.