In a Danish single-institution study reported in JACC: CardioOncology, Mette Marie A. Søndergaard, MD, of the Department of Cardiology, Aarhus University Hospital, Denmark, and colleagues found a high rate of undetected or inadequately treated preexisting cardiovascular disease (CVD) prior to receipt of chemoradiation and a high rate of cardiovascular events during follow-up in patients undergoing curative treatment for esophageal cancer.¹

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 via an open thoracic approach, minimally invasive surgery, or a combination of both.

“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, and colleagues

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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 CVD

Patients had a median age of 67 years (range = 50–86 years), and 89% were male. Among the 55 patients, 18 (33%) had CVD diagnosed during evaluation (n = 12, 22%) or were not being treated for CVD 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 NT-proBNP (N-terminal prohormone of brain natriuretic peptide) at baseline, with 6 having preexisting CVD, and 12 (22%) had elevated troponin T, with 4 having preexisting CVD.

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 CVD 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 the onset of atrial fibrillation (n = 5), atrioventricular nodal re-entry 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 because of cancer following a cardiovascular event and one due to an unknown cause.

On a univariate analysis, factors significantly associated with an increased risk of cardiovascular events were preexisting atrial fibrillation (events in 3 of 5 with vs 10 of 50 without; hazard ratio [HR] = 4.35, 95% CI = 1.18–16.1) and a dilated left atrium (events in 8 of 20 with left atrial volume index ≥ 34 mL/m 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 less than 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 risk of a cardiovascular event included age, sex, body mass index, systolic and diastolic blood pressures, heart rate, total and low-density lipoprotein 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 CVD, inadequately treated preexisting CVD, 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 CVD treatment.” 

DISCLOSURE: This study was supported by the Danish Cancer Society, the Carpenter Jorgen Holm and Wife Elisa F. Hansen’s Memorial Scholarship, and the Radiumstationens Research Fund. Dr. Søndergaard and the other study authors reported no conflicts of interest.

REFERENCE

1. Søndergaard MMA, Nordsmark M, Nielsen KM, et al: Cardiovascular burden and adverse events in patients with esophageal cancer treated with chemoradiation for curative intent. JACC CardioOncol 3:711-721, 2021.