Introduction: Patients with cancer in esophagus and gastroesophageal junction (EGEJ) treated with chemoradiotherapy (chemoRT) have increased risk of cardiovascular disease. EGEJ patients often have frailty and pre-existing cardiovascular disease. This may disqualify them for standard trimodal curative treatment and offer surgery alone, chemoRT alone or palliative treatment only. The current understanding of radiation induced heart disease (RIHD) in EGEJ patients is limited. Hence, there is a need for additional studies. Especially on myocardial function during and after chemoRT as congestive heart failure is a serious complication associated with increased morbidity and mortality. Proton-based radiation therapy (RT) is a new alternative to standard photon-based radiation therapy, that is likely to reduce the risk of cardiovascular complications.

Hypothesis: Treatment with chemoRT might induce myocardial dysfunction, symptoms of heart failure and decreased physical performance in patients with EGEJ Cancer.

The aim: Is to investigate the influence on chemoRT on myocardial function in EGEJ patients and evaluate the cardiac prognosis and eventually identify potential high-risk patients who might benefit from proton-based RT instead of the current photon-based RT.

Method: From power calculation the investigators plan to include 56 patients with EGEJ cancer during a period of two years. Inclusions criteria: biopsy verified EGEJ cancer supported by findings from gastroscopy, PET CT scan and with the final diagnosis locally advanced, non-metastatic. The patients will be examined with serial cardiac investigations to evaluate if they develop impairment of the heart function during or after chemoRT. The investigations include; electrocardiogram, cardiac biomarkers, echocardiography and cardio pulmonary exercise test. The examinations will be performed at study entry (baseline) and after six weeks and again after six months.

Background:

Patients with cancer in the esophagus and gastroesophageal junction (EGEJ) treated with chemoradiotherapy (chemoRT) have increased risk of cardiovascular disease. Both chemotherapy and radiotherapy have been reported to be associated with increased cardiovascular morbidity. Still, there is a survival benefit due to multimodal treatment and a careful patient selection. Radiation induced heart disease (RIHD) may include pericarditis, systolic and diastolic myocardial dysfunction, coronary heart disease, valvular heart disease and conduction abnormalities. Standard treatment of locally advanced EGEJ cancer today consists of neoadjuvant chemoRT followed by surgery or chemoRT alone. Elderly patients with frailty and pre-existing cardiovascular disease are in general not offered surgery but might be candidates for treatment with chemoRT alone, still with curative intent. However, the current understanding of RIHD in EGEJ patients is limited as data are sparse. In Sweden a single study has shown that chemoRT might potentially induce acute impairment of both systolic and especially diastolic left ventricular function. The lack of more substantial evidence leaves room for variation in clinical practice. Hence, there is a need for additional studies to provide more insights into the risk of RIHD, in particular on myocardial function during and after chemoRT as congestive heart failure is a serious complication associated with increased morbidity and mortality. Proton-based radiation therapy (RT) is a new alternative to standard photon-based radiation therapy, which reduces the radiation dose to the heart and subsequent risks of cardiovascular complications. However, the availability of proton therapy is still relatively limited for the general EGEJ population, and the indication for proton based RT is not yet evidence based. It is crucial to evaluate risk of heart failure during and after standard chemoRT and to identify potential high-risk patients who might benefit from proton therapy instead of the current standard therapy.

Hypothesis:

Treatment with chemoRT might induce myocardial dysfunction, symptoms of heart failure and decreased physical performance in patients with EGEJ Cancer.

The aim is:

• to identify systolic and diastolic myocardial dysfunction at rest and during peak exercise with advanced non-invasive imaging (echocardiography) following chemoRT.
• to evaluate if baseline myocardial biomarkers (Troponin T (TNT) and N-terminal pro b-type natriuretic peptide (NT-pro-BNP)) and risk factors (diabetes, smoking, hypertension, dyslipidemia) can predict development of myocardial dysfunction.
• to detect whether exercise echocardiography compared to resting echocardiography can identify additional patients with myocardial dysfunction following chemoRT.
• to examine whether development of myocardial dysfunction in EGEJ patients will be reflected in impairment of psychical capacity evaluated by cardiac pulmonary exercise test with assessment of maximal oxygen consumption.
• to evaluate if baseline symptoms classification with clinical frailty score and New York Heart Association (NYHA) and can predict development of myocardial dysfunction.

Method:

Design:

A prospective observational study of patients with EGEJ cancer. Fifty-six patients will be enrolled during a period of 18 months. For the individual patient the heart check investigations will be performed within six months and follow up in general is until 5 years.

After informed consent in the Department of Oncology, the patients will be examined with heart investigations (ECG, Echocardiography rest/exercise and CPX test) in the Department of Cardiology before they start oncologic treatment (baseline) after 6 weeks and again after 6 months.

Clinical frailty, risk factors and cardiac symptoms will be evaluated from structured interview at follow-ups. The investigators will use validated models for graduating risk factors, clinical frailty and shortness of breath (NYHA classification). The patients will serve as own controls comparing the baseline findings with the findings thereafter.

The heart investigations:

Electrocardiogram (ECG): Is made to detect ST-segment depression, elevation or negative T-waves, LV strain or arrhythmias.

Blood samples (Cardiac biomarkers): TNT to detect myocyte necrosis and NT-pro-BNP to detect myocardial dysfunction and lipids to be used in risk evaluation.

3D echocardiography at rest and during exercise: Two-and three-dimensional Doppler echocardiography is used to evaluate Left ventricular (LV) systolic and diastolic function.

LV systolic function is evaluated by 3D echocardiography estimated ejection fraction (LVEF) and by 2D global longitudinal strain (GLS), which is a sensitive marker of myocardial function beyond LVEF. The test will be performed at rest and at peak exercise using a semi-supine ergometer bicycle. Determination of LV contractile reserve capacity is evaluated by the difference in GLS and LVEF at rest and at peak exercise. Myocardial systolic reserve capacity in other cardiac diseases has demonstrated to be a significant marker of functional capacity.

LV diastolic function is evaluated by left atrial volume and pulsed and tissue-Doppler parameters according to current guidelines by the European Society of Cardiology.

Cardio pulmonary exercise (CPX) test:

Maximum oxygen uptake (VO2 max) from a cardio pulmonary test is gold standard to measure the physically capacity of patients and is known to add prognostic information in patients with heart failure independently of etiology. The patient will be placed on a semi-supine special designed bicycle with simultaneous determination of VO2 during increasing watts. Hemodynamic parameters as pulse, blood pressure and ECG will be measured continuously. Echocardiography will be performed at rest and during peak exercise

Inclusion Criteria:

• Biopsy verified EGEJ cancer verified by gastroscopy, biopsy and PET/CT scan.
• The final diagnosis must be locally advanced, non-metastatic as determined at a multidisciplinary team conference.
• Patients referred to curative treatment with preoperative or definitive chemo- and radiotherapy.

Exclusion Criteria:

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• Age < 18 years
• Patients not being able to give informed consent (decided by the investigator).
• Patients not being able to understand Danish language.
• Acute myocardial infarct within the last 6 months.
• Present clinical severe heart valve disease and/or congestive heart failure with left ejection fraction < 25 %.
• Patients with prior thoracic radiation and overlapping RT fields.