Purpose: The incidence of cardiotoxicity and clinical cardiac events following mantle irradiation (RT) in patients with Hodgkin's disease using modern techniques is controversial. The use of quantitative, prognostically validated noninvasive tests to assess systolic and diastolic cardiac function and regional myocardial blood flow may reveal preclinical abnormalities associated with subsequent clinical events of myocardial infarction, cardiac death, or angina. The goals of this study are to determine, through noninvasive measures, the presence and time course of alterations in cardiac systolic and diastolic function and of relative myocardial blood flow in long-term survivors of Hodgkin's disease, and assess their correlation with subsequent clinical cardiac end points.
Methods and materials: Equilibrium radionuclide angiocardiography (ERNA) was used to assess left ventricular (LV) systolic and diastolic function by measuring LV ejection fraction (LVEF) and peak filling rate (PFR), respectively, in patients without known ischemic heart disease who received RT. Electrocardiography was performed to assess electrical cardiac function under conditions of rest and either exercise or dipyridamole vasodilator stress. Quantitative rest/stress myocardial perfusion imaging with thallium-201 and/or Tc-99m sestamibi was used to assess myocardial perfusion. Patients at least 1.0 year after RT were eligible if they were <50 years old at RT, had no known cardiac disease, and remained free of clinical recurrence of Hodgkin's disease. Fifty patients, ages 10.2-46.1 years (mean 26.0 +/- 8.6) at RT, were tested 1.1 to 29.1 years (mean 9.1 +/- 7.5) after RT. Seventeen of these patients were tested two times separated by 1.1 to 8.1 years. The mean central cardiac RT dose was 35.1 +/- 7.8 Gy (range 18.5-47.5) in daily 15-2.0 Gy fractions. Twelve patients were concomitantly irradiated to the left ventricle, usually through partial transmission left lung shields (mean 17.0 +/- 2.2 Gy, range 14.3-21.3).
Results: No patients had signs or symptoms of cardiac disease at the time of evaluation. The mean LVEF at the time of initial testing was 59.6 +/- 6.2% (n = 50; range 42-73%; normal > or =50%), and the mean peak filling rate (PFR) was 3.46 +/- 0.88 end diastolic volumes per second (EDV/s) (range 1.5-5.4 EDV/s; normal > or =2.54 EDV/s). The 12 patients also treated to the left ventricle had a normal mean ejection fraction that was lower (56.6 +/- 5.0%) than that of the other 38 patients (LVEF = 60.6 +/- 6.3%, p = 0.051) when initially evaluated. Average PFR was similar in the two groups. For the 15 patients who had repeat tests, changes in LVEF were generally modest in individual patients, and there was no change in the group mean. For all patients, no significant association was found between cardiac function indices and age at RT, dose, or interval from RT to testing. Myocardial perfusion scintigraphy demonstrated mild ischemia in one or more segments in two patients, and borderline normal perfusion in three patients. Rest and stress ECG testing demonstrated mild repolarization abnormalities in three, and one patient was abnormal at rest and had nondiagnostic changes with stress.
Conclusions: Patients irradiated to the heart incidental to the treatment of Hodgkin's disease using modern techniques have generally normal measures of left ventricular function and myocardial perfusion. Modest differences in the normal left ventricular ejection fraction observed may be attributable to the cardiac volume irradiated. Some patients may manifest improved cardiac function as time from RT elapses, while a significant deterioration of ejection fraction was not observed and reduction in diastolic peak filling rate is uncommon. The previously reported increased risk of cardiac death may relate to use of older techniques of RT employing higher doses and lack of cardiac shielding, and uncontrolled patient selection with additional behaviors and cardiac risk factors.