Ischemic heart disease after mantlefield irradiation for Hodgkin's disease in long-term follow-up

Abstract

Background and purpose: In patients with Hodgkin's disease treated by radiotherapy with a moderate total dose and a low (mean) fraction dose to the heart, the risk of ischemic heart disease was investigated during long-term follow-up.

Materials and methods: The medical records of 258 patients treated in the period 1965–1980 with radiotherapy alone as the primary treatment were reviewed. The median follow-up was 14.2 years (range 0.7–26.2). The mean total dose and fraction dose to the heart were 37.2 Gy (SD 2.9) and 1.64 Gy (SD 0.09), respectively. The impact on the development of ischemic heart disease of treatment-related parameters, such as the applied (fraction) dose, irradiation technique (one or two fields per day), and chemotherapy in case of a relapse, was investigated. The incidence of ischemic heart disease in this patient population was compared with the expected incidence based on gender, age and calendar period-specific data for the Dutch population.

Results: Thirty-one patients (12%) experienced ischemic heart disease (actuarial risk at 20–25 years: 21.2% (95% C.I. 15–30). Twenty-five of them were hospitalized. When compared with the expected incidence, the relative risk (RR) of hospital admission for ischemic heart disease was 2.7 (95% C.I. 1.7–4.0). There were 12 deaths (4.7%) due to ischemic myocardial or sudden death (actuarial risk at 25 years: 10.2% (95% C.I. 5.3–19), compared to 2.3 cases that were expected to have died from these causes, yielding a standardized mortality ratio (SMR) of 5.3 (95% C.I. 2.7–9.3). Gender (male), pretreatment cardiac medical history and increasing age appeared to be the only significant factors for the development of ischemic heart disease.

Conclusions: Despite the moderate total dose and the low (mean) fraction dose to the heart, the observed incidence of ischemic heart disease is high, especially after long follow-up periods. Treatment related cardiac disease in patients treated for Hodgkin's disease has only been reported for doses above 30 Gy. Although the optimum curative dose is still under debate, some studies recommend a dose as low as 32.5 Gy. The observed high rate of severe heart complications in this study advocates a dose reduction to this level, particularly in the regions where the coronary arteries are located.

Introduction

Patients treated for Hodgkin's disease have an excess mortality risk even when the risk of recurrent disease is negligible [26]. One of the major causes of the excess mortality is cardiac disease [3], [8], [13], [17], [19], [20], [26]. With increased control rates and the availability of a variety of therapeutic options, it has become extremely important to be aware of the various complications associated with radiotherapy. It is well known that cardiac events such as pericardial effusions and acute and constructive pericarditis can be related to the applied radiotherapy technique, that is, to the proportion of the dose delivered to the heart by the anterior portal, the total dose, and the daily fraction dose [2], [5], [6], [7], [9], [14], [17], [19], [31], [32]. For myocardial infarction and coronary artery disease it is as yet unclear whether and to what extent the applied radiotherapy technique influences the likelihood of occurrence of these events. Somewhat conflicting data regarding the benefit of a low cardiac fraction dose and a low total dose have been reported [1], [13], [15], [16], [24], [25], [27], [28], [33], [34], [35], [36].

In most institutes the daily fraction dose for a mantlefield irradiation is prescribed to the midplane in the patient in the center of the field. As of the mid sixties, in the Daniel den Hoed Cancer Center (DDHCC) the daily fraction dose (2.0 Gy) has been prescribed midplane in the area with the smallest patient diameter, usually the neck [10]. Due to the large diameter of the inferior part of the mediastinum, this type of dose prescription leads to a relatively low fraction dose to the heart. Because of the potential importance of the fraction size for the development of cardiac complications, we have retrospectively analyzed the medical records of patients, treated initially with radiotherapy alone, for the development of symptomatic ischemic cardiac events.