Irradiation-related ischemic heart disease.

REVIEW ARTICLE

Irradiation-Related Ischemic Heart Disease By Benjamin W. Corn, Bruce J. Trock, and Robert L. Goodman An expectation for long-term survival has emerged among several groups of cancer patients treated with therapeutic irradiation (eg, Hodgkin's disease, early stage breast cancer). Therefore, the cardiovascular sequelae of thoracic irradiation have recently come under scrutiny. Animal models have demonstrated that cardiac irradiation can directly damage the myocardial microvasculature and can indirectly damage the coronary macrovasculature when coupled with cholesterol feeding. A clear association between tho-

BEFORE THE

1960s, the heart was considered to be relatively resistant to doses of ionizing irradiation that were used in clinical radiation therapy.1' 2 Since that time, however, a spectrum of cardiac pathologies including pericarditis, pancarditis, cardiomyopathy, and conduction defects has been reported in patients who received radiotherapy.3 "9 The issue of whether irradiation induces coronary artery disease has been quite unclear. Numerous anecdotal reports have described patients suffering myocardial infarctions months to years following therapeutic mediastinal irradiation.'0- 14 When these cases are examined more closely, it usually becomes apparent that few patients have irradiation as their sole risk factor for developing ischemic heart disease. 1"5 6 Nonetheless, as the population surviving Hodgkin's disease and other radiocurable tumors ages and becomes exposed to the risk factors of coronary artery disease, it is possible that excess morbidity and mortality from coronary artery disease could occur if indeed irradiation causes, aggravates, or accelerates atherosclerosis. Recently, a number of long-term cohort studies have addressed the issue of irradiationrelated ischemic heart disease (Blitzer et al,

racic radiotherapy and ischemic heart disease was observed among older clinical studies using radiotherapeutic techniques that are no longer optimal by today's standards. Such a relationship could not be confirmed in modern studies in which treatment factors (such as dose and volume of heart irradiated) were more carefully controlled. J Clin Oncol 8:741-750. v 1990 by American Society of ClinicalOncology.

disease through two pathogenic mechanisms: microvascular damage and macrovascular damage. Microvasculopathy Stewart et al performed experiments on over 500 New Zealand white rabbits maintained on a normal diet. The rabbit represents a useful model, in part because lesions that were morphologically analogous to the late irradiation-induced effects seen in human hearts were produced with either single high doses of 2,000 cGy (rad) or biologically equivalent doses of fractionated radiotherapy. In the rabbit, three phases of irradiationinduced cardiac injury were observed. An acute phase, characterized by a neutrophilic infiltrate involving all layers of the heart, occurred within a few days of radiation treatment. A latent phase followed, during which none of the animals manifested any light microscopic signs of cardiac disease. Subsequent to the latent phase, a delayed phase began, manifested by pericardial and myocardial fibrosis. 24 Fajardo and Stewart used electron microscopy to gain insight into the development of the latent phase. They noted ultrastructural damage to the

personal communication, September 1988 ).17-23

This review will synthesize information from epidemiological studies along with the available experimental animal data to assess the role of therapeutic irradiation in the development of ischemic heart disease. EXPERIMENTAL EVIDENCE

Data from animal models suggest that therapeutic irradiation can lead to ischemic heart

From the Department of Radiation Oncology, University of Pennsylvania School of Medicine; and the Division of Cancer Control, The Fox Chase Cancer Center, Philadelphia,PA. Submitted May 11, 1989; accepted December 6, 1989. Address reprint requests to Benjamin W. Corn, MD, Departmentof RadiationOncology, University of Pennsylvania School of Medicine, 3400 Spruce St, 2 Donner Building, Philadelphia,PA 19104-4283. © 1990 by American Society of Clinical Oncology. 0732-183X/90/0804-0019$3.00/0

Journalof Clinical Oncology, Vol 8, No 4 (April), 1990: pp 741-750

Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 21, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

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742

CORN, TROCK, AND GOODMAN

capillaries that caused swelling of endothelial cytoplasm with progressive obstruction of the lumen. In addition, they observed alterations in the membranes of the endothelial cells with resultant formation of thrombi. Only insignificant damage to myocardial myocytes was seen. After approximately 100 days, they saw a significant reduction in the ratio of capillaries to myocytes (capillary:myocyte ratio, 0.35 in irradiated animals v 0.64 in control animals; P < .005).26 Thus, Fajardo and Stewart proposed that irradiation may damage the microvasculature, leading to an ischemic microenvironment and the formation of dense fibrosis. Macrovasculopathy Another line of animal evidence points to the effects of irradiation on the coronary arteries themselves. Amronim and Solomon looked at the individual and joint effects of irradiation and cholesterol feeding in rabbits using a 2 x 2 factorial design. Radiotherapy alone produced only rare areas of medial degeneration in the coronary arteries. They found marked atherosclerosis in the coronary arteries of rabbits subjected to both x-irradiation and high cholesterol feedings. In fact, the degree of atherosclerosis was disproportionately higher than what might have been expected from the summation of the changes in irradiated animals and those on high cholesterol diets alone. 27 Other investigators have observed similar findings in other animal models 0 including rats, pigeons, and monkeys. 28-3 Thus, these studies suggest that, at least in some species, the combined effects of irradiation and cholesterol are necessary to produce significant arteriosclerosis. TECHNICAL CONSIDERATIONS Before reviewing the data from specific malignancies, a summary of the principles that underlie the technical considerations of radiotherapy and the resultant effect upon cardiac dose is indicated. Hodgkin's disease represents a useful model to illustrate the evolution of refinements in radiotherapeutic technique. Although it would be ideal to use clinical studies to determine cardiac doses associated with the various radiotherapeutic approaches to Hodgkin's disease, such information is not easily extracted from the published literature. Instead, a theoretical over-

view can be offered. The planning of radiation treatment for Hodgkin's disease has unfolded over the past 4 decades. Up to 1951, most external beam radiotherapy used relatively lower energy photon beams generated by orthovoltage units.31 During the 1950s, higher energy machines (eg, cobalt-60) became widely used in treatment. Eventually, in the early 1970s, linear accelerators of even higher energy (eg, 6 MV) became available.32 In the ensuing years, linear accelerators began to replace cobalt machines in the treatment of Hodgkin's disease. The higher energy machines are characterized not only by skin sparing but also by improved penetrability. Since megavoltage x-rays penetrate well to depth, and because Hodgkin's disease often arises in the anterior mediastinum, many radiotherapists felt that patients with the disease could be adequately treated with only a single radiation beam from the anterior or an anteriorly weighted pair of opposed beams.33'34 Unfortunately, the use of such beam arrangements brought about higher doses to the heart, which is situated anterior to the midline nodes that are considered to be at risk in Hodgkin's disease. In comparing the use of linear accelerators with cobalt-60 irradiation, one must be mindful of two factors that influence the dose fall-off through the patient. One factor is the increased ability of higher energy radiation to penetrate through tissue. Since radiation is attenuated as it passes through tissue, points close to the surface experience a more intense radiation beam than the more deeply situated tissues. Consequently, the highest dose from a single radiation beam occurs close to the surface. The dose fall-off is less pronounced with the higher energy linear accelerators. The second factor that accentuates this phenomenon is the decrease in the intensity of the beam that occurs as the distance from the radiation source increases (ie, inverse square effect). The superficial tissues that are closer to the source are again more intensely irradiated due to this latter effect. This effect is less pronounced when larger treatment distances are used. In general, the treatment distances now used with linear accelerators are greater than those used with cobalt-60 machines.3 5 An obvious problem stemmed from the sheer amount of cardiac tissue that was sometimes unnecessarily exposed to the radiation beam. In


743

IRRADIATION-RELATED ISCHEMIC HEART DISEASE

the latter part of the 1960s, Kaplan and Carmel addressed this issue. Initially, the Stanford technique included mantle fields with generous lung blocks, but only modest protection of the heart. The technique was, therefore, modified to include a subcarinal block that was inserted between the lung blocks from the level of the diaphragm up to the inferior margin of the subcarinal lymph nodes, thereby providing additional protection of ' the heart.3 637 To demonstrate the potential aggregation of these problems, we carried out three-dimensional photon treatment planning of a 17-year-old woman who presented with stage IIA Hodgkin's disease manifested by supraclavicular and mediastinal adenopathy (Fig 1). The treatments were planned using computed tomography (CT) scans obtained in the treatment position. Target volumes as well as normal structures were contoured at the appropriate slices. Based on this information, beams were positioned and fields were shaped to provide coverage of the tumor while sparing sensitive tissues. Dose distributions were calculated. The percentage of the cardiac volume that received a particular dose was determined, and the results were expressed as a

Fig 1. Anteroposterior radiograph of mantle portal. Lung blocks (diagonal hatching), subcarinal block (horizontal hatching).

1UU

-I ''

"'" '

"'

V

CU

a, E 3

50

····· , · ·. ·. 0

20

40

60

Dose (Gy) Fig 2. Comparison of integral doses-volume histograms from two different treatment plans. Solid line refers to anteriorly weighted cobalt-60 irradiation without subcarinal block. Broken lines refer to equally weighted 6 MV irradiation with subcarinal block.

histogram. As an example, Fig 2 shows an integral dose-volume histogram that displays on the ordinate the percent volume of heart irradiated in comparison to the respective dose that was specified on the abscissa. We constructed a hypothetical plan, which may have been accepted in the 1950s and 1960s, that consisted of treatment from a single anterior cobalt-60 beam (Theratron 780; AECL Ltd, Ottawa, Canada) at a distance of 80 cm, which did not include insertion of a subcarinal block. We compared this to a modern plan, more typical of planning during the 1970s and 1980s, which was derived from a 6 MV linear accelerator (Mevatron 12; Siemens Medical Laboratories, Walnut Creek, CA) at a distance of 100 cm using equally weighted anterior and posterior fields, that included insertion of a full thickness subcarinal block after 2,500 cGy (of a total of 4,000 cGy) had been delivered. Comparison of several points in Fig 2 shows that in the case of the cobalt-60 plan, approximately 65% of the heart would receive a dose exceeding the prescription dose (4,000 cGy), whereas, in the linear accelerator plan, less than 4% of the heart exceeds the prescription dose. Further, approximately one fourth of the heart would receive a dose 1,000 rad above the prescription dose using the cobalt-60 plan. In addition to the physical factors enumerated,


744


certain biological principles were uncovered that influenced the radiotherapeutic approach to Hodgkin's disease. In the past, it was common to treat only one field per day rather than both fields daily when treating with multiple beams.38 Wilson and Hall 39 demonstrated that treatment of one field per day produces greater biological damage than treating two fields per day despite the fact that the total dose is the same. This phenomenon, known as the "edge effect," becomes more severe when larger thicknesses are treated with one field per day using lower energy beams.3 5 Further, in the treatment of Hodgkin's disease, the edge effect would be most significant in the anterior portion of the heart, precisely where most coronary vasculature lies. Another biological parameter to consider is the fractionation of total dose. A given total dose can be attained through the administration of relatively large or small individual fractions of radiotherapy. Fraction size is the dominant factor in determining late effects such as cardiac damage. For a specified total dose of irradiation, late responding tissues, by virtue of the fact that their dose-response relationship is markedly curved, show more damage from a small number of large fractions as opposed to a large number of small fractions. 40 Therefore, the older regimens, which used larger daily fractions of irradiation, were theoretically more harmful to late responding tissues such as the heart. As mentioned above, radiation therapy for Hodgkin's disease has evolved during the past 40 years. By highlighting two extreme examples of techniques used to treat Hodgkin's disease, we have demonstrated the range of possible doses delivered to the heart. In this manner, we have amplified the dose differential between old and new techniques. Although a clinical correlate is obviously not available from our patient to attest to the greater likelihood of developing an ischemic event from the older technique, review of the literature (vide infra) is consistent with the idea that higher doses engendered by the older treatment plans gave rise to more ischemic episodes. CLINICAL EVIDENCE While the animal models have existed for many years, clinical papers have been published regarding irradiation-related ischemic heart dis-

ease only relatively recently. To date, our knowledge of the potential of radiotherapy to induce ischemic disease arises from descriptions of morbidity associated with the treatment of three tumors: breast cancer, Hodgkin's disease, and seminoma. Breast Cancer Blitzer et al reported on a group of 1,489 women who underwent radical mastectomy between 1959 and 1972. Nine hundred sixteen of these women received postoperative radiotherapy. The majority of irradiated patients received 4,500 cGy (rad) in a 3-week period through parasternal and supraclavicular fields. A minority of women were irradiated through tangential portals (which include a smaller volume of the heart than the parasternal field). Life-table analysis and proportional hazards models were used to demonstrate an excess of cardiac death in the irradiated women (even after controlling for age, electrocardiographic abnormalities, and previous heart disease). This excess in mortality did not appear until a point 10 years after treatment. The authors concluded that irradiation of the heart predisposes to cardiac deaths more than 10 years after therapy (Blitzer et al, personal communication, September 1988). Although this report appears to show excess risk associated with radiotherapy, a number of qualifications need to be made. First, the Blitzer data included women who died of all types of cardiac death delineated in the eighth revision of the International Classification of Disease.41 It is not clear how many of these women actually died from ischemic disease as opposed to other cardiac conditions. Second, the women in that study received larger daily doses of irradiation (which are known to be more biologically damaging to normal tissues)4" than the doses used today. Third, the bulk of the women in that study were treated through radiotherapy portals, which are no longer used (in part because CT volumetric data have shown that an unacceptable amount of the heart is included in such treatment fields). 42 Although data on premastectomy EKG abnormalities and/or heart disease were only available for 386 women, adjusting for these variables in analysis of this smaller group did not substantially alter the risk associated with irradiation. However, no data were available on other cardio-



745

vascular risk factors for these women (eg, cigarette smoking, hypertension, diabetes, family history, etc). It is likely that any confounding introduced by imbalance in risk factors would result in observed risk underestimating the true risk, the reason being that patients with excess cardiovascular risk may be deemed poor risks for radiotherapy, resulting in an apparent excess of coronary events among nonirradiated patients. There is no likely scenario under which patients with high cardiovascular risk would be more likely to receive irradiation. The latter problem was ostensibly dealt with by Host and Loeb in a report of the long-term results of the Oslo breast cancer study (a prospective randomized trial). In that study, over 1,100 stage I and II breast cancer patients who had undergone radical mastectomy were randomized to receive either postoperative irradiation or no further treatment. Theoretically, confounding by other cardiovascular risk factors should have been controlled by the randomization. The radiotherapy arm of the trial was modified after several years. Initially (1964 to 1967), 2,500 to 4,100 cGy (rad) of orthovoltage radiation were delivered through parasternal and supraclavicular ports. Subsequently (1968 to 1972), larger doses of cobalt-60 irradiation were used. In order to ablate ovarian function, all patients received 650 to 900 cGy (rad) of ovarian irradiation before the randomization. Host and Loeb observed that beginning at 5 years after treatment, stage I patients treated with cobalt-60 irradiation began to show significantly more nonbreast cancer-related mortality than those stage I patients who were randomized to receive no adjuvant therapy. Analysis of specific causes of death showed that the difference in mortality resulted entirely from an excess of acute myocardial infarctions (10 patients in the cobalt-60 group, one in the control group). Such differences were not seen in the stage II patients or in patients treated with orthovoltage radiotherapy."7 Although this study suggests that thoracic irradiation is associated with increased incidence of coronary artery disease, it should be pointed out that an increased cardiac mortality was not seen in all groups. However, the influence of breast cancer as a competing cause of death was stronger in stage II patients than in stage I, so it is difficult to interpret the lack of cardiac effects

of cobalt-60 on stage II patients. Here, too, the radiotherapeutic techniques that were used (eg, large daily doses through fields that included relatively large amounts of the heart) would be considered suboptimal today.43 The effect of irradiation castration (and its attendant hypoestrogenism) in promoting atherogenesis cannot be interpreted, as all patients received this treatment. Hodgkin's Disease Thus far, four groups have looked at intercurrent cardiac disease in Hodgkin's disease patients treated with radiotherapy. Boivin and Hutchison analyzed the results of 957 patients treated at Harvard teaching hospitals between 1942 and 1975. Limited technical details of the treatment were provided in the report. However, it may be inferred from the appendix of the report that a variety of techniques were used during that 33-year period to treat the 678 patients who received radiotherapy. The authors concluded that irradiated patients did not have an increased relative coronary death rate when compared with nonirradiated patients or to the general population."8 Our analysis of the Boivin and Hutchison' 8 data leads us to a different set of conclusions. In comparing the irradiated and nonirradiated Hodgkin's patients, the overall relative death rate of 1.5 (95% confidence interval, 0.40 to 2.1) did not represent a statistically discernible excess. However, when the authors stratified their analysis of coronary mortality by follow-up interval in addition to adjusting for stage and class, they observed relative death rates of 0.68 and 2.9 for follow-up intervals of less than 1 year and 1 or more years, respectively. The authors stated that neither of these rates differed "significantly from unity" but did not provide confidence intervals. They hypothesized that the apparent dependence of mortality on follow-up interval (effect modification) could have resulted from radiotherapists avoiding irradiation of patients with obvious high coronary risk, although data on coronary risk factors were not available in the report. However, such a bias would not be likely to result in a spurious excess risk among irradiated patients at intervals greater than 1 year if irradiation truly had no cardiotoxic effect. It should be noted that excess irradiation-related cardiotoxicity may be


746


more fully manifested with longer follow-up since the median age at diagnosis for this series was in the early 20s. In addition, when comparing irradiated Hodgkin's patients with the general population, Boivin and Hutchison 18 found a relative coronary death rate of 2.1 (95% confidence interval, 1.0 to 3.9). Although these authors judged this result to be a nonsignificant finding, we feel that this reflects overreliance on P values. A relative risk in excess of two, with a confidence interval bounded below by one appears to be a clinically meaningful finding.44 Finally, the authors did not even consider the impact of Hodgkin's disease and second primaries as competing causes of death, which could also result in underestimation of true risk compared with a general population. However, our interpretation of these data is tempered by the fact that the reported cardiac sequelae reflect in large part the use of radiotherapeutic technique, which is no longer considered to be state-of-the-art. 36 Brosius et al reported on autopsy findings in 16 patients aged under 35 years who received a minimum of 3,500 cGy to the heart.4 5 Thirteen patients had Hodgkin's disease, two had carcinoid, and one had histiocytic lymphoma. Fourteen of the patients were treated with anteriorly weighted radiation portals. Nine of the patients were treated with relatively low-energy photons (ie, 2 MV). Six patients were cigarette smokers, two had elevated cholesterol levels, and three had received doxorubicin. A comparison was made to 10 age- and sex-matched control patients. Cause of death was not indicated for either the irradiated or control patients. In 10 of 16 irradiated patients and in all 10 control subjects, the four major coronary arteries were examined in detail. It is unclear why the authors chose to exclude six of the 16 cases from this part of the analysis. The arteries were excised, transversely cut into 5 mm segments, and studied for degree of luminal narrowing. Of the 469 five mm segments of major coronary arteries examined in the 10 study patients, 131 (28%) were narrowed from 0% to 25% (controls, 21%), 207 (44%) were narrowed from 26% to 50% (controls, 67%), 103 (22%) were narrowed from 51% to 75% (controls, 12%), and 28 (6%) were narrowed from 76% to 100% (controls, 0.2%). The comparison appeared to yield significantly more narrowing within the

irradiated patients in the subgroup with greater than 75% arterial obliteration. Despite the presence of these anatomic abnormalities, only one death in the cases studied was clearly attributable to clinically significant coronary artery narrowing. Of interest, the occlusive changes in not only the irradiated patients but also the control subjects were predominantly fibrotic. Indeed, others have contended that it is not possible to morphologically distinguish spontaneous atherosclerosis from irradiation damage. 46 The study exhibits methodologic flaws that hinder assessment of the atherogenic effects of irradiation, including possible lack of comparability between groups and inappropriate statistical techniques (eg, lack of within-group independence). Nonetheless, the excess of coronary artery lesions seen by Brosius et a145 are certainly consistent with irradiation changes. As such, the data from Brosius et al may represent a clinical example of macrovasculopathic changes associated with techniques, which, by the authors' admission, are unacceptable to most modern radiotherapists. To date, two groups have reported on intercurrent coronary death in a group of Hodgkin's patients treated with modern radiotherapeutic technique. Hancock et al reviewed the Stanford experience of 362 patients treated since 1967 with either irradiation alone or radiotherapy with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy in a randomized clinical trial. 19 Of note, patients treated during this period have benefitted from refinements in blocking techniques, dose considerations, and treatment planning. 37 Nine patients succumbed to acute myocardial infarctions, which occurred 2 to 19 years following therapy. Five of these patients died between the ages of 33 and 43 years, having no known cardiovascular risk factors. However, mortality related to acute myocardial infarction in the group studied was not significantly different from that expected for an age- and sex-matched control population. Unlike some of the other studies discussed, the life-table methods applied here did take account of differential follow-up due to competing risk, allowing a valid comparison to a standard population. Investigators from the Joint Center for Radiation Therapy (Boston, MA) recently described the outcome for patients with Hodgkin's disease



who were treated with precise techniques characterized by the use of treatment simulators, linear accelerators, equal doses from anterior and posterior fields, as well as contoured cardiopulmonary blocks. 4 7 The treatment was delivered to 315 patients with surgically staged Hodgkin's disease treated from 1969 to 1984. Median follow-up was nine years (range, 2 to 16 years). Only three patients developed myocardial infarction posttreatment. The authors noted that two of these three patients had significant risk factors for arteriosclerotic heart disease. This incidence rate does not appear to be in excess of that expected in a healthy population of similar age and sex distribution. However, the follow-up may have been inadequate if late effects are not manifested until 10 years, as suggested by Blitzer et al (personal communication, September 1988). Thus, the two series that looked at Hodgkin's disease patients treated with sophisticated radiotherapeutic technique and followed for extended periods of time could not establish radiotherapy as a risk factor for the development of coronary artery disease. Seminoma The final radioresponsive tumor that has been analyzed in terms of cardiovascular side effects is testicular seminoma. Lederman et al compared the outcome among 57 patients treated with prophylactic mediastinal irradiation and infradiaphragmatic irradiation with that of 66 patients who received only infradiaphragmatic irradiation. Of note, the patients who were treated to the mediastinum received relatively low doses (median dose, 2,400 cGy) through equally weighted anterior and posterior fields. While six patients in the group who received mediastinal irradiation developed some type of cardiac complication, only three of these had clear evidence of ischemic heart disease. Although none of the patients who received only infradiaphragmatic irradiation suffered ischemic events, differences in the development of ischemic disease were not statistically significant between the two groups. 20 If all six cardiac complications were considered to be ischemic events, that would represent a significant excess risk associated with mediastinal irradiation. However, the observed cardiac disease incidence rates for seminoma patients (even considering all six as ischemic disease) did not

747 differ significantly from the rates for a comparable normal population generated from the Framingham study.48 Similarly, follow-up data from three other large series of seminoma patients 21-23 gave no evidence of an increase in the development of coronary artery disease among those who received prophylactic mediastinal irradiation. Again, the lack of data on cardiovascular risk factors leaves open the possibility that the observed rates underestimated true risk. DISCUSSION Only recently has the question of irradiationrelated ischemic heart disease been studied in rigorous fashion (Table 1). Data from animal models suggest that irradiation alone can damage the microvasculature, while irradiation coupled with other insults (eg, high cholesterol feeding) can damage the macrovasculature. The clinical literature seems to be composed of conflicting results. We believe that the conflicts are in part resolved by considering that irradiation has only been found to be a risk factor for coronary artery disease when it was delivered with techniques currently considered to be outdated. We are aware of no series of patients treated with modern techniques who were found to have an increased coronary morbidity or mortality attributable to mediastinal irradiation. However, most series did not adjust for the potentially confounding effects introduced by a variety of unmeasured contributors to cardiac mortality (eg, cigarette smoking, hypertension, hypercholesterolemia, doxorubicin chemotherapy, etc), resulting in possible underestimation of true risk. Most of the studies reviewed used cardiovascular mortality as an end point for analysis. We recognize that mortality may be somewhat insensitive for assessing the contribution of irradiation to atherosclerotic disease. It is hoped that future studies will provide data on coronary heart disease incidence, permitting a more sensitive evaluation of the long-term effects of irradiation on coronary artherosclerosis. The important problem of competing risk from recurrent disease or second primaries has not been consistently addressed in the studies reviewed here. 49,50 In two of the three studies in which excess coronary disease risk was associ-


748

CORN, TROCK, AND GOODMAN Table 1. Radiation Related Ischemic Heart Disease (Clinical Trials) Series

Study Design

Technique

Findings

Blitzer (personal communications)

Retrospective analysis of a cohort

Breast cancer

Disease

Postmostectomy; 4,500 cGy delivered to parasternal/suproclav ("hockey-stick") fields; anterior weighting

Excess "cardiac" deaths in irradiated women after 10 years

Qualifications (Comments) "lschemic" deaths not scored separately; large daily fractions, large heart volumes included in portals; incomplete risk factor profile

Host and Loeb"

Randomized trial

Breast cancer

Postmastectomy; 2,5004,100 cGy; hockey-stick fields; anterior weighting

Excess MI after 5 years in stage I patients treated with cobalt-60

Large daily fractions; large heart volumes included in portals; competing risk in stage II patients

Boivin and Hutchison"


Hodgkin's disease

Variable

No significant increased relative death rate in irradiated patients

Confidence intervals suggest excess CHD risk compared with general population; sources of bias could have produced underestimation of risk

Hancock et al"


Hodgkin's disease

4,000 cGy (mega-voltage), mantle fields (AP: PA:: 1: 1); refined blocking; s 200 cGy/ fraction

Mortality related to acute MI not significantly different from age- and sex-matched controls

Modem techniques; long F/U

Mauch et all


Hodgkin's disease

3,600-4,600 cGy; 4-6 MV photons; mantle fields (AP:PA::1:1); daily fractions of 150200 cGy; customized cardiac blocks inserted

MI develops in three of 315 patients; median F/U = 9 years

Two of three patients who developed MI had significant risk factors for arteriosclerotic heart disease; no comparison to control group

Brosius et al"

Autopsy series

Hodgkin's disease (13/16)

Anteriorly-weighted mantie portals; low energy photons

Increased narrowing of coronary arteries in irradiated patients

No significant increase in clinically evident ischemic disease

Lederman et al2


Seminoma (testicular)

Prophylactic mediastinal RT;2,400 cGy, megavoltage RT, AP:PA::1:1 : 200 cGy/fraction

Increased incidence of "cardiac" disease in patients receiving mediastinal irradiation; no statistically significant difference in cardiac disease compared with normal sample without seminoma

No significant risk of "ischemic" heart disease in comparison to control; no adjustment for other CHD risk factors

Peckham and 2 McElwain



Prophylactic mediastinal RT; 3,000 cGy, megavoltage RT

2 MI in 80 stage I patients who did not have mediastinal RT; 5 MI in 37 stage II patients who did have mediastinal RT

No statistically significant differences in ischemic deaths; no adjustment for other CHD risk factors

Hunter and Pesche13



Prophylactic mediastinal RT; mean, 2,320 cGy

No MI in 19 stage I, II patients receiving mediastinal irradiation or in 60 stage I, II patients treated without mediastinal irradiation

No ischemic complications reported

Willon and McGowan"



Not specified

No coronary events in 11 stage II patients receiving mediastinal RT; one MI in 23 stage II patients who did not receive mediastinal RT

No identifiable excess of ischemic events in patients receiving mediastinal RT; no adjustment for other CHD risk factors

Abbreviations: cGy, centiGray radss); MI, myocardial infarction; CHD, coronary heart disease; MV, megavolts; RT, radiotherapy; AP:PA, anteroposterior: posteroanterior; F/U, follow-up.

ated with techniques that are no longer considered optimal (Host and Loeb' 7 and Boivin and Hutchison"8) the observed risks may underestimate the true risk by failing to consider compet-

ing causes. However, of the two studies that used modern techniques and observed no significant excess coronary disease risk, only one (Hancock et a119) could have been subject to competing risk


IRRADIATION-RELATED ISCHEMIC HEART DISEASE problems, but those authors used statistical methods to reduce the potential for such bias. The techniques for delivering radiation therapy have undergone considerable evolution during the past 3 decades. Patients treated with older radiotherapeutic techniques have been shown to be at increased risk for the development of ischemic heart disease, probably resulting from the delivery of unnecessarily high doses of irradiation. It is not clear that the data accumulated from the use of what are now considered to be suboptimal radiotherapeutic methods can be extrapolated to patients being treated today. Current radiotherapy treatment planning attempts to minimize the volume of heart treated. Although no excess risk was observed in the three studies using modern techniques, definitive evaluation of the effect of modern radiotherapy upon atherogenesis must await longer follow-up and more rigorous evaluation of large series of pa-

749 tients treated with the new, more sophisticated techniques. Current practice for early-stage seminoma and Hodgkin's disease is predicated on the use of radiotherapy alone for the majority of patients."53 Therefore, controlled analysis of the cardiac sequelae of modern radiotherapy is precluded for these disease entities. Early-stage breast cancer, however, offers the potential for an analysis of comparable patient groups treated with or without radiotherapy. Several large randomized trials5 56' that compared mastectomy with excision plus radiotherapy could provide appropriate patient samples for such an analysis. ACKNOWLEDGMENT The authors wish to acknowledge the thoughtful comments of Drs W. Gillies McKenna, Gerald E. Hanks, Paul F. Engstrom, and James Galvin who reviewed the manuscript, and the assistance of Merceda Lafferty and Lisa Salerno who prepared the manuscript. In addition, the authors are indebted to Elizabeth Cheng who provided dosimetric expertise.

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