Radiation-associated cardiovascular disease

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Abstract

As the number of cancer survivors grows because of advances in therapy, it has become more important to understand the long-term complications of these treatments. This article presents the current knowledge of adverse cardiovascular effects of radiotherapy to the chest. Emphasis is on clinical presentations, recommendations for follow-up, and treatment of patients previously exposed to irradiation. Medline™ literature searches were performed, and abstracts related to this topic from oncology and cardiology meetings were reviewed. Potential adverse effects of mediastinal irradiation are numerous and can include coronary artery disease, pericarditis, cardiomyopathy, valvular disease and conduction abnormalities. Damage appears to be related to dose, volume and technique of chest irradiation. Effects may initially present as subclinical abnormalities on screening tests or as catastrophic clinical events. Estimates of relative risk of fatal cardiovascular events after mediastinal irradiation for Hodgkin's disease ranges between 2.2 and 7.2 and after irradiation for left-sided breast cancer from 1.0 to 2.2. Risk is life long, and absolute risk appears to increase with length of time since exposure. Radiation-associated cardiovascular toxicity may in fact be progressive. Long-term cardiac follow-up of these patients is therefore essential, and the range of appropriate cardiac screening is discussed, although no specific, evidence-based screening regimen was found in the literature.

Introduction

Although the heart was initially thought to be relatively resistant to radiation-induced injury, cardiovascular disease resulting from therapeutic irradiation of the chest is now well recognized [1]. The majority of radiation-induced cardiovascular disease has been reported in patients previously treated for Hodgkin's disease. Because these patients tend to be young, they generally live long enough to develop delayed sequelae, and thus the potential loss of productive life years is large. While the literature of radiation-associated cardiovascular disease in survivors of Hodgkin's disease is the largest and oldest, dating from the 1960 and 1970s, survivors of other malignancies, primarily breast cancer, lung cancer and seminomas treated with chest irradiation are also at risk [2].

The purpose of this article is to summarize and disseminate current knowledge about the appropriate long-term care of patients at risk for radiation-induced cardiovascular disease. A review of the literature is provided to demonstrate the different long-term cardiotoxic effects of chest irradiation. However, the review is not intended to be a single source for determining the appropriateness of using a potentially cardiotoxic therapy in a particular patient. This is because such a decision involves the comparison of efficacy and multiple potential toxicities of different alternatives, which vary depending upon cancer type, severity and treatment technique. Such a comparison for each of the many cancers that can be treated with radiotherapy overlying the heart is beyond the scope of a single article. Disease- and treatment-specific reviews for breast cancer [3], [4], [5] and Hodgkin's disease [6] provide such comparisons, and thus, are a better source of guidance for choosing an anti-cancer regimen in a particular patient.

Section snippets

Methods

Medline™ literature searches were performed using the keywords: radiation, radiation injury, radiation therapy, Hodgkin's disease, breast cancer, anthracycline, doxorubicin, heart disease, cardiotoxicity, cardiovascular disease, arrhythmia, coronary artery disease, cardiomyopathy, electrocardiogram, echocardiogram, pericarditis, and valvular disease. English language articles were collected and reviewed. Published abstracts from oncology and cardiology meetings during 1999 and 2000 were

Myocardium

All structures of the heart including the pericardium, myocardium, valves, conduction system, and coronary arteries have the potential to be damaged by irradiation. Myocardial injury is marked by non-specific, diffuse interstitial fibrosis [7]. Lesions can measure from a few millimeters to several centimeters in diameter but usually do not involve the entire myocardium. Severity of fibrosis from one region to another can be markedly different. At a microscopic level, collagen not only increases

Clinical sequelae

The spectrum of radiation-induced cardiac disease is broad (Table 1, Table 2). Severity and types of manifestations often depend upon the risk factors listed in Table 3. Estimates of clinically evident cardiac complications range as high as 15–30%, 5–10 years after anterior-weighted therapy for Hodgkin's disease [30]. The prevalence of asymptomatic abnormalities is even higher. In one study, 88% of patients exposed to between 22.5 and 76 Gy of irradiation (via older and current techniques) had

Screening (Table 4)

The broad range of radiation-induced abnormalities described above suggests multiple potential diagnostic modalities. The most concerning issue is that radiotherapy appears to increase the risk of fatal ischemic cardiovascular disease. The next most concerning issue is the potential for loss of life and quality of life due to radiation-associated heart failure, either through direct damage to the myocardium or indirectly through an increased incidence of myocardial infarction. Those most at

Prevention and treatment

Prevention is the best way to ‘treat’ radiation-induced cardiotoxicity. Modern irradiation techniques seem to decrease the risk of most types of cardiac disease, but not eliminate it. Modern techniques including 3-dimensional treatment planning, using a linear accelerator as a radiation source, equally weighting anterior/posterior portal treatments daily, using a subcarinal block after ≥30 Gy, and treating with a shrinking field technique, minimize the volume of heart irradiated. Although

Conclusion

Radiation-induced heart disease has been a significant source of morbidity and mortality to those exposed to therapeutic doses of chest irradiation. The spectrum of disease both in manifestation and severity is broad. Damage appears to occur primarily by microvascular injury. The resulting symptoms may not occur until decades later, though subclinical abnormalities are seen much earlier. Subclinical dysfunction may be progressive and may eventually cause morbidity and mortality. While studies

Reviewers

Professor John Kurtz, Division of Radiation Oncology, University Hospitals of Geneva (HUG), Rue Micheli-Du-Crest 24, CH-1211, Geneva 14, Switzerland.

Vita J. Land, M.D., M.B.A., 100 East Huron Street #2205, Chicago, IL 60611-5904, USA

Acknowledgements

We appreciate the expert advice provided by Daniel M. Green, MD, Lisa Diller, MD and David Korones, MD in preparing this manuscript. Supported by the National Cancer Institute (CA-79060) and (CA-68484); National Heart, Lung, and Blood Institute (HL-53392), (5K30HL04161), Preventive Cardiology Training Grant (1T32HL07937); Department of Defense Breast Cancer Risk Group DAMD 17-98-1-8071; David B. Perini, Jr., Quality of Life Program; James A Manning Fellowship; Gilbert Forbes Fellowship for

Dr Adams is a Fellow in Preventive Cardiology in the Department of Community and Preventive Medicine and a Research Fellow in Pediatric Cardiology at the University of Rochester School of Medicine and Dentistry. He is a graduate of the Johns Hopkins School of Medicine, and he completed his pediatric internship at the University of Rochester Medical Center. He is developing expertise in the cardiovascular side effects of the treatment of childhood cancers.

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    Dr Adams is a Fellow in Preventive Cardiology in the Department of Community and Preventive Medicine and a Research Fellow in Pediatric Cardiology at the University of Rochester School of Medicine and Dentistry. He is a graduate of the Johns Hopkins School of Medicine, and he completed his pediatric internship at the University of Rochester Medical Center. He is developing expertise in the cardiovascular side effects of the treatment of childhood cancers.

    Dr Hardenbergh was an Assistant Professor at Duke University Medical Center, Department of Radiation Therapy. She has been awarded grants from the National Institute of Health, Department of Defense Program for Breast Cancer Research, Duke University SPORE breast cancer project, American Society for Therapeutic Radiation Oncology, American Society for Clinical Oncology, and the American Association of Cancer Research. A primary focus of her research has been studying the effects of radiation and chemotherapy on the heart of breast cancer patients. She presently practices radiation oncology in Vail, Colorado.

    Dr Constine has been the Associate Chair, University of Rochester Department of Radiation Oncology since 1997. He is a Professor of Radiation Oncology and a Professor of Pediatrics at the University of Rochester School of Medicine and Dentistry. He is a graduate of the Johns Hopkins School of Medicine, and he is board certified in pediatrics, pediatric oncology/hematology and radiation oncology. Dr Constine's research interests include secondary cancers and other long-term effects of chemotherapy and radiotherapy used to treat malignancies. He is currently a co-investigator on the NCI funded Cardiovascular Risk Factors in Long-Term Survivors of Childhood Cancer (CA-79060). In addition, Dr Constine is Vice-Chair of the Hodgkin's Disease Committee and a member of the Late Effects Committee of the Children's Oncology Group, the national (USA) multi-center childhood cancer research cooperative.

    Dr Lipshultz has been the Chief of the Division of Pediatric Cardiology, University of Rochester Medical Center and Strong Children's Hospital, and Director, Children's Heart Center at Strong since 1997. He is a Professor of Pediatrics and a Professor of Oncology at the University of Rochester School of Medicine and Dentistry. Dr Lipshultz is a graduate of the Dartmouth Medical School. He completed a residency in pediatrics at Rainbow Babies and Children's Hospital/Case Western Reserve Medical Center (Cleveland, OH) and a fellowship in pediatric cardiology at Children's Hospital (Boston, MA), where he remained on faculty until 1997. His primary research interests are in the pediatric cardiomyopathies, especially those of genetic/metabolic, toxic (e.g., those associated with cancer therapy), or infections/inflammatory (e.g., viral and HIV) etiologies. He is currently the principal investigator of the NHLBI funded Pediatric Cardiomyopathy Registry (HL53392-07) and the NCI funded Cardiovascular Risk Factors in Long-Term Survivors of Childhood Cancer (CA-79060) studies. Dr Lipshultz is the director of the Children's Oncology Group Cardiology Care Laboratory, a member of its Cancer Control Committee, and a Study Chair or participant on several COG protocols. Dr. Lipshultz has NCI and FDA funding as an investigator on the Dana Farber Childhood ALL Consortium, a Hodgkin's disease late effects study, cardioprotection with dexarazoxane and L-carnitine studies, and a physical activity late effect intervention study in long-term cancer survivors.

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