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Cardiovascular Status in Long-Term Survivors of Hodgkin's Disease Treated With Chest Radiotherapy

From the Department of Community and Preventive Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY; Department of Radiation Oncology, Massachusetts General Hospital; Department of Radiation Oncology, Brigham and Women's Hospital; Department of Cardiology, Department of Oncology and the Department of Radiology, The Children's Hospital; The Dana-Farber Cancer Institute; Harvard University School of Medicine, Boston, MA; Department of Biostatistics, Medical University of South Carolina, Charleston, SC; Department of Pediatrics, University of Miami School of Medicine, the Holtz Children’s Hospital of the University of Miami/Jackson Memorial Medical Center, and the Sylvester Comprehensive Center, Miami, FL

Address reprint requests to Steven E. Lipshultz, MD, Department of Pediatrics, University of Miami School of Medicine, PO Box 016820, Miami, FL 33101; e-mail: slipshultz{at}med.miami.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: Cardiovascular status was assessed in 48 Hodgkin's disease (HD) survivors at a median of 14.3 years (range, 5.9 to 27.5 years) after diagnosis because they may be at increased risk for cardiovascular abnormalities.

PATIENTS AND METHODS: Patients completed the Short-Form 36 quality-of-life instrument and were screened by echocardiography, exercise stress testing, and resting and 24-hour ECG.

RESULTS: All patients received mediastinal irradiation (median, 40.0 Gy; range, 27.0 to 51.7 Gy) at a median age of 16.5 years (range, 6.4 to 25.0 years). Four patients received an anthracycline. Although every patient described their health as good or better, and none had symptomatic heart disease at screening, all but one had cardiac abnormalities on screening. Restrictive cardiomyopathy was suggested by reduced average left ventricular (LV) dimension (P < .001) and mass (P < .001), without increased LV wall thickness. Significant valvular defects were present in 42%; 75% had conduction defects. One survivor developed complete heart block shortly after the study visit. Autonomic dysfunction was suggested by a monotonous heart rate in 57%, persistent tachycardia in 31%, and blunted hemodynamic responses to exercise in 27%. Peak oxygen uptake (VO₂max) during exercise, a predictor of mortality in heart failure, was significantly reduced (< 20 mL/kg/m²) in 30% of survivors. VO₂max was correlated with increasing fatigue, increasing shortness of breath (both, r = –0.35; P = .02), and decreasing physical component score on the SF-36 (r = 0.554; P = .00017).

CONCLUSION: A variety of unsuspected, clinically significant cardiovascular abnormalities are common in long-term survivors of HD who are treated at a young age with mediastinal irradiation. We recommend serial, comprehensive cardiac screening of HD survivors who fit this profile.

	INTRODUCTION

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As a result of advances in therapy, one in every 570 young adults is predicted to be a survivor of childhood malignancy by the year 2010.¹ Many will have been treated with anthracyclines or chest radiation, both of which may cause cardiovascular damage. In particular, Hodgkin's disease survivors treated with chest radiotherapy are at increased risk of death as a result of cardiovascular causes, particularly fatal coronary artery disease² and symptomatic cardiovascular disease.³ Nevertheless, the importance of subclinical cardiac damage in symptomatic and fatal radiation-associated cardiovascular disease remains unclear.

Mediastinal radiotherapy can cause a variety of cardiovascular complications, including pericarditis, myocardial fibrosis, coronary artery disease, valvular abnormalities, and conduction disturbances.^4-10 Over the last 30 years, radiotherapy techniques have greatly reduced the dose and volume of radiation exposure to the heart. Although systolic function seems to be better preserved with these newer techniques,^11,12 research into the occurrence of other types of cardiovascular abnormalities after modern radiotherapy is limited.³

Although multiple studies have evaluated cardiovascular status in long-term survivors of cancer treated with chest radiotherapy, these studies have generally evaluated diverse populations in terms of age,^13,14 diagnosis,^15-17 and/or other cancer treatments that are known to cause cardiovascular dysfunction.^18-20 Anthracyclines such as doxorubicin are known to adversely affect left ventricular (LV) systolic function.²¹ Thus it is difficult to separate the effects of radiotherapy and anthracyclines in studies in which patients received both. In addition, most studies have screened cancer survivors with a limited number of testing modalities and therefore have not comprehensively evaluated the full range of cardiovascular abnormalities—anatomic, myopathic, ischemic, and electrical—though individual studies have looked at each.

This lack of comprehensive evaluation is problematic, because radiation causes damage to normal tissue through inflammation, which leads to fibrosis.⁴ Thus restrictive cardiomyopathy is the predominant type of myopathic abnormality expected in those treated with mediastinal radiotherapy alone. It is more likely to be associated with diastolic LV dysfunction rather than LV systolic dysfunction in its earlier stages of progression.³ Therefore, studies focused on LV systolic dysfunction alone may not adequately characterize the degree of cardiovascular abnormalities. Fibrosis may also affect electrical conduction pathways, causing intracardiac conduction delay, arrhythmias, and autonomic dysfunction.³ These possibilities also have not been well studied in those treated with mediastinal irradiation without other known cardiotoxic agents.²²

To address these issues, we prospectively and comprehensively evaluated cardiovascular function in a population of Hodgkin's disease survivors treated during childhood or young adulthood with mediastinal radiotherapy. We sought to determine whether the reduced amounts of radiation used between 1970 and 1990 was associated with an elevated frequency of cardiovascular abnormalities and whether these abnormalities were serious enough to affect quality of life.

	PATIENTS AND METHODS

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Survivors of Hodgkin's disease were eligible if they had been diagnosed at 25 years of age, were 5 years since diagnosis, had reached the age of 18 years, and had been treated with mantle irradiation at the Harvard Joint Center for Radiation Therapy (JCRT). Individuals treated with chemotherapy were eligible if they also received mantle irradiation. Survivors had to be diagnosed after 1969. This ensured that all patients had been treated with the following techniques: 4- or 6-MV radiation source, equal weighting of daily fraction from anterior and posterior portals, less than 2 Gy daily fraction size, and similar heart and lung blocking. We excluded survivors if they were pregnant at the time of the study, were contemplating pregnancy in the near future, were unable to perform exercise stress testing, or had cardiovascular disease before therapy for Hodgkin's disease.

Patient Recruitment
Review of the JCRT medical records identified individuals who had been diagnosed with Hodgkin's disease between January 1, 1970, and June 1, 1991. Permission to contact the patient was requested from the primary oncologist of record, as required by Children's Hospital Boston institutional review board. Written informed consent was obtained at the beginning of the study visit. The Children's Hospital Boston and the Dana-Farber Cancer Institute institutional review boards approved this study.

Evaluations
Participants were evaluated as outpatients at Children's Hospital Boston National Institutes of Health–funded General Clinical Research Center. Tests included an echocardiogram, an ECG, an exercise stress test, and a 24-hour ECG (Holter monitor). Subjects also completed two health questionnaires, a general health questionnaire and the Short-Form 36 instrument (SF-36). Visits occurred between April 1996 and April 1997.

Echocardiography included evaluation of LV mass, end-diastolic wall thickness, and end-diastolic dimension. Functional assessment measured end-systolic and peak LV wall stress, LV fractional shortening, and LV stress-velocity index, a load-independent measure of contractility.²³ These measurements were converted into z scores based on age- and body surface area–matched norms as described by Colan et al²⁴ and Lipshultz et al.²⁵ These z scores were derived from a normal population numbering 335 individuals at the time of this study, between 0 and 45 years of age, screened in the cardiac echocardiography laboratory at Children's Hospital Boston.²⁴ Valvular abnormalities were assessed with two-dimensional and Doppler echocardiography. A single pediatric cardiologist reviewed all echocardiograms without knowledge of patient characteristics or other study data.

Two physicians independently reviewed all resting 12-lead ECGs using predetermined standards, and consensus interpretations were analyzed. Cardiologists at Children's Hospital Boston evaluated the 24-hour ECG for heart rate variability, arrhythmia, and conduction abnormalities as a matter of routine clinical practice. Physicians evaluating both tests were blinded to the specifics of the patient's medical history.

Blood pressure, heart rate, and rhythm were continuously monitored during exercise stress testing, and oxygen consumption was measured. A single blinded cardiologist interpreted all stress tests using predetermined criteria.^26-28 Testing was stopped if a consistent pattern of ischemic changes was noted on the ECG or if the participant complained of fatigue, chest pain, or dizziness.

Patients self-completed two questionnaires. The SF-36 was designed to measure general health-related quality of life,²⁹ and it has been used in many research studies of different populations, including patients with heart failure.^30,31 Norms and distributions of scores have been established for healthy populations based on sex and age.^30,31 The second survey, the general health status form, asks about general health, health concerns related to having survived cancer, current medications, symptoms potentially related to cardiovascular dysfunction, and habits related to risk of myocardial infarction. This instrument was created for this study, borrowing questions from other surveys. Using predesigned forms, research assistants abstracted information about therapy for Hodgkin's disease from the medical records of Children's Hospital Boston and the JCRT.

Statistical Analysis
Echocardiographic variables were expressed as z scores (normal deviates) relative to the age- or body surface area–appropriate distribution in healthy children as previously described.^24,25 The Student's t test was used to test whether the mean z scores were different from 0, the expected mean z score in a healthy population. The frequency of other cardiovascular abnormalities in this sample of Hodgkin's disease survivors was compared with published frequencies in similar populations or simply described when no controls could be found in the literature. Frequencies were compared using Pearson's ² test.

A secondary goal was to test whether associations existed between specific treatment characteristics and cardiovascular abnormalities or self-rated health status. Treatment characteristics specified for analysis before the study were total radiation dose, use of an anthracycline along with radiotherapy, age at diagnosis, and time since diagnosis. Associations between objective abnormalities and cardiovascular symptoms/quality-of-life measures were also evaluated. Strength of association between all pairs of variables (continuous or discrete) was measured using Pearson's correlation coefficient.³² Categoric variables were assigned discrete scores when calculating Pearson's correlation coefficient, as suggested by Agresti.³³ For correlations found to be statistically significant in which the first variable was dichotomous, a relative risk (both variables dichotomous) or a mean (second variable continuous) was calculated to compare those with the abnormality to those without. When frequencies of one of the variables was less than 5, a P value for association was calculated using Fisher's exact test or ordinal exact tests.³³ Statistical analyses were performed using SAS (SAS Institute, Cary, NC). All tests were two-sided and performed at an of .05. Because this was an exploratory analysis, we did not adjust for multiple testing.

	RESULTS

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Search of the medical record database revealed 319 potentially eligible patients. Fifty-three were later determined to be deceased or ineligible. Another 52 patients had no primary oncologist of record or had not been seen for years, so the individual could not be recruited per institutional review board protocol. The primary oncologist expressly withheld consent for 15 patients, usually because of the patient's current noncardiac health. Of the remaining 199 survivors, 45 patients had no valid contact information; 69 patients declined to participate, mostly because they lived out of state or could not afford to miss work; and 37 others provided no response. The remaining 48 survivors agreed to participate in the study, resulting in a participation rate of 24% (48 of 199 patients).

Participants' baseline characteristics are presented in Table 1. Although age of diagnosis ranged from 6 to 25 years of age, only three patients were 10 years of age at diagnosis, and only three patients were older than 22 years. All except six patients received between 36 and 44 Gy of mediastinal irradiation; two patients received less than 36 Gy, and four received more than 44 Gy. Only four patients (all women) received an anthracycline; cumulative dose of anthracycline was not recorded. All of these patients had follow-up time since diagnosis less than the median for the study group as a whole.

Exercise Stress Testing
Survivors performed a stress test on stationary bicycle (n = 45) or on a treadmill using the Bruce protocol (n = 1; Table 4). Nine individuals (19.6%) exercised for less than 6 minutes. Twenty-seven percent had a blunted blood pressure or heart rate response to exercise, findings suggestive of autonomic dysfunction. One survivor had ischemia with exercise. More than half (n = 24) had an abnormality on their exercise stress test. Thirty percent of the cohort (14 of 46 patients) had a peak oxygen consumption during exercise less than 20 mL/kg/m², and female survivors had a significantly lower average than men (22.5 mL/kg/m² v 30.0 mL/kg/m²; P = .0003).

Quality of Life
All participants completed both questionnaires, and all rated their health as good or better on a five-point scale (Table 5). Nevertheless, 67% reported feeling fatigued, with 35% stating that it was a moderate to severe problem ( 2 on a 0 to 4 scale). A total of 39.5% of patients complained of shortness of breath, but only 12.5% reported it as a significant problem ( 2 on a 0 to 4 scale). Twenty-five percent reported problems with chest pain, and 10% reported significant dizziness.

Associations
Peak oxygen consumption (VO₂max) and self-reported health were significantly related (Tables 6 and 7). Lower values of VO₂max were correlated with greater self-reported problems with multiple symptoms, including shortness of breath (r = –0.353; P = .02) and fatigue (r = –0.35; P = .022). In fact, the average PCS in those with abnormally low VO₂max ( 20 mL/kg/m²) was 47.4, compared with 54.1 (P = .011) in those with a normal value. In a univariate linear regression model, the PCS increased by 0.60 points for each unit increase in VO₂max (P = .0002).

Three echocardiographic findings were related to greater self-reported problems with physical activity and health. The presence of aortic regurgitation was associated with a lower PCS (P = .011) and more coughing over the preceding 4 weeks (P = .018). Although found in only three individuals, aortic stenosis was associated with increased fatigue (P = .0021), increased difficulty working around the house (P < .0001), increased difficulty earning a living (P = .0004), and decreased PCS (P < .0001). Smaller LV end-diastolic dimension z score was associated with greater fatigue (r = –0.378; P = .0125) and a tendency to rate one's health as poor (r = 0.43; P = .0038) or not as good as others (r = 0.47; P = .0016), but not with PCS.

No association existed between radiation dose and any LV chamber parameter or measure of systolic function. Nevertheless, exploratory analysis revealed some potentially significant correlations between other objective abnormalities and treatment factors. Having received an anthracycline was associated with aortic insufficiency (P = .0025), lower LV fractional shortening z score (P = .0179), and higher LV wall stress z score (P = .0199). Those who received an anthracycline also had a higher average 24-hour heart rate (94.8 v 84.7 beats per minute; P = .0079). However, only four survivors had received an anthracycline. Age at diagnosis was inversely correlated with LV end diastolic wall-thickness z score (r = –0.50; P = .0008). Younger age was also associated with an increased likelihood of sinus bradycardia on resting ECG (P = .0049). Longer follow-up was correlated with an increased likelihood of aortic stenosis (P = .0055).

	DISCUSSION

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The overall picture revealed by this study is of a population with a high degree of unsuspected cardiovascular dysfunction at a mean 15.5 years after radiotherapy for Hodgkin's disease. All but one of the 48 survivors had cardiovascular abnormalities. The significantly decreased mean LV mass, end-diastolic dimension, and end-diastolic wall thickness suggests that this population suffers from restrictive cardiomyopathy. This is confirmed by the high frequency of individuals screened with Doppler echocardiography with a possibly³⁶ or definitively³⁷ prolonged E/A ratio. Although these findings are not diagnostic, as invasive procedures are required to quantitatively measure diastolic function, they are strongly suggestive. Correlations of self-reported symptoms and physical limitations with reduced LV end-diastolic dimension support the interpretation that restrictive cardiomyopathy is associated with significant morbidity in this population, despite the fact that this cohort of Hodgkin's disease survivors described their overall health as good-to-excellent. Although this study confirms other studies³⁸ that modern therapeutic irradiation does not seem to be associated with LV systolic dysfunction 15 years after therapy, cardiac muscle is still significantly affected.

The high frequency (30%) of survivors with abnormally low peak oxygen consumption (< 20 mL/kg/m²) is striking. Peak oxygen consumption during exercise is a confirmed surrogate marker for death in patients with congestive heart failure.³⁹ A value less than 14 mL/kg/m² in such patients is clearly an indication for heart transplantation,³⁹ whereas a value between 14 and 20 mL/kg/m² suggests a patient should be listed for heart transplantation.

The frequency of valvular abnormalities is high in comparison with that of historical controls. Nine survivors (19%) suffered from mild aortic regurgitation, whereas the rate of mild or greater aortic regurgitation was 4.1% in a slightly older control population⁴⁰ and 0% in a population of 26- to 39-year-olds from the Framingham Heart Study.³⁴ Among our survivors, 19% also had mild or greater mitral regurgitation in comparison with 23.9% and 9.7%, respectively, in the above control populations. Overall, 36% of survivors had a significant left-sided valvular defect. Although none were particularly severe, the knowledge of their presence would lead to recommendations for antibiotic prophylaxis for endocarditis and regular follow-up in many patients.

These findings are consistent with three of four studies that have used echocardiography to evaluate valvular defects in Hodgkin's disease survivors.^13,20,41,42The one exception reported that only one of 49 survivors had left-sided valve regurgitation, though approximately 40% had left-sided valve thickening.²⁰ This study, however, contained 18 patients who received no irradiation, and none of the patients received 30 Gray. In Glanzmann et al's¹³ series in which 16% of 112 survivors had left-sided valve regurgitation, only patients treated with more than 30 Gy had a left-sided valve abnormality. This suggests that a threshold dose for valvular regurgitation exists at approximately 30 Gy. The largest study to date demonstrated a 24% frequency of left-sided regurgitation in 116 Hodgkin's disease patients treated with chest radiotherapy with or without chemotherapy between 1980 and 1988 at a range of 5 to 13 years after therapy.⁴² Our cohort demonstrated a higher frequency of left-sided valve regurgitation because of several reasons: our smaller sample size provides less precision, almost all our patients received more than 30 Gy of irradiation, and our patients had longer follow-up. The latter is particularly important, because radiation-associated valvular disease may be progressive.⁴³

We also uncovered a high frequency of conduction abnormalities in this cohort. The most common conduction defect, an RSR prime pattern in the right precordial leads (occurring in 28 survivors), indicates a conduction delay in the right anterior bundle, the most anterior structure of the intracardiac conduction system. Two other survivors had complete right bundle branch block. These results suggest that the most anterior structures of the intracardiac conduction system are most at risk for fibrosis from mediastinal radiotherapy. This pattern may also indicate a course of progressive damage, a conclusion strengthened by the example of the individual with right bundle branch block who later developed complete heart block.

Whether elevated heart rates are caused by autonomic dysfunction or as compensation for impaired cardiac output is unclear; almost one third of the survivors had persistent tachycardia, defined as a daily average heart rate 90 bpm. In a healthy population 18 to 71 years of age, only 5% of women had an average daily heart rate greater than 92.1 bpm, and only 5% of men had an average heart rate greater than 91.3 bpm.⁴⁴

This study was limited in the number of individuals who chose to participate. There are potential biases that may have caused our sample to be sicker than the population we sought to study (eg, volunteer bias), as well as potential biases that would have made our sample healthier (eg, the need to get primary oncologist's consent before contacting potential patients). We therefore believe that our sample was fairly representative of the population targeted, though we did not have the data to formally analyze this. We also were unable to analyze dose effect, because total radiation doses were narrowly clustered between 36 and 42 Gy. Even had there been a broader range, the actual dose of interest, the dose to particular cardiac structures, was not available. However, this is probably unknown for most patients, because such data were not easily calculated during this era. The total mediastinal dose we have used, although less precise, is more typical of the information available to physicians to guide long-term care.

Although associations between particular objective abnormalities and specific symptoms should be considered exploratory, the overall picture of repeated correlations confirmed our concern that cancer therapy that includes mediastinal radiotherapy is associated with frequently unrecognized, clinically significant cardiovascular abnormalities.³ Pulmonary abnormalities may have affected exercise stress test performance, but pulmonary function testing was not performed as part of this protocol. But even if the low maximal oxygen consumption is due to pulmonary abnormalities as opposed to cardiac, a recent report by Schroeder et al⁴⁵ suggests this would still be associated with an increased risk of myocardial infarction in the next 10 years. This report analyzed 14,480 participants in the Atherosclerosis Risk in Communities Study, a large cohort study of the general population, and found that reduced forced expiratory volume in 1 second values were associated with an increased risk of myocardial infarction in the next 10 years.⁴⁵ Finally, our study did not include children treated with the most modern techniques introduced in the mid to late 1990s, such as limiting dose to less than 25 Gy and the use of conformational therapy. Although these changes are expected to decrease cardiotoxicity, such survivors still should be comprehensively screened. These modern protocols usually combine radiotherapy with low-dose anthracyclines, and the long-term cardiovascular effects of this combination are not well studied.

In conclusion, this study demonstrated that cardiovascular abnormalities are common in long-term survivors of Hodgkin's disease treated with relatively modern methods of mediastinal radiotherapy. Even though the patients were asymptomatic and all survivors reported their health as good or better, a comprehensive battery of tests uncovered multiple types of cardiovascular abnormalities in this population. Survivors are particularly at high risk for restrictive cardiomyopathy, valvular abnormalities, conduction defects, autonomic dysfunction, and significantly reduced peak oxygen consumption. Peak oxygen consumption and 24-hour average heart rate, measures of cardiovascular status not frequently used to screen cancer survivors, were most strongly correlated with decreased physical functioning. Therefore, for this population, we strongly recommend multiple screening modalities that are capable of detecting the different manifestations of radiation-associated heart disease, even in those treated with modern protocols of mediastinal radiotherapy.²² Furthermore, one-time screening is not enough, because certain abnormalities may be associated with time since diagnosis. Although further research is required to determine the optimal schedule of cardiovascular follow-up for those treated with chest radiotherapy, this study has demonstrated that even Hodgkin's disease survivors who seem to be in good cardiovascular health have significant cardiac abnormalities.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Supported by the United States Food and Drug Administration, National Institutes of Health (grant Nos. RRO2172, CA79060, CA68484, HL53392, HL04161, HL07937, HL59837, and HL70930), and Wilmot Cancer Research Fellowship of the James P. Wilmot Foundation.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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Submitted September 22, 2003; accepted May 3, 2004.

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