Hull MC, Morris CG, Pepine CJ, Mendenhall NP. Valvular Dysfunction and Carotid, Subclavian, and Coronary Artery Disease in Survivors of Hodgkin Lymphoma Treated With Radiation Therapy. JAMA. 2003;290(21):2831-2837. doi:10.1001/jama.290.21.2831
Author Affiliations: Departments of Radiation Oncology (Drs Hull and Mendenhall and Mr Morris) and Medicine (Dr Pepine), University of Florida College of Medicine, Gainesville.
Context The majority of patients with Hodgkin lymphoma are young and highly
curable. This necessitates concern for prevention, diagnosis, and optimal
management of potential treatment-related complications.
Objective To identify and quantify the incidence of and factors contributing to
long-term cardiac and vascular complications after radiation therapy for Hodgkin
Design and Setting Retrospective study comparing patients treated from 1962 to 1998 at
a university–based referral center with a matched general population.
Patients Four hundred fifteen consecutive patients who fulfilled the inclusion
criteria of a minimum 2-year follow-up (median, 11.2 years) and whose radiation
fields included the heart or carotid or subclavian arteries.
Main Outcome Measures Multivariable analyses of potential risk factors and observed-to-expected
ratios for cardiac valve surgery, coronary artery bypass graft surgery, percutaneous
coronary intervention, or both based on Surveillance, Epidemiology, and End
Results (SEER) and National Hospital Discharge Survey (NHDS) data.
Results Forty-two patients (10.4%) developed coronary artery disease at a median
of 9 years after treatment, 30 patients (7.4%) developed carotid and/or subclavian
artery disease at a median of 17 years after treatment, and 25 patients (6.2%)
developed clinically significant valvular dysfunction at a median of 22 years.
The most common valve lesion was aortic stenosis, which occurred in 14 valves.
The observed-to-expected ratio for valve surgery was 8.42 (95% confidence
interval [CI], 3.20-13.65) and the observed-to-expected ratio for coronary
artery bypass graft surgery or percutaneous coronary intervention was 1.63
(95% CI, 0.98-2.28). At least 1 cardiac risk factor was present in all patients
who developed coronary artery disease. The only treatment-related factor associated
with the development of coronary artery disease was utilization of a radiation
technique that resulted in a higher total dose to a portion of the heart (relative
risk, 7.8; 95% CI, 1.1-53.2; P = .04) . No specific
treatment-related factor was associated with carotid or subclavian artery
disease or valvular dysfunction. Freedom from any cardiovascular morbidity
was 88% at 15 years and 84% at 20 years.
Conclusions Among patients treated with radiation therapy for Hodgkin lymphoma,
there are statistically higher than expected rates of valve surgery and coronary
revascularization procedures over the next 10 to 20 years. Coronary vascular
disease is associated with higher radiation doses and traditional coronary
heart disease risk factors. Noncoronary vascular disease and clinically important
valvular dysfunction are less well understood complications at 15 to 20 years
after radiation, requiring surveillance and further study.
Hodgkin lymphoma is 1 of the first cancers in which high cure rates
were achieved with both radiation and chemotherapy. With longer follow-up,
it is apparent that survivors carry risks for treatment-related effects that
may not manifest until many years later. The focus of therapeutic trials in
most stages of the disease has now shifted from a search for more effective
therapy to a search for less toxic therapy. Documentation of the incidence
and severity of these late complications, as well as contributing factors,
is crucial in surveillance and intervention for late treatment effects in
patients already treated, as well as prevention of late effects in future
patients through optimal individual treatment decisions and clinical trial
Several studies have reported an increase in premature death from myocardial
infarction among patients treated for Hodgkin lymphoma with mediastinal radiotherapy.1- 8 Reports
of valvular disease9- 14 and
peripheral vascular disease15,16 after
radiotherapy have been sporadic.
Our study was designed to estimate the incidence, severity, and risk
factors associated with 3 potential radiation treatment–related complications—coronary
and noncoronary atherosclerotic vascular disease and clinically important
valvular disease—in a group of patients who have survived Hodgkin lymphoma.
Four hundred fifteen patients treated from 1962 through 1998 at the
University of Florida met the following criteria for study inclusion: treatment
with curative intent; a minimum of 2 years of follow-up; and radiation therapy
(RT) delivered at the University of Florida to fields including a portion
of the heart, carotid, or subclavian arteries. Patients whose RT fields included
heart tissue comprised the cardiac subgroup; those with RT fields including
carotid and/or subclavian arteries comprised the carotid–subclavian
artery subgroup. The cardiac subgroup and the carotid–subclavian artery
subgroup each had a total of 404 patients, with 393 included in both subgroups.
Information was obtained retrospectively through RT, hospital, and physician
records and through direct contact with the majority of patients or their
families within a year of the time of analysis. Median follow-up was 11.2
years (range, 2.1-36.3 years); 345 patients (83.1%) had follow-up for more
than 5 years, and 100 patients (24.1%) for more than 20 years, for a total
of 5588 person-years of follow-up.
Coronary artery disease (CAD) was defined as
a history of documented myocardial infarction, coronary artery bypass graft
surgery, percutaneous coronary intervention, or more than 75% diameter stenosis
on coronary angiography or autopsy. Noncoronary atherosclerotic
disease was defined as 40% or more stenosis of the carotid or subclavian
artery by ultrasound or angiography, transient ischemic attack (TIA), or stroke. Clinically important valvular dysfunction was defined as
moderate or severe stenosis or insufficiency on echocardiogram or angiogram,
or marked abnormality on autopsy. The presence or absence of hypertension,
diabetes, hypercholesterolemia (total cholesterol, ≥200 mg/dL [5.19 mmol/L]),
family history of CAD (at least 1 first-degree relative), history and quantity
of cigarette smoking, and hypothyroidism were researched in each patient;
diagnoses were based on medical records and self-reports during patient contacts.
Our cohort consisted of 251 men (60%) and 164 women (40%) with a median
age at diagnosis of 25 years (range, 4-75 years). The Ann Arbor stages were
99 patients (24%), stage I; 184 patients (44%), stage II; 105 patients (25%),
stage III; and 27 patients (7%), stage IV. Two hundred fifty-seven patients
(62%) received chemotherapy and RT and 158 patients (38%) received RT alone.
The initial treatment in the chemotherapy and RT subgroup was combined RT
and chemotherapy for 188 patients (73%), initial RT alone followed by chemotherapy
for recurrence for 48 patients (19%), and chemotherapy alone followed by RT
for recurrence for 21 patients (8%; Table
Two hundred nine patients (50%) received chemotherapy as part of the
initial treatment plan; 90 (43%) of the chemotherapy regimens were doxorubicin-based.
The RT fields were mantle alone for 54 patients (13%), mantle and subdiaphragmatic
fields for 339 patients (81%), primarily subdiaphragmatic treating only the
inferior portion of the heart for 11 patients (3%), and involved field for
11 patients (3%).
Treatment factors investigated for their impact on the late effects
of interest were: (1) total dose delivered to various structures, (2) a field-matching
technique resulting in a higher (up to 50% more than prescribed) total dose
over the base of the heart beneath the junction of mantle and subdiaphragmatic
radiation fields,17 (3) a technique used before
1975 in which the entire daily mantle dose was given through the anterior
field 3 days a week and the posterior field 2 days a week, delivering a higher
incremental dose to the heart and coronary arteries 3 days a week, (4) an
anteriorly weighted radiation approach in which the majority of the mantle
dose was delivered through the anterior field, and (5) the use of chemotherapy
and particular chemotherapeutic agents (Table 1).
All radiation doses were calculated prospectively using Clarkson calculations18 and confirmed retrospectively. The calculated mid-mediastinal
dose, located near the base of the heart, was used to estimate the radiation
dose delivered to both coronary arteries and valves. The calculated low-mediastinal
dose was not used because of the difficulty in precisely determining the actual
delivered dose in the area of potential field overlap from abutting mantle
and subdiaphragmatic fields. The calculated low-cervical dose was used to
estimate the dose delivered to the carotid and subclavian arteries.
For all analyses, SAS software was used.19 Actuarial
incidence estimates were computed using the Kaplan-Meier method.20 The
Kruskal-Wallis κ-sample test was used to compare ages and doses across
event groups. The procedure incidence data from the National Hospital Discharge
Survey (NHDS) from 1999 were accessed to estimate a baseline age- and sex-stratified
national utilization rate for valve surgery (International
Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 35.00 to 35.28), percutaneous intervention
(ICD-9-CM codes 36.01 to 36.09), and coronary artery
bypass graft surgery (ICD-9-CM codes 36.10 to 36.19).21 This utilization rate was applied to the 1999 US
population estimate obtained from the Surveillance, Epidemiology, and End
Results (SEER) database to establish an expected incidence for these procedures.22 The incidence of utilization of these procedures
was taken as a surrogate for clinically significant valvular dysfunction and
CAD. The incidence of these procedures in our database was compared with the
expected national incidence to generate observed-to-expected ratios (OERs).23
Cox multiple regression analyses24 were
used to evaluate the previously described treatment- and patient-related covariates
as potential predictors of incidence of CAD, noncoronary arteriovascular disease,
or clinically significant valvular dysfunction. Before initiating the analyses,
the proportional hazards assumption was evaluated by testing each covariate
with a corresponding time-dependent covariate in the same model. The assumption
was found to be reasonable in all cases. A bootstrapping procedure was then
implemented (1000 simple random samples were generated from the original dataset),
in order to objectively select a reduced number of covariates to go into each
final model and thereby prevent overfitting the model. Each of the 1000 bootstrapped
samples was then analyzed with imputation to impute any randomly missing data.
Each multiply imputed, bootstrapped sample was then analyzed via Cox regression.
The results were summarized, and those covariates that entered a given model
most frequently were entered into a Cox model to analyze the complete dataset.
Backward selection was implemented to build the final model. A value of P ≤.05 was considered to be statistically significant.
Coronary artery disease was diagnosed in 42 patients (30 men and 12
women) at a median of 9 years after RT (range, 1-32 years). The actuarial
incidence of CAD was 3% at 5, 6% at 10, and 10% at 20 years. Those who developed
CAD were somewhat older (median, 34 years; range, 16-67 years) at initiation
of RT compared with the remainder of the cardiac subgroup (median, 24 years).
The mid-mediastinum radiation dose was similar in patients who subsequently
developed CAD (median, 35 Gy; range, 25-42 Gy) to patients who did not develop
CAD (median, 33 Gy; range, 10-47 Gy).
Twenty patients had coronary artery revascularization procedures, with
coronary artery bypass graft surgery in 13 patients, percutaneous coronary
intervention in 11, and both procedures in 5. The OERs for these procedures
were as follows: coronary artery bypass surgery, 2.42 (observed, 13; expected,
5.30; 95% CI, 1.11-3.74); percutaneous coronary intervention, 0.86 (observed,
11; expected, 12.77; 95% CI, 0.04-1.37), and total procedures, 1.63 (observed,
24; expected, 14.75; 95% CI, 0.98-2.28). Available coronary angiography reports
described localized stenosis of more than 75% in the left main (3), left anterior
descending (12), right coronary (13), and circumflex (5) arteries.
All traditional cardiac risk factors tested (male sex, hypertension,
hypercholesterolemia, and age) were significantly associated with the development
of CAD. All 42 patients with CAD had at least 1 of these cardiac risk factors.
The only treatment-related covariate significantly associated with development
of CAD was the field matching technique (P = .04).
Neither the use of chemotherapy nor any specific chemotherapeutic agents were
associated with the development of CAD (Table 2).
Thirty patients had at least 1 of the following events: 10 patients
had stroke; 7, TIA; 14, carotid artery stenosis; and 7, subclavian artery
stenosis. Two of the 14 patients with image-documented carotid artery disease
were among the 7 patients diagnosed as having subclavian artery stenosis.
The actuarial incidence of noncoronary atherosclerotic disease was 2% at 5,
3% at 10, and 7% at 20 years. Six patients underwent carotid endarterectomy;
1 patient, carotid artery stent placement; 1, subclavian artery stent placement;
and 1, subclavian artery bypass graft surgery. The median age for all patients
who developed noncoronary vascular disease was 34 years when undergoing RT,
and the median time from therapy to event was 17 years. However, among those
who experienced TIA or stroke, the median age when undergoing RT was 51 years
and the median time from therapy to event was only 5.6 years. In contrast,
the median age of patients with isolated subclavian or carotid artery stenosis
was 20 years when undergoing RT (range, 5-58 years) and the median time from
therapy to event was 21 years (range, 5.4-33 years). The median low-cervical
radiation dose was 44 Gy (range, 37-48 Gy) for those who developed subclavian
stenosis and 36 Gy (range, 13-76 Gy) for those who did not (P = .002). The median low-cervical radiation dose was 38 Gy (range,
30-57 Gy) for those who developed carotid artery diseases and 36 Gy (range,
13-76 Gy) for those who did not (P = .05). Hypertension
and diabetes were the only patient- or treatment-related covariates associated
with the development of noncoronary atherosclerotic vascular disease (Table 3).
Clinically important valvular dysfunction developed at a median of 22
years after RT (range, 6-31 years) in 25 patients, a total of 29 valves were
involved: 15 aortic, 11 mitral, and 3 tricuspid. The actuarial incidence of
clinically important valvular dysfunction was 1% at 10, 4% at 15, and 6% at
20 years. None of these patients had a known history of rheumatic fever; however,
1 patient had subacute bacterial endocarditis and a second patient had a bicuspid
aortic valve. The median age at initiation of RT was 22 years (range, 5-48
years) for patients with clinically important valvular dysfunction, which
was at a significantly younger age than for those who developed CAD or noncoronary
vascular disease (P<.001). The median mid-mediastinum
radiation dose was 37 Gy (range, 23-44 Gy) for patients who developed and
33 Gy (range, 10-47 Gy) for patients who did not develop clinically important
valvular dysfunction (P = .01). The dominant lesions
were aortic stenosis in 14 valves, mitral insufficiency in 8, mitral stenosis
in 3, tricuspid insufficiency in 3, and aortic insufficiency in 1. Valve surgery
was required in 7 (47%) of 15 patients with dysfunctional aortic valves and
3 (27%) of 11 patients with dysfunctional mitral valves. The OER for valve
surgery was 8.42 (observed, 10; expected 1.19; 95% CI, 3.20-13.65).
None of the potential patient- or treatment-related risk factors was
significantly associated with the development of clinically important valvular
dysfunction (Table 4).
In our study, the actuarial freedom from any cardiovascular morbidity
was 88% at 15 years and 84% at 20 years. An increased risk of CAD among patients
successfully treated for Hodgkin lymphoma has been well documented,25 but the extent and severity of subsequent cardiac
valve dysfunction is unclear. Most evidence for potential radiation-related
valvular dysfunction comes from scattered reports and screening echocardiography
in asymptomatic patients.9- 13 To
the best of our knowledge, this is the first study to quantify a significant
risk of clinically important valvular dysfunction in Hodgkin lymphoma survivors
(5% at 20 years post-RT). Twenty-six of the 29 clinically significant valvular
lesions were left-sided with the dominant dysfunction more likely to be stenosis
(17 of 29) rather than insufficiency. The substantial incidence of valvular
dysfunction in this study may be due to the extended follow-up; more than
24% of patients had more than 20 years of follow-up after RT. Given the median
of a 22-year interval post-RT to diagnosis, clinically important valvular
dysfunction is emerging as an important source of long-term morbidity among
Hodgkin lymphoma survivors. Patients at risk for valve dysfunction differ
from those at risk for CAD because of the absence of other risk factors, earlier
age of RT, and longer post-RT latency period, suggesting the possibility that
the mechanism of action in radiation–induced valve dysfunction may be
different from that in CAD.
The 10.4% (42 of 404 patients) incidence of clinical CAD (corresponding
to a 20-year actuarial incidence of 9.9%) with a median 11.2-year follow-up
reported herein confirms and extends findings from previous reports.26,27 Although a comparison group for incidence
is not available, the OER for surgical or percutaneous revascularization procedures
suggests a trend toward an increased risk of CAD. A typical mantle radiation
field includes at least the right coronary and left anterior descending coronary
arteries, which were the arteries most commonly affected in our series as
well as in 2 other series.23,27 The
typical patterns of presentation in Hodgkin lymphoma preclude complete elimination
of these vessels from the treatment field. Coronary artery disease, in our
series and others,7,9,23,27 occurs
almost exclusively in patients with known cardiac risk factors. The correlation
between radiation treatment technique and/or dose and the risk of pericarditis
and myocarditis is clear, but the correlation between treatment technique
and/or dose and CAD is less clear.28- 30 In
our study, a previous irradiation technique used before 1990 that resulted
in a 50% or more increase in total dose over a small section of cardiac tissue
was significantly associated with the development of CAD, suggesting that
radiation dose may be a factor.
Most publications reporting radiation-related non–coronary atherosclerotic
vascular disease describe patients treated for carcinomas with higher doses
of radiation than those used for Hodgkin lymphoma.15,16,31- 37 Based
on our observations, we believe there were 2 distinct subgroups of Hodgkin
lymphoma survivors who developed non–coronary atherosclerotic vascular
disease. The first group is an older population with probable preexisting
disease either not affected or only accelerated by radiation. These patients
experienced strokes and TIAs, were older at RT exposure (median age, 51 years),
and had a relatively short time interval (median, 5.6 years) to development
of the vascular disease. The second group differs in that the patients were
younger (median, 20 years) at RT exposure, had a longer latency period before
diagnosis (median, 20.8 years), and had lesions not commonly seen in the general
population that are more likely to be related to cell loss from radiation
exposure at an early age. No national database is available to estimate the
incidence of non–coronary atherosclerotic vascular disease in a matched
cohort of patients, but an overall incidence of 7.4% (including a 3.5% incidence
of documented carotid artery stenosis and a 1.7% incidence of subclavian artery
stenosis) seems high in this relatively young patient population. Given the
long latency period, it is probable that the frequency of these problems will
increase as more patients, who were treated before the radiation dose reductions
in the 1990s, reach their 20-year survival milestone.
Because most radiation effects are dose-related, it is probable that
there is actually a dose effect for both noncoronary artery disease and clinically
important valvular dysfunction not identified in this study because of the
uniformity of doses used over the study period. It is probable that modern
techniques using lower radiation doses and smaller treatment volumes combined
with chemotherapy may reduce these risks. We believe that there should be
a low threshold for evaluation of potential cardiac and vascular symptoms
in survivors of Hodgkin lymphoma and that routine counseling and surveillance
are indicated after Hodgkin lymphoma therapy to ensure timely interventions.
New evaluation tools such as electron beam computed tomography imaging or
magnetic resonance coronary angiography may facilitate better screening in
high-risk asymptomatic subgroups of patients who survived Hodgkin lymphoma.38,39