Download A Surveillance, Epidemiology and End Results Analysis

JOURNAL OF ADOLESCENT AND YOUNG ADULT ONCOLOGY
Volume 5, Number 2, 2016
ª Mary Ann Liebert, Inc.
DOI: 10.1089/jayao.2015.0067
Original Article
Cardiac Mortality in Children and Adolescents
with Hodgkin’s Lymphoma:
A Surveillance, Epidemiology and End Results Analysis
Arya Amini, MD,1,* Blair Murphy, MD,1,2,* Carrye R. Cost, MD,3 Timothy P. Garrington, MD,3
Brian S. Greffe, MD,3 and Arthur K. Liu, MD, PhD1
Purpose: The purpose of this study was to evaluate the risk of cardiac death in pediatric Hodgkin’s lymphoma
(HL) survivors and identify high-risk groups that may need additional surveillance.
Methods: The Surveillance, Epidemiology and End Results program database was queried to analyze the rates
of radiation therapy (RT) use and cardiac-specific mortality (CSM) in HL patients, aged 0–21 years, treated
from 1973 to 2007. Primary endpoint was cardiac mortality.
Results: A total of 6552 patients were included. Median follow-up was 12 years (range, 0–40). Median age at
diagnosis was 17 years (range, 0–21). The majority were white (85.5%), from western states (41.2%), had
nodular sclerosis HL (73.2%), presented with stage I or II disease (51.5%), and received RT (56.1%). Death
from cardiac disease occurred in 114 patients (9.2% of all deaths). CSM for the entire cohort at 10-, 20-, and 30year time points was 0.3%, 1.6%, and 5.0%, respectively. Median age at the time of cardiac death was 39 years
(range, 18–58 years). Under multivariate analysis (MVA), adolescent patients (ages 13–21) had higher rates of
CSM (hazard ratio [HR], 3.05; p = 0.005). Female gender (HR, 0.43; p < 0.001), patients treated from 1998 to
2007 (HR, 0.19; p = 0.018), and those with lymphocyte-rich histology (HR, 0.14; p = 0.047) had significantly
lower rates of CSM. Use of RT was not associated with CSM under MVA (HR, 1.18, p = 0.452).
Conclusion: The cumulative incidence of CSM in this population analysis of pediatric HL was 9.2%, with a
steady decline over the past several decades. Adolescent patients at diagnosis and males were more likely to die
of cardiac-related causes.
Keywords:
Hodgkin lymphoma, cardiotoxicity, pediatric, radiation therapy
Introduction
H
odgkin’s lymphoma (HL) represents a success in the
progress of pediatric cancer treatment. Current therapy
regimens for children typically include a combination of
multiagent chemotherapy and radiation therapy (RT). Outcomes overall for these children are very good, and for a
majority of patients, the goal is to decrease therapy to minimize late toxicities.
Multimodality treatment with chemotherapy and radiation
are well-known risk factors for long-term cardiovascular
mortality in adult survivors of childhood cancer.1–5 A large
European analysis found significantly higher rates of cardiovascular mortality after childhood cancer treatment in
people receiving a cumulative anthracycline dose greater
than 360 mg/m2 and radiation doses greater than 5 Gy.5 Numerous other studies describe long-term cardiac toxicities,
including myocardial infarction, decreased ventricular function, valvular disorders, and congestive heart failure.6–8 Efforts
have been made to minimize the use of treatment modalities, in
particular RT that puts survivors at risk for developing these
long-term side effects later in life.
We sought to expand these data by using the Surveillance,
Epidemiology and End Results program (SEER) database to
evaluate the rate of cardiac mortality in the pediatric population. The goal of using this large population database was to
potentially identify patient and treatment risk factors associated with higher rates of cardiac death.
1
Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, Colorado.
Department of Radiation Oncology, Oregon Health and Science University, Portland, Oregon.
Department of Pediatrics, Division of Hematology and Oncology, University of Colorado School of Medicine, Aurora, Colorado.
*These two authors contributed equally to this article.
2
3
181
182
Methods
Patient selection
The National Cancer Institute (NCI)-sponsored SEER
database, including 18 registries, was queried using SEER*Statv8.2.1 (seer.cancer.gov). A total of 8862 pediatric and adolescent patients, aged 0–21years, who were diagnosed with
HL between 1973 and 2007 were initially selected. For inclusion, complete data on survival and receipt of RT were
required. Patients included were coded as either receiving or
not receiving external beam RT; unknowns were excluded
(n = 341). A sensitivity analysis was performed categorizing
patients with unknown RT as receiving RT and not receiving
RT, with similar results. The cutoff year of 2007 was chosen
to allow for a minimum 5-year follow-up. A total of 6552
patients met inclusion criteria.
Patient demographics and treatment variables
Patient variables included age, gender, race, census region,
year of diagnosis, tumor histology, tumor stage, and receipt
of external beam RT. Census region was coded as facility
location and defined by SEER and categorized as West/
Alaska, East, Northern Plains, and Southwest. Stage designation was based on the Ann Arbor staging system. Receipt
of chemotherapy was not included as SEER does not record
this information. The primary endpoint of the study was
cardiac-specific mortality (CSM). CSM was determined using
cause-specific survival coded as diseases of the heart, which
is inclusive of congestive heart failure, ischemic heart disease, and other cardiomyopathies.9 Age at time of cardiac
death was determined by adding the follow-up in years to the
initial age at diagnosis.
Percent rate of cardiac mortality for the study cohort was
calculated by dividing the number of cardiac deaths by the
total number of deaths for each time period (every 4-year
increments).
Statistical analyses
All statistical analyses were performed using SPSS V22.0
(SPSS, Inc., Chicago, IL). CSM was calculated from the date
of diagnosis to the date of death. CSM was first examined
using the Kaplan–Meier method. Univariate and multivariate
Cox regression analyses were performed using CSM as the
outcome with a significance level of p < 0.05. Two-sided pvalues and 95% confidence intervals (CIs) are reported. The
following variables were included under multivariate analysis (MVA): age at diagnosis (0–12 vs. 13–21 years), gender,
race, census region, year of diagnosis (1973–1977, 1978–
1987, 1988–1997, 1998–2007), histology, Ann Arbor stage
(I/II vs. III/IV), and receipt of RT.
Results
Table 1 illustrates the baseline patient and treatment
characteristics of 6552 individuals included in the analysis.
Median follow-up was 12 years (range, 0–40 years). Median
age at diagnosis was 17 years (range, 0–21 years). The majority were white (85.5%), were from western states (41.2%),
had nodular sclerosis HL (73.2%), presented with stage I or II
disease (51.5%), and received RT (56.1%). RT use in the
study declined from 1973 to 2007 (73% of patients underwent
AMINI ET AL.
Table 1. Patient and Treatment Characteristics
Characteristic
Age (years)
0–12
13–21
Gender
Male
Female
Race
White
African American
Others
Missing
Census region
West/Alaska
East
Northern Plains
Southwest
Year of diagnosis
1973–1977
1978–1987
1988–1997
1998–2007
Histology
Nodular sclerosis
Lymphocyte rich
Lymphocyte depleted
Mixed
Nodular lymphocyte predominant
NOS
Staging
I/II
III/IV
Missing
Radiation
No
Yes
All patients (No., %)
1002 (15.3)
5550 (84.7)
3386 (51.7)
3166 (48.3)
5605
623
278
46
(85.5)
(9.5)
(4.2)
(0.7)
2698
1944
1322
588
(41.2)
(29.7)
(20.2)
(9.0)
620
1290
1443
3199
(9.5)
(19.7)
(22.0)
(48.8)
4793
201
67
721
176
594
(73.2)
(3.1)
(1.0)
(11.0)
(2.7)
(9.1)
3373 (51.5)
1693 (25.8)
1486 (22.7)
2876 (43.9)
3676 (56.1)
NOS, not otherwise specified.
RT in the years 1973–1977 compared with 50% in the years
1998–2007).
Rates of cardiac mortality (divided by all deaths) declined
from 1973 to 2007, with cardiac death rates of 14% in patients treated from 1973 to 1977 compared with 1% in patients treated from 2003 to 2007 (Fig. 1). At the time of this
analysis, 1240 patients had died (18.9%); of the 1240 deaths,
114 were cardiac related (9.2%), 716 were due to HL
(57.7%), and 410 were from other causes (33.1%). CSM for
the entire cohort at 10-, 20-, and 30-year time points was
0.3%, 1.6%, and 5.0%, respectively. Median age at the time
of cardiac death was 39 years (range, 18–58 years).
In univariate analysis (UVA), predictors for higher rates of
CSM included those patients who were adolescents at diagnosis (13–21 vs. 0–12 years) ( p = 0.007) (Fig. 2A). Under
UVA, predictors for lower rates of CSM included female
gender ( p = 0.001) (Fig. 2B) and year of treatment, including
1988–1997 ( p = 0.012) and 1998–2007 ( p = 0.006). Under
MVA, patients who were adolescents at diagnosis had higher
rates of CSM (hazard ratio [HR], 3.05; p = 0.005). Female
gender (HR, 0.43; p < 0.001), patients treated from 1998 to
CARDIAC MORTALITY IN PEDIATRIC HODGKIN’S LYMPHOMA
FIG. 1. Percent rate of cardiac mortality for the study
cohort from 1973 to 2007 queried from the SEER database.
Values were calculated by dividing the number of cardiac
deaths by the total number of deaths for each time period (4year increments).
2007 (HR, 0.19; p = 0.018), and those with lymphocyte-rich
histology (HR, 0.14; p = 0.047) had significantly lower rates
of CSM. Use of RT was not associated with CSM under MVA
(HR, 1.18, p = 0.452) (Table 2). On subset analysis, RT was
not associated with CSM in patients treated from 1973 to
1987 (HR, 1.31; 95% CI, 0.81–2.14; p = 0.273) or 1988 to
2007 (HR, 0.79; 95% CI, 0.29–2.19; p = 0.656) under MVA.
Discussion
Treatment-associated cardiovascular toxicity is of significant clinical importance in pediatric HL given the high survival rates. The leading cause of noncancer mortality in HL is
cardiovascular disease.10 Well-described treatment risk factors include RT treatment, especially at doses >30 Gy, dose
per fraction, volume of heart in the RT field, and use of
chemotherapy, including anthracyclines.7,11,12 The incidence
of anthracycline-induced cardiotoxicity ranges from 4% to
36% depending on cumulative dose and age at treatment.7,13
Previous studies demonstrated that RT-induced cardiotoxicity
contributes to 2%–5% of overall mortality in patients with HL
FIG. 2.
183
and includes coronary artery disease (CAD), chronic heart
failure (CHF), valvular disease, arrhythmias, and myocardial
infarction.6,7,14–16 One study evaluating the rates of CAD on
CT angiography in pediatric HL patients found the risk of
coronary artery abnormalities to be 16% in the first 10 years
after definitive treatment; the risk was 6.8 times higher in
patients receiving mediastinal RT, especially >20 Gy.17 Furthermore, the combination of both RT and anthracyclines can
compound these risks when compared with treatment with RT
or chemotherapy alone.18 For example, one study found that
the addition of anthracyclines caused a significant increase
in CHF (HR, 2.81) and valvular disorders (HR, 2.10) in HL
patients undergoing mediastinal radiotherapy; the cumulative
rate of CHF after multimodality treatment was 7.9%.6
To our knowledge, our SEER analysis is the first populationbased longitudinal evaluation of CSM for pediatric and adolescent HL patients. The results demonstrate a gradual decline
in cardiac mortality for pediatric and adolescent HL since
1973. Cumulative incidence of CSM at 30-year follow-up was
5.0% consistent with other reports.3 The median age of cardiac
mortality in this study was 39 years (*22 years after their
initial diagnosis and treatment). Data from this study support a
recent publication by Al-Kindi et al.,19 who queried the SEER
database to evaluate rates of CSM in adults (ages 20–49 years)
treated for HL. They demonstrated a similar drop in CSM, with
a 5-year cumulative incidence decreasing from 1.17% in 1990
to 0.19% in 2006, in addition to showing higher rates of CSM
in older patients and males. Male gender and older age at time
of cancer treatment have also been demonstrated to be predictive factors for CSM in other studies as well.16,20,21 Somewhat surprisingly and discordant with the literature, RT was not
found to correlate with CSM. However, the use of RT has
decreased over time, along with a decrease in CSM. Conclusions assessing RT correlation with CSM in the SEER database
can be difficult due to lack of information on RT field (i.e.,
inclusion of the heart within the treatment field) and total dose.
Last, data from a recent study reviewing echocardiograms of
childhood cancer survivors found similar results demonstrating
no correlation between receipt of RT and echocardiographic
abnormalities.22 The authors concluded that this was likely due
to the lower median RT dose of their study population and that
RT-associated valvular abnormalities may not have been
captured as they may occur more than 20 years after treatment.
Kaplan–Meier curves demonstrating cardiac-specific mortality by gender (A) and age group (B).
184
AMINI ET AL.
Table 2. Univariate and Multivariate Analyses of Predictors of Cardiac-Specific Mortality
Univariate
Variable
Age (years)
0–12
13–21
Gender
Male
Female
Race
White
African American
Others
Census region
West/Alaska
East
Northern Plains
Southwest
Year of diagnosis
1973–1977
1978–1987
1988–1997
1998–2007
Histology
Nodular sclerosis
Lymphocyte rich
Lymphocyte depleted
Mixed
Nodular lymphocyte predominant
NOS
Staging
I/II
III/IV
Missing
Radiation
No
Yes
Multivariate
HR
95% CI
p
HR
95% CI
p
1
2.84
1.32–6.11
0.007
1
3.05
1.41–6.60
0.005
1
0.50
0.34–0.74
0.001
1
0.43
0.29–0.64
<0.001
1
1.07
0.95
0.52–2.19
0.30–3.01
0.86
0.934
1
1.14
1.30
0.55–2.36
0.40–4.22
0.734
0.665
1
1.12
0.91
0.81
0.70–1.80
0.57–1.46
0.42–1.56
0.645
0.700
0.534
1
1.16
0.89
0.84
0.71–1.89
0.55–1.44
0.43–1.62
0.549
0.624
0.593
1
0.93
0.42
0.17
0.60–1.44
0.21–0.83
0.05–0.61
0.747
0.012
0.006
1
0.91
0.50
0.19
0.56–1.46
0.21–1.19
0.05–0.75
0.686
0.116
0.018
1
0.16
0.56
0.91
2.30
0.82
0.02–1.16
0.08–4.00
0.54–1.53
0.72–7.32
0.42–1.60
0.070
0.559
0.715
0.159
0.565
1
0.14
0.43
0.79
2.16
0.70
0.02–0.98
0.06–3.11
0.46–1.35
0.67–7.00
0.35–1.40
0.047
0.402
0.384
0.199
0.314
1
0.80
1.83
0.37–1.73
1.10–3.04
0.575
0.019
1
0.76
1.27
0.35–1.66
0.69–2.34
0.496
0.448
1
1.26
0.83–1.92
0.280
1
1.18
0.77–1.82
0.452
CI, confidence interval; HR, hazard ratio.
However, the study did find that patients receiving anthracycline doses q250 mg/m2 had significantly higher rates of
persistent echocardiographic abnormalities.
Data presented in this study demonstrate that adolescent
males diagnosed with having HL are at highest risk for cardiac
mortality. There may be several reasons, including treatment
differences and lifestyle factors between the groups. A recent
study evaluating metabolic health risk factors in childhood
cancer survivors found that males and adolescent young adults
were more likely to have hypertension, obesity, and elevated
transaminases; participants in the study with all three risk
factors present were males who were in the 18–34 age group.23
Lifestyle factors, including smoking, inactivity leading to
obesity, and hypertension, were thought to be more prevalent
in the older age group and among males, which may be contributing to the findings observed in our study as well. Additional studies specific to HL survivors have also shown male
gender to be an independent risk factor for developing CAD
and myocardial infarction.6,16 It is less likely that treatment
itself is contributing to our findings as guidelines for treatment
have not significantly differed by gender and age group
(pediatrics vs. adolescents). While close monitoring based on
current cardiac screening guidelines for childhood and adolescent cancer survivors ought to be followed, our results
suggest that adolescent males treated for HL are at exceptionally high risk and perhaps may benefit the most from cardiac screening exams and education on lifestyle modifications.
The risk of CSM is known to be particularly high in cancer
patients treated at younger ages.24 Incidences of CHF in longterm HL survivors have been shown to be 10-fold higher for
those receiving treatment before the age of 40 and at followup after 20 years.4 The same study found these rates to be
even higher in patients with a family history of heart disease.
Similar to our study, the period 20 years after treatment appears to be when most cardiac events occur. A study, including HL patients treated in Britain, found that the relative
risk of death from a myocardial infarction was twofold higher
than the general population in years 1 through 14 after the start
of treatment, fourfold higher during years 15 through 19, and
remained significant during years 20 through 24 after the start
CARDIAC MORTALITY IN PEDIATRIC HODGKIN’S LYMPHOMA
of treatment.20 Particular attention therefore during the first 20
years post-treatment is critical and may extend to at least 30
years or more post-treatment, as one multi-institutional study
found.3 Furthermore, models may be helpful in categorizing
patients into cardiac risk categories based on age at time of
treatment, gender, chemotherapy and radiation use, family
history, and patient comorbidities. The Childhood Cancer
Survivor Study (CCSS)-CHF is an available risk assessment
tool to predict CHF in childhood cancer survivors, including
treatment use (radiation, anthracyclines), gender, and age at
diagnosis as measures of risk.2 These models can enable clinicians to better target high-risk patients. Given the unique
characteristics of pediatric and adolescent patients, separate
models may need to be tested for them.
Additional factors that may be contributing to the decrease in the rate of CSM in this study are improvements in
screening and early intervention for this high-risk population.
Studies have demonstrated that several modifiable risk factors
in adult survivors of childhood malignancies can significantly
contribute to CSM, including hypertension, diabetes, dyslipidemia, obesity, and smoking.1 This has led to better education
on lifestyle modifications and use of pharmaceutical interventions when indicated. Furthermore, screening guidelines
are now in place for high-risk childhood cancer survivors. The
current NCCN guidelines suggest a stress test/echocardiogram
at 10-year intervals after RT is completed.25 The Children’s
Oncology Group (COG) long-term follow-up guidelines
established cardiovascular screening recommendations in
survivors of childhood cancer. These guidelines suggest
baseline electrocardiogram and echocardiogram. Patients who
receive mediastinal radiation with or without anthracyclines
should be closely followed by annual physical exams and every
1–2-year echocardiograms with fasting blood glucose and lipid
profiles.26,27 The European Society for Medical Oncology
(ESMO) also provides a similar list of recommendations to
screen for chemotherapy and radiation-induced heart disease.7
While RT was not found to impact cardiac mortality in this
analysis, we expect the potential contribution of RT to cardiac toxicity to continue to decrease as the treatment paradigm for HL continues to evolve. For example, over the past
several decades, RT doses and treatment fields have significantly decreased. The transition from high-dose extendedfield RT to involved-field RT and more recently involved
nodal radiotherapy, which covers only postchemotherapy
treatment nodal volumes, has substantially reduced cardiac
dose by as much as 50%.28,29 In addition, response-adapted
RT identifying a select group of patients who may not need
additional RT after chemotherapy is currently underway in
multiple studies and may further reduce rates of RT-induced
cardiac mortality.30
Our study has several limitations. SEER does not contain
certain patient and treatment characteristics, including smoking
status, alcohol consumption, body–mass index, and other
associated medical conditions (e.g., lung disease), all of
which are potential confounders for our results. RT total dose,
fraction size, and treatment site were unknown and therefore
conclusions on RT use and CSM cannot be made from this
study. Additionally, we could not account for anthracyclineinduced cardiotoxicity, which is known to correlate with
cardiac mortality. Several studies, including one from Princess Margaret Hospital, demonstrated a strong association
between cardiac toxicity and cumulative anthracycline dose
185
received.18,31 Anthracycline-based chemotherapy regimens
are known to independently contribute to cardiotoxicity, including decreased left ventricular function, arrhythmias,
valvular disorders, and congestive heart failure.6 Therefore,
given the findings in this SEER analysis, it is very likely that
anthracycline use and total dose are contributing to CSM.
Because the SEER database combines ischemic disease, cardiomyopathy, and myocardial infarction into one category
called diseases of the heart, we were unable to differentiate
between the different types of events. Last, the low rate of
cardiac mortality in the last 10 years demonstrated in Figure 1
may also be related to limited follow-up. While it is likely
these numbers would increase with longer follow-up, the
downtrend in cardiac death is noteworthy in patients diagnosed
and treated over 20 years ago.
In summary, the cumulative incidence of CSM in this large
population analysis of pediatric and adolescent HL was 9.2%,
with a steady decline over the past several decades. While
routine cardiac screening should continue to be performed for
childhood cancer survivors, males and patients who were
adolescents at the time of diagnosis may be at particularly
higher risk for long-term cardiac mortality as demonstrated in
our study. In conclusion, cardiac mortality rates appear to be
decreasing and will likely continue due to improved awareness on lifestyle modifications and routine cardiac surveillance for childhood and adolescent cancer survivors.
Author Disclosure Statement
No competing financial interests exist.
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Address correspondence to:
Arthur K. Liu, MD, PhD
Department of Radiation Oncology
University of Colorado School of Medicine
1665 Aurora Court
Room 1032
Aurora, CO 80045
Email: [email protected]