Radiotherapy and Oncology xxx (xxxx) xxx

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Radiotherapy and Oncology

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Original Article

Heart substructural dosimetric parameters and risk of cardiac events

after definitive chemoradiotherapy for stage III non-small cell lung
cancer
Bum-Sup Jang a,1, Myung-Jin Cha b,1, Hak Jae Kim c, Seil Oh b, Hong-Gyun Wu c, Eunji Kim d,
Byoung Hyuck Kim e, Jae Sik Kim f, Ji Hyun Chang c,f,⇑
a
Department of Radiation Oncology, Seoul National University Bundang Hospital, Seongnam-si; b Division of Cardiology, Department of Internal Medicine and Cardiovascular Center,
Seoul National University Hospital; c Department of Radiation Oncology, Seoul National University College of Medicine; d Department of Radiation Oncology, Korea Institute of
Radiological and Medical Sciences, Seoul; e Department of Radiation Oncology, SMG-SNU Boramae Medical Center; and f Department of Radiation Oncology, Seoul National University
Hospital,

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: We evaluated the incidence of cardiac events after chemoradiotherapy in patients with
Received 12 August 2020 stage III non-small cell lung cancer (NSCLC) based on baseline cardiovascular risk and the heart substruc-
Received in revised form 17 September tures’ radiation dose.
2020
Methods: From 2008 to 2018, the cardiac events of 258 patients with stage III NSCLC who received defini-
Accepted 28 September 2020
Available online xxxx
tive chemoradiotherapy were reviewed. The 10-year cardiovascular risk was calculated using the
Atherosclerotic Cardiovascular Disease (ASCVD) scoring system. Dose-volume histograms were estimated
for each cardiac chamber. A multivariate competing-risk regression analysis was conducted to assess
Keywords:
Chemoradiotherapy
each cardiac event’s subhazard function (SHR).
Cardiac event Results: The median follow-up was 27.5 months overall and 38.9 months for survivors. Among the 179
Dosimetry deaths, none was definitely related to cardiac conditions. Altogether, 32 cardiovascular events affected
Heart substructure 27 patients (10.5%) after chemoradiotherapy. Ten were major cardiac adverse events, including heart fail-
Lung cancer ure (N = 6) and acute coronary syndrome (ACS, N = 4). Most cardiovascular events were related to well-
known risk factors. However, the volume percentage of the left ventricle (LV) receiving 60 Gy (LV V60) > 0
was significantly associated with ACS (SHR = 9.49, 95% CI = 1.28–70.53, P = 0.028). In patients with high
cardiovascular risk (ASCVD score > 7.5%), LV V60 > 0% remained a negative ACS prognostic factor
(P = 0.003). Meanwhile, in patients with low cardiovascular risk, the LV radiation dose was not associated
with ACS events (P = 0.242).
Conclusions: A high LV radiation dose could increase ACS events in patients with stage III NSCLC and high
cardiovascular risk. Pre-treatment cardiac risk evaluation and individualized surveillance may help pre-
vent cardiac events after chemoradiotherapy.
Ó 2020 Elsevier B.V. All rights reserved. Radiotherapy and Oncology xxx (2020) xxx–xxx

The relationship between radiotherapy (RT) and heart disease
has been reported mostly in patients receiving RT for breast cancer
or Hodgkin lymphoma in their long-term disease course [1,2].
Since Darby et al. [3] addressed the risk of ischemic heart disease
after RT in patients with breast cancer, much attention has been
paid to RT-related cardiac toxicity. Still, the long-term effects of
RT on cardiovascular (CV) disease have been underestimated in
patients with locally advanced lung cancer due to the relatively
short survival outcome.
⇑ Corresponding author at: Department of Radiation Oncology, Seoul National
University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea.
E-mail address: jh.chang@snu.ac.kr (J.H. Chang).
1
These authors contributed equally to this work.
Recently, the relationship between cardiac toxicity and RT has
also been studied in patients with lung cancer. The dose escalation
study in the non-small-cell lung cancer (NSCLC)—Radiation Ther-
apy Oncology Group (RTOG) 0617 trial [4] revealed that heart V5
(percentage of volume receiving  5 Gy) and V30 were prognostic
factors for overall survival (OS) in the unplanned analysis. This led
to multiple other studies on the relationship between dosimetric
parameters, cardiac mortality [5], and OS [6–8] in patients with
lung cancer. However, these results should be interpreted cau-
tiously since patients with lung cancer commonly share risk factors
with patients with CV disease, such as smoking. Indeed, the preva-
lence of preexisting CV disease is as high as 43% in patients with
lung cancer [2,9] Thus, the clinical association between cardiac

https://doi.org/10.1016/j.radonc.2020.09.050
0167-8140/Ó 2020 Elsevier B.V. All rights reserved.

Please cite this article as: Bum-Sup Jang, Myung-Jin Cha, Hak Jae Kim et al., Heart substructural dosimetric parameters and risk of cardiac events after
definitive chemoradiotherapy for stage III non-small cell lung cancer, Radiotherapy and Oncology, https://doi.org/10.1016/j.radonc.2020.09.050
Risk of cardiac events after CCRT for stage III NSCLC
adverse events and RT should be clarified considering the baseline
CV disease risk.
Previous studies mainly focused on the whole-heart RT dose
[6,7,9–13] and rarely analyzed the heart substructure RT dose
[14,15]. Since the whole-heart dose can be estimated from the
any heart location, it is not likely to represent the specific dose
of each substructure. CV events may be dependent on the heart
substructures receiving RT. Analyzing the relationship between
the heart substructure and subcategories of CV events would
therefore be more informative.
Thus, the aim of current study was to investigate the relation-
ship between the heart substructure dose and subcategories of
CV events in RT-treated patients with advanced stage NSCLC based
on the atherosclerotic cardiovascular disease (ASCVD) risk score.
Material and methods
Study population and treatment
This study was approved by the institutional review board (IRB
No. 1904-091-1026) that also waived the need for informed con-
sent. From 2008 to 2018, altogether 258 patients with stage III
NSCLC patients eligible for radical concurrent chemoradiation
therapy (CCRT) were identified in our institution and their medical
records were retrospectively reviewed. Patients who received
neoadjuvant chemotherapy followed by CCRT were excluded. RT
was delivered by using 3-dimensional conformal or intensity-
modulated radiotherapy (IMRT) technique with a dose of 50 to
72 Gy with conventional fractionation. Planning objectives were
as follows: mean lung dose  20 Gy and lung V20  35–40%.
Depending on plan objectives, radiation oncologist determined
the radiation doses and fractions. After treatment, patients were
evaluated at least at every 3 months using chest computed tomog-
raphy for 1 year and every 6 months during the following year.
Dosimetric parameters of heart substructures
To evaluate heart substructure doses, two radiation oncologists
(J.H.C and J.S.K) delineated the whole heart, left atrium (LA), right
atrium (RA), left ventricle (LV), and right ventricle (RV). These
structures were reviewed by a cardiologist (M.J.C) and the dose-
volume histogram was derived based on the original treatment
plan. For the dosimetric endpoints, the mean dose, V5, V10, V20,
V30, V40, V50, and V60 were calculated for each substructure. Vol-
ume percentage (V5 to V60) was transformed into the natural
number. Dosimetric parameters were represented in heatmaps as
continuous values using the Euclidean clustering method. To ana-
lyze dosimetric parameters as categorical values, the median value
was used to divide patients into high and low groups.
Evaluation of CV risk, cardiac adverse events, and mortality
To estimate the baseline CV risk at the start of CCRT, we calcu-
lated the ASCVD risk score [16] based on age, sex, race, total and
high-density lipoprotein cholesterol (mg/dL), systolic and diastolic
blood pressure (mmHg), diagnosis of hypertension or diabetes, and
smoking status. Patients who were indicated for chemoradiation
undergo baseline blood laboratory test including lipid panel. The
time frame should be within 1-month before chemoradiation.
The ASCVD risk score can be interpreted as the probability of the
10-year risk of heart disease or stroke. The 2014 ACC/AHA guideli-
nes [17] recommend primary prevention in patients with a 10-year
ASCVD risk > 7.5%. Accordingly, study patients with a 10-year
ASCVD risk > 7.5% were assigned to the high-risk group and the
remaining patients constituted the ASCVD low-risk group.
2
We first identified major cardiac adverse events (MACE), which
included cardiac death, acute myocardial infarction (AMI), unstable
angina hospitalization, and heart failure (HF), according to the
AHA/ACC guidelines [18]. We also reviewed intermediate coronary
artery disease (CAD) with elective percutaneous coronary inter-
vention (PCI) or any cardiac disorder with grade  3 according to
the Common Terminology Criteria for Adverse Events v.4.03 –
available at https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/.
Among these events, only the earliest event was included in the
study. Event-free survival was defined from the start of CCRT to
event occurrence or death. Patients with previous CV disease that
remained stable after radiotherapy (by comparison to the 6-
month interval preceding RT) were not recorded as having events.
The death registry was obtained from the Ministry of Public
Administration and Security as of February 17, 2020. Two cardiol-
ogists (M.J.C & S.O.) reviewed medical records and assessed CV
events. For example, heart failure was diagnosed with cardiac
echography and acute coronary syndrome was with cardiac
enzyme, ECG, cardiac CT, and coronary angiography. Arrythmia
was diagnosed with ECG which was formally read by experienced
cardiologists. Pericardial effusion was diagnosed when effusion
was clearly observed in cardiac echograph or CT. Despite a patient
had symptom such as chest pain or dyspnea, this was not consid-
ered as cardiac event according to a cardiologist’s discretion.
Symptoms of cardiac death can be confused with symptoms of
cancer-progression death. Patients with lung cancer often experi-
ence exertional dyspnea or chest pain at the end of the clinical
course. Causes of death were therefore thoroughly evaluated
through in-depth medical record review; cases of sudden or
unknown death were excluded from cardiac mortality. Fatalities
of patients lost to follow-up or without evidence of disease pro-
gression at the last visit were attributed to unknown causes.
Cancer-related death was coded if progression of disease was evi-
dent at the time of death. Respiratory system-related death under
stationary or partially regressed NSCLC was defined as respiratory
failure.
Statistical analysis
Patient and dosimetric parameters were compared between the
ASCVD low and high-risk group using Fisher’s exact test or Wil-
coxon rank sum test. In patients with cancer, death is a major com-
peting risk for CV events [19]. Using the Fine-Gray model [20],
univariate and multivariate competing-risks regression analyses
were performed to estimate the subhazard function (SHR) of each
event. Baseline ASCVD risk and significant covariates were incorpo-
rated in the multivariate model. The cumulative incidence plot
with Gray’s test was plotted when a specific dosimetric parameter
achieved significance in the multivariate model. All statistical tests
were two sided, with P  0.05 indicating statistical significance.
Statistical analyses were performed using STATA software version
15 (StataCorp, College Station, TX). The distribution pattern of the
dosimetric parameters from heart substructure was visualized as a
heatmap using the ‘ComplexHeatmap’ package [21] in R software
(R Foundation for Statistical Computing, Vienna, Austria).
Results
Altogether, 258 patients with stage III NSCLC received CCRT. Of
those, 53 (20.5%) and 205 (79.5%) patients were classified into the
ASCVD low- and high-risk groups, respectively. Median age was
higher in the ASCVD high-risk than in the low-risk group (66 vs.
55 years, P < 0.001). Median body mass index (BMI) was not statis-
tically different between these two groups (P = 0.053). Male
patients and current smokers were more prevalent in the ASCVD
Bum-Sup Jang, Myung-Jin Cha, Hak Jae Kim et al.
high-risk group. There was no significant difference in RT dose
between groups (P = 0.160). Altogether 7 patients received a cumu-
lative dose of 50 Gy. Of those, two patients were planned up to
60 Gy, but toxicity occurred in lung and trachea, leading the dis-
continuation of RT up to 50 Gy. The five patients were planned
up to 50 Gy since the planning objectives-- was not fulfilled. The
prevalence of diabetes was significantly higher in the ASCVD
high-risk group compared with the low-risk group (22.0% vs.
1.9%, P < 0.001). There was no significant difference in the preva-
lence of hypertension and chronic kidney disease (CKD) between
groups and no patients with history of cancer or CV disease history
were found in the ASCVD low-risk group. Statin use was more fre-
quent in the ASCVD high-risk than in the low-risk group but this
difference did not achieve significance (16.1% vs. 11.3%,
P = 0.520). In terms of dosimetric parameters, we could not observe
a significant difference in the median value between the ASCVD
high- and low-risk patients. To visualize the correlations between
whole-heart and heart substructures RT dose, CV events, and
ASCVD risk, we plotted the heatmap representing the pattern of
dose parameters in Fig. 1. A relatively low dose (5–20 Gy) was
administered to the whole heart as well as to each of the four heart
chambers in most patients. A minority of patients were irradiated
with relatively high dose (40–60 Gy) to their LV or RV. Detailed
patient and dosimetric characteristics are summarized in Table 1.
With a median follow-up of 27.5 months (range, 2.0–
119.2 months), altogether 32 CV events in 27 patients (10.3%) were
reported during the study period, including HF (N = 6, 2.3%), ACS
(N = 4, 1.5%, including 2 AMI and 2 hospitalizations due to unstable
angina), intermediate CAD with revascularization (N = 2, 0.7%),
clinically significant arrhythmia (N = 13, 4.9%), pericardial effusion
Fig. 1. Heatmap showing the pattern of dosimetric parameters. Column indicates patients, and row represents dosimetric parameters. Dose to specific volume is transformed
to log10. Both column and rows are clustered by Euclidean method. Abbreviations: ASCVD, atherosclerotic cardiovascular disease; CV, cardiovascular; LV, left ventricle; RV,
right ventricle; LA, left atrium; RA, right atrium.
3
Radiotherapy and Oncology xxx (xxxx) xxx
(N = 7, 2.7%), pulmonary thromboembolism (N = 2, 0.7%), and pro-
gressive pulmonary hypertension (N = 1, 0.3%). There were no def-
inite cardiac death events. One patient experienced HF and
pulmonary embolism (PE) with progressive pulmonary hyperten-
sion. One patient experienced both progressive CAD with revascu-
larization and AMI events with a 1-year interval and pericardial
effusion after another year. One patient had pulmonary embolism
and arrhythmia. Three patients experienced both HF and arrhyth-
mia. Of arrythmia events, there were atrial fibrillation (N = 8), ven-
tricular tachycardia N = 1), atrial flutter (N = 3), atrial tachycardia
(N = 1), and sick sinus syndrome (N = 2). The total annual incidence
of cardiac events was 7 events/1000 person-years, respectively.
The mean and median duration from RT to the first cardiac event
was 30.6 and 24.2 months (range, 1.8 – 103.5), respectively. The
median survival from cardiac event to death (N = 23) or last
follow-up (N = 4) was 27.7 months (range, 4.67–98.6).
There were MACE in 10 patients (3.8%), an annual incidence of
2/1000 person-years. The two patients with non-ST elevation AMI
received successful revascularization with PCI. They lived for 14
and 46 months after AMI until cancer-related death. Another two
patients hospitalized due to unstable angina were found to have
severe multivessel CAD confirmed by coronary angiography.
Instead of revascularization, they were treated only with medica-
tions due to the cancer progression and the procedural risk and
died 16 and 6 months after the event. Among the four patients
with non-ischemic HF, three had underlying cardiac disease, and
one experienced HF during septic shock following severe pneumo-
nia. Two patients with ischemic HF accompanied by intermediate
CAD were well controlled by optimal medical treatment until
cancer-related death.
Risk of cardiac events after CCRT for stage III NSCLC

Table 1
Patient and dosimetric characteristics.

Variables ASCVD Low-risk ASCVD High-risk P Dosimetric Parameters ASCVD Low-risk (7.5) ASCVD High-risk (>7.5) P
(7.5) (N = 53) (>7.5) (N = 205) (N = 53) (N = 205)
Median Age (year, range) 55 (33–70) 66 (49–89) <0.001 Mean Heart Dose (cGy) 1054.6 (64.1–3933.0) 1186.2 (10.1–4206.4) 0.929
Median BMI (kg/m2) 22.2 (16.1–27.9) 22.7 (14.4–31.8) 0.053 Mean LV Dose (cGy) 408.0 (25.5–4012.6) 345.2 (6.5–4332.8) 0.859
Median ASCVD Risk Score 4.1 (0.8–7.4) 17.4 (7.6–59.9) <0.001 Mean RV Dose (cGy) 438.5 (20.9–3765.0) 316.0 (5.6–4665.0) 0.916
Gender <0.001 Mean LA Dose (cGy) 1373.7 (71.8–5970.8) 1710.8 (13.2–5901.6) 0.861
Male 22 (41.5%) 195 (95.1%) Mean RA Dose (cGy) 822.9 (36.1–5292.0) 871.9 (10.9–5633.1) 0.973
Female 31 (58.5%) 10 (4.9%) Whole Heart V5 (%) 42 (0–100) 44 (0–100) 0.675
Current Smoker <0.001 Whole Heart V10 (%) 30 (0–99) 32 (0–100) 0.974
No 37 (69.8%) 51 (24.9%) Whole Heart V20 (%) 18 (0–89) 20 (0–97) 0.844
Yes 16 (30.2%) 154 (75.1%) Whole Heart V30 (%) 11 (0–77) 14 (0–75) 0.957
RT Dose (Gy) 0.160 Whole Heart V40 (%) 7 (0–55) 8 (0–57) 0.815
<66 17 (32.1%) 90 (43.9%) Whole Heart V50 (%) 4 (0–38) 4 (0–40) 0.676
66 36 (67.9%) 115 (56.1%) Whole Heart V60 (%) 2 (0–18) 1 (0–30) 0.163
HTN 0.051 LV V5 (%) 21 (0–100) 20 (0–100) 0.703
No 41 (77.4%) 128 (62.4%) LV V10 (%) 9 (0–100) 4 (0–100) 0.582
Yes 12 (22.6%) 77 (37.6%) LV V20 (%) 0 (0–100) 0 (0–97) 0.259
DM <0.001 LV V30 (%) 0 (0–100) 0 (0–95) 0.225
No 52 (98.1%) 160 (78.0%) LV V40 (%) 0 (0–62) 0 (0–67) 0.149
Yes 1 (1.9%) 45 (22.0%) LV V50 (%) 0 (0–20) 0 (0–42) 0.284
Chronic Kidney Disease 0.350 LV V60 (%) 0 (0–10) 0 (0–13) 0.405
No 53 (100.00%) 198 (96.7%) RV V5 (%) 21 (0–100) 16 (0–100) 0.677
Yes 0 (0.00%) 7 (3.3%) RV V10 (%) 13 (0–100) 4 (0–100) 0.575
Cancer History 0.010 RV V20 (%) 1 (0–93) 0 (0–98) 0.267
No 39 (73.6%) 143 (69.8%) RV V30 (%) 0 (0–84) 0 (0–95) 0.400
Yes 0 (0.0%) 22 (10.7%) RV V40 (%) 0 (0–36) 0 (0–93) 0.248
Unknown 14 (26.4%) 40 (19.5%) RV V50 (%) 0 (0–11) 0 (0–33) 0.437
CV Disease History 0.046 RV V60 (%) 0 (0–0) 0 (0–25) 1.000
No 53 (100.0%) 190 (92.7%) LA V5 (%) 74 (0–100) 84 (0–100) 0.829
Yes 0 (0.0%) 15 (7.3%) LA V10 (%) 52 (0–100) 62 (0–100) 0.843
Statin Therapy 0.520 LA V20 (%) 28 (0–100) 28 (0–100) 0.598
No 47 (88.7%) 172 (83.9%) LA V30 (%) 16 (0–100) 18 (0–100) 0.885
Yes 6 (11.3%) 33 (16.1%) LA V40 (%) 8 (0–91) 11 (0–93) 0.947
LA V50 (%) 3 (0–83) 6 (0–83) 0.872
LA V60 (%) 0 (0–67) 0 (0–66) 0.409
RA V5 (%) 40 (0–100) 42 (0–100) 0.911
RA V10 (%) 28 (0–100) 26 (0–100) 0.916
RA V20 (%) 9 (0–100) 7 (0–100) 0.766
RA V30 (%) 0 (0–95) 1 (0–100) 0.783
RA V40 (%) 0 (0–85) 0 (0–100) 0.943
RA V50 (%) 0 (0–77) 0 (0–82) 0.802
RA V60 (%) 0 (0–52) 0 (0–64) 0.428

Abbreviations: BMI, body mass index; ASCVD, atherosclerotic cardiovascular disease; LV, left ventricle; RV, right ventricle; LA, left atrium; RA, right atrium; RT, radiation
therapy; HTN, hypertension; DM, diabetes; CKD, chronic kidney disease; CV, cardiovascular; cGy, centi Gray; Vx, the volume (%) receiving  Gy. P-values were estimated from
Fisher’s exact test or Wilcoxon rank sum test. For a continuous variable, the median, the minimum and the maximum values were represented.

There were 179 deaths in the cohort. Of those, 2 (1.1%) patients
died of other causes (suicide and burn inhalation injuries). The
remaining 177 (98.9%) patients died of disease progression.
The results of the univariate analyses are summarized in Sup-
plementary Table A1. ASCVD risk score was associated with the
total CV events [subhazard function (SHR) = 1.03, 95% CI = 1.00–
1.06, P = 0.036], MACE (SHR = 1.04, 95% CI = 1.01–1.09,
P = 0.022), HF events (SHR = 1.06, 95% CI = 1.01–1.11, P = 0.030),
and arrhythmia events (SHR = 1.06, 95% CI = 1.03–1.10, P < 0.
001). BMI was significantly associated with MACE (SHR = 1.23,
95% CI = 1.02–1.49, P = 0.029) and HF events (SHR = 1.38, 95%
CI = 1.05–1.82, P = 0.023). Age was the only significant factor for
PE events (SHR = 0.93, 95% CI = 0.89–0.99, P = 0.014). Moreover,
CKD and CV disease history were associated with MACE and HF
events. There were no significant factors associated with stable
angina with revascularization events.
Regarding the dosimetric parameters, we found that LV
V60 > 0% was significantly associated with ACS events
(SHR = 9.60, 95% CI = 1.33–72.30, P = 0.026).
Most patients regularly visit our center after chemoradiation.
However, they were often lost in follow-up, and turned out to be
death based on national registry. We found that eight patients
(4.5% of all death) were died of unknown cause in death registry.
They were ASCVD high-risk with median ASCVD risk score of
23.1 (range 12.9–31.1). We performed univariate regression analy-
ses for unknown cause of death with a competing risk of known
death (Supplementary Table A2). As a result, we found than no
dosimetric parameters were associated with unknown death.
In the multivariate competing-risk regression model, we
adjusted the ASCVD risk score as well as covariates showing a sig-
nificance in univariate analyses (Table 2). Multivariate analyses
revealed that LV V60 > 0% was an independent factor for worse
prognosis of ACS events (SHR = 9.49, 95% CI = 1.28–70.53,
P = 0.028). For CV event, MACE, and HF events, the results of mul-
tivariate analyses are listed in Supplementary Table A3; these
models did not include dosimetric parameters due to their non-
significance seen in the univariate model.
Multivariate competing-risk regression analyses considering
the categorical ASCVD risk group revealed that LV V60 > 0% was
significantly associated with a high risk of ACS events
(SHR = 10.06, 95% CI = 1.49–69.46, P = 0.019), In addition, ASCVD
high-risk (7.5) was also independently associated with ACS
events (P < 0.001, Table 2).
Based on these results, we estimated the cumulative incidence
of ACS events, stratified by ASCVD risk (low vs. high) and LV V60
(0% vs. > 0%). As shown in the cumulative incidence plot (Fig. 2),

4
Bum-Sup Jang, Myung-Jin Cha, Hak Jae Kim et al. Radiotherapy and Oncology xxx (xxxx) xxx

Table 2
Multivariate competing-risk regression analysis for ACS event.

SHR 95% CI P SHR 95% CI P

ASCVD Score 1.02 0.98 1.05 0.313 ASCVD High-risk (>7.5) 3.0E + 12 1.0E + 12 8.5E + 12 <0.001
LV V60 High (>0%) 9.49 1.28 70.53 0.028 LV V60 High (>0%) 10.06 1.46 69.46 0.019

Abbreviations: SHR, subdistribution hazard ratio; CI, confidence interval; BMI, body mass index; ASCVD, atherosclerotic cardiovascular disease; LV, left ventricle; ACS, acute
coronary syndrome.

and 5.3% in patients with high ASCVD risk and V60 > 0%, and
0.3% and 0.5% in patients with high ASCVD risk and V60 = 0, respec-
tively (Gray’s test, overall P = 0.014).
Fig. 3 shows the representative case of a patient with high
ASCVD group and V60 > 0%. We identified the occlusion site in cir-
cumflex artery region which was correlated with the LV irradiated
with 60 Gy.

Discussion

To the best of our knowledge, the current study is the largest

Fig. 2. The cumulative incidence plots after the start of radiation therapy. (A) For
ACS event, the ASCVD risk group (high-risk vs. low-risk) and LV60 (0% vs > 0%) are
stratified. LV60 indicates the the volume (%) of left ventricle receiving 60 Gy
radiation dose. Abbreviations: ASCVD, atherosclerotic cardiovascular disease; LV, left
ventricle. P-value was estimated by Gray’s test. *, 0.003; ns, no significance.
ACS events were observed 225 days after the start of CCRT. Regard-
less of the V60 status, the ASCVD low-risk group did not demon-
strate a meaningful cumulative incidence of ACS events.
Meanwhile, the 1- and 2-year cumulative incidences were 2.7%
evaluating cardiac toxicity in patients with NSCLC with respect to
the radiation dose to each cardiac substructure. We showed that
both high ASCVD risk and LV V60 (>0%) were independently asso-
ciated with the cumulative incidence of ACS events. Meanwhile,
patients with low ASCVD risk did not demonstrate a significant
cumulative incidence of ACS events regardless of LV V60 status.
To evaluate cardiac toxicity in patients receiving thoracic RT,
their cancer-dependent survival and late effects of RT should be
considered [22]. Assuming that cancer-related death is the domi-
nant factor for patients with NSCLC, death was considered a com-
peting risk in the current study. We found that LV V60 is an
important predictor of ACS events. LV V60 > 0% significantly
increased the incidence of ACS event in a time-dependent manner,
particularly in the ASCVD high-risk group. To the best of our
knowledge, this is the first dosimetric parameter to be associated
with ACS events. Atkins et al. [5] showed that patients without pre-

Fig. 3. A 62-year old man with clinical stage T2aN2 disease received definitive CCRT with a total of 60 Gy in 30 fractions. After 6 years after the start of CCRT, he complained of
chest pain and visited the emergency room. With an impression of non-ST elevation myocardiac infarction, coronary angiography was performed. A. Representative
contouring image of RT plan CT. LA (yellow), RA (blue), RV (orange), LV (green), and whole heart (magenta) are contoured, then dose-volume histogram were calculated. B.
The dose distribution are shown in the contoured axial CT image. The isodose line of 60 Gy (red) covers the gross tumor. C. Left coronary angiography showed non-calcified
chronic total occlusion (white arrow) at proximal left circumflex artery with grade 1 collateral flow from both left anterior descending artery (LAD) and right coronary artery
(RCA). The estimated length of the occluded segment was approximately 3.5 cm, where 60 Gy were irradiated. Abbreviations: CCRT, concurrent chemoradiation therapy;
ASCVD, atherosclerotic cardiovascular disease; CV, cardiovascular; LV, left ventricle; RV, right ventricle; LA, left atrium; RA, right atrium.

5
Risk of cardiac events after CCRT for stage III NSCLC
vious CV disease who received a mean heart dose  10 Gy had an
increased MACE rate and all-cause mortality. We did not find sim-
ilar results in the current study (data not shown) possibly due to
the fact that a high mean heart dose can originate from various
substructures such as the LA, LV, RA, or RV. For example, a patient
receiving a high focal dose to the RA could show LV HF with a mean
heart dose > 10 Gy, possibly confounding the relationship between
anatomic structure and its dependent CV event. Unlike the tangen-
tial beam RT used in breast cancer, the mean whole-heart RT dose
is not representative of the LV dose in lung cancer [23]. There is
even controversy regarding whether the mean heart dose is the
appropriate surrogate for LV or CAD in breast cancer [24]. There-
fore, it is crucial to explore the optimal dose constraint to prevent
RT-related CV toxicity based on each substructure.
Previous studies investigated the cardiac toxicity or mortality
mainly in relation to whole-heart dose parameters (whole-heart
V50 [6], V5 [8,10], V30 [10]) or mean heart dose [12]. To date,
delineating cardiac substructures to constrain RT dose is not
mandatory in lung cancer. However, cumulating studies have
reported the results of heart substructure dosimetric analysis, sug-
gesting the need of evaluation of heart substructure dose in
patients with lung cancer [14,15,25,26] or breast cancer [27].
Wang et al. analyzed 112 patients with stage III NSCLC who
received dose-escalated RT (70–90 Gy) with a median follow-up
of 8.8 years and suggested that distinct heart subvolumes showed
different RT-associated cardiotoxicity [15]. They reported that
pericardial events were related with RA and LA dose, and ischemic
events were associated with the LV dose. Yegya-Raman et al. [26]
also analyzed the relationship between cardiotoxicity and RT in
140 patients, adjusting for the baseline WHO/ISH risk score. They
reported that higher doses to both ventricles and the left anterior
descending coronary artery were related to ACS and congestive
HF. Borkenhagen et al. [14] also reviewed 76 cases and reported
that higher ventricular V45 was associated with cardiotoxicity.
Exploring cardiac substructures in a relatively large number of
patients is one of the strengths of the current study. We analyzed
heart substructure dosimetric data collected from 258 patients and
revealed the importance of LV V60 dosimetric parameters. This
result considered the baseline ASCVD risk score in the multivariate
competing risk model. We showed that RT-related ACS events
were associated with the baseline CV risk and that LV V60 did
not impact coronary events incidence in the ASCVD-low risk
group; meanwhile, a high LV V60 resulted in a 4-year cumulative
incidence > 8% in the ASCVD high-risk group. This result suggests
the need of active screening in patients with high ASCVD risk, in
line with current guidelines, which recommend primary preven-
tion for CV disease [17].
Our results also showed that ASCVD risk factors can be modified
to prevent future RT-related CV events. In NSCLC, RT doses for
definitive treatment were routinely determined (60-66 Gy), since
the RTOG 7301 trial showed a better survival outcome with higher
RT doses [28]. A cumulative dose of up to 60 Gy with conventional
fractionation in radical RT for gross tumors is largely accepted by
radiation oncologists due to its tumoricidal effect based on radia-
tion biology [29]. Technically, cardiac-dose sparing and avoidance
could be applied in patients with breast cancer using IMRT or pro-
ton beam therapy [30]. However, lung tumors may be located close
to the heart and are move during ventilation, which precludes a
dose reduction without compromising effectiveness. Therefore,
there are patients who inevitably receive a high dose to the heart,
including the LV, in order to control disease. Thus, lowering the
baseline ASCVD risk could be an important strategy for patients
receiving high-dose thoracic RT. In the current study, statin use
did not differ according to ASCVD risk. According to existing guide-
lines [17], statin therapy is recommended for patients with high
ASCVD risk. Thus, we suggest that the ASCVD risk is evaluated in
6
patients with NSCLC when receiving definitive CCRT. According
to the individual ASCVD risk, the appropriate intervention may
prevent RT-related cardiac events. However, this should be vali-
dated by prospective clinical trials.
Study limitations include its retrospective nature and the possi-
bility of misreporting cardiac events due to the common symptoms
between lung cancer and CV disease. In the clinical course of
patients with lung cancer, the evaluation of heart disease or the
distinction of cause of death is often overlooked. Our study showed
a relatively low CV event rate compared to previous studies, which
is possibly explained by the exclusion of unclear events from the
analysis based on the strict application of current guidelines to
define CV events. We did not consider a sudden death of unknown
cause as a cardiac death. All unknown cause of death within
national registry cannot be a cardiac death without any cardiolo-
gist’s records. Given that CV disease was not routinely evaluated
in patients with advanced stage cancers, future prospective studies
aiming to detect CV events more precisely should be performed.
Our results suggest the need for a discussion between radiation
oncologists and cardiologists in terms of establishing the cardiac
substructures receiving RT and the optimal surveillance modality
to prevent possible CV events. For RT-treated patients with high
risk of CV events, radiation oncologists should lower the RT dose
to the relevant heart chambers as much as possible without com-
promising target coverage. Simultaneously, a cardiologist can pro-
vide individualized optimal prevention such as statin therapy and
chamber-focused surveillance. The current study also shows that
initiating coronary evaluation should be considered within 1 year
in RT-treated patients with high CV risk when their LV volume
receiving an RT dose of 60 Gy is >0%.
In conclusion, high-dose RT (60 Gy) to the LV increased ACS
events in patients with stage III NSCLC and high CV risk (ASCVD
risk 7.5%). Based on the evaluation of baseline CV risk and
cardiac-substructure dosimetric parameters, an individualized
approach should be deployed to prevent cardiac events following
thoracic RT. Prospective studies are needed to validate the modu-
lation effect of CV risk and dosimetric parameters.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgement
This work was supported by National Research Foundation of
Korea grant funded by the Korean government [grant numbers
NRF-2018M2A2B3A01070410] to Ji Hyun Chang.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.radonc.2020.09.050.
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