# Dose-volume predictors of cardiac adverse events after high-dose thoracic radiation therapy for lung cancer: a systematic review and meta-analysis

Médéa Locquet, Sophie Jacob, Xavier Geets, Charlotte Beaudart

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Médéa Locquet, Sophie Jacob, Xavier Geets, Charlotte Beaudart. Dose-volume predictors of cardiac adverse events after high-dose thoracic radiation therapy for lung cancer: a systematic review and meta-analysis. BMC Cancer, 2024, 24 (1), pp.1556. 10.1186/s12885-024-13281-8. hal-04867983

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## SYSTEMATIC REVIEW

### Open Access

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# Dose-volume predictors of cardiac adverse events after high-dose thoracic radiation therapy for lung cancer: a systematic review and meta-analysis

Médéa Locquet<sup>1,2,5*</sup>, Sophie Jacob<sup>3</sup>, Xavier Geets<sup>4</sup> and Charlotte Beaudart<sup>1,2</sup>

### Abstract

**Background** Lung cancer is a leading cause of cancer mortality and may require high-dose thoracic radiation therapy (RT). However, RT significantly increases the risk of radiation-induced cardiac events, such as pericarditis, cardiomyopathy, and ischemic heart diseases. Despite evidence from clinical trials showing that higher RT doses are associated with poorer survival outcomes due to these cardiac effects, data on dose-volume predictors of such events in lung cancer remain sparse.

**Objective** To systematically synthesize the incidence of cardiac events following radiation therapy for lung cancer treatment and dose-volume metrics predictors of radiation therapy-induced cardiac events in lung cancer treatment.

**Methods** This systematic review, registered on PROSPERO (CRD42024565103), adhered to PRISMA guidelines to investigate cardiac events and its dose-volume predictors following high-dose radiation therapy in adults with lung cancer. Data were extracted from longitudinal observational studies and randomized controlled trials. A comprehensive literature search was conducted across MEDLINE, Cochrane CENTRAL, and Embase, with studies selected based on predefined criteria, focusing on clinical cardiac outcomes. Data extraction followed CHARMS guidelines, and study quality was reported using the PROBAST tool. Results were synthesized narratively, with meta-analyses performed where appropriate using R software to estimate pooled effect sizes, heterogeneity, and publication bias.

**Results** The systematic review included 21 studies and identified a significant association between high-dose thoracic radiation therapy (RT) and an increased incidence of cardiac adverse events in lung cancer patients. The review revealed that higher dose-volume parameters, notably higher mean heart doses (MHD), were predictive of major cardiac events such as pericardial effusion, arrhythmias, and acute coronary syndrome. The meta-analysis showed a significant 4% (95% confidence interval: 3%-6%) increased probability of the occurrence of cardiac events per additional Gray of MHD, with low heterogeneity among studies ($I^2$ = 23%). No publication bias was evidenced.

**Conclusion** This study underscores the importance of dose-volume parameters as predictors of cardiac adverse events following high-dose thoracic RT in lung cancer treatment. The findings highlight the need for careful consideration of heart dose constraints in RT planning to mitigate the risk of radiation-induced cardiotoxicity, thereby

<footnote>*Correspondence:
Médéa Locquet
medea.loquet@gmail.com; medea.loquet@inserm.fr
Full list of author information is available at the end of the article</footnote>
improving the therapeutic ratio for lung cancer patients. Future research should focus on refining these dose con-
straints and exploring cardioprotective strategies during lung cancer radiotherapy.

**Keywords** Lung cancer, Cardiotoxicities, Radiotherapy, Meta-analysis, Review

**Introduction**

Lung cancer, which includes both non-small cell lung
cancer (NSCLC) and small cell lung cancer (SCLC),
remains the leading cause of cancer-related deaths glob-
ally, presenting a significant public health challenge [1].
Furthermore, the incidence of lung cancer is expected to
rise by 65% by 2035 [2]. Prognosis and treatment options
are widely determined by the stage of diagnosis, histo-
logical (sub type, and molecular profile of the cancer. For
patients with locally advanced, non-resectable NSCLC,
as well as those with limited-stage SCLC, standard treat-
ment typically involves high-dose thoracic radiation ther-
apy, often in combination with chemotherapy.

However, RT is not without iatrogenic risk, the
most life-threatening being the potential for radia-
tion-induced cardiac events, which can occur due to
the proximity of the heart to the tumor target within
or near the radiation field. Significant evidence from
three phase III randomized trials has demonstrated
that high-dose thoracic RT increases the risk of car-
diac events in lung cancer patients. In the RTOG 0617
trial for stage III NSCLC, patients receiving higher
doses (74 Gray (Gy)) had a significantly lower median
survival (20 months) compared to those receiving
standard doses (60 Gy) (28 months). Moreover, the
heart dose was also reported among the predictors of
worse survival in this trial. In other words, the heart
dose was associated with a worse survival at a median
follow-up of 2 years, indicating a significant contribu-
tion to radiation-induced cardiac morbidity and still
relatively soon after treatment. In the CALGB 30610/
RTOG 0538 trial for limited-stage SCLC, no survival
benefit was observed with 70-Gy compared to 45-Gy,
potentially due to grade 5 adverse events such as sud-
den deaths or cardiac arrests (6 in the 70-Gy arm versus
2 in the 45-Gy arm). In the LungART trial for postop-
erative stage II NSCLC, postoperative RT improved
local tumor control but did not confer a survival benefit
due to cardiopulmonary toxicities (11% in the postop-
erative RT arm versus 5% in the control arm). In each
of these trials, the benefit of RT was disadvantaged by
excess harmful cardiac events. Since the initial rand-
omized controlled trials, several observational studies
have sought to identify the best dose-volume predic-
tors of cardiotoxicity following RT for lung cancer. For
example, a retrospective study demonstrated that a
mean heart dose (MHD) above 10 Gy significantly

increased the risk of major adverse cardiac events in
patients without a history of cardiovascular diseases
[3]. Another study found that a dose of 40 Gy received
by at least 40% of the heart was strongly associated with
reduced overall survival [4]. Given these divergent find-
ings and the complexity of dose-volume interactions,
this topic must be addressed in a systematic review to
clarify the most relevant predictors and optimize car-
diac protection for patients undergoing lung cancer
treatment.

Many studies have shown that RT for breast cancer or lymphoma can increase the risk of cardiac events, and the spectrum of cardiac events following radiation exposure is broad, including acute pericarditis, pericardial effusion, constrictive pericarditis, cardiomyopathy, heart failure, ischemic heart diseases, valve regurgitation and stenosis, and new-onset arrhythmias. A notable study published in *The New England Journal of Medicine* (Darby et al., 2013) found that the risk of major coronary events increased by 7.4% for each gray (Gy) of radiation delivered to the heart, with the risk becoming apparent within the first five years after treatment and continuing for at least 20 years [5]. Given the significantly higher doses of radiation delivered to the heart in lung cancer treatment compared to other malignancies such as breast cancer or lymphomas, the incidence of cardiac events following RT for lung cancer warrants separate consideration. Moreover, the current literature regarding radiation-induced cardiac events predominantly focuses on medium-term and long-term cardiac outcomes in breast cancer or lymphoma patients, given their long-term survival expectations, which contrasts with the more limited survival of lung cancer patients. Furthermore, lung cancer patients often present with more cardiovascular risk factors than other cancer populations, making them potentially more vulnerable to cardiac risk after cancer treatment. The question then becomes whether the cardiac risk is linked to the patient's baseline characteristics or the effect of RT, making the investigation of dose-response relationships crucial for refining our understanding of the causal relationship.

As survival rates improve due to advancements in
therapy for lung cancer, clarifying the existence of a
potential dose-response relationship between heart
exposure during lung cancer RT and cardiac events
and identifying the dose-volume predictors of cardiac
adverse events becomes crucial for optimizing treatment plans and minimizing long-term morbidity. However, data on dose-volume predictors of cardiac events in lung cancer patients remain sparse and heterogeneous. Several retrospective studies provided data on the incidence of cardiac events following RT and heart dose-volume metrics predictors of RT-induced cardiac events to evaluate the risk of cardiac events after RT for lung cancer. However, variability in studied dose-volume parameters and cardiac outcomes yielded various findings, and it would be relevant to synthesize results through a systematic literature review and identify key dose-volume parameters associated with cardiac toxicity following high-dose thoracic RT in lung cancer patients.

In this context, we aimed to systematically review and perform a meta-analysis of cardiac disease risk in patients treated with RT for lung cancer, providing critical insights for clinicians aiming to balance efficacy and safety in treatment protocols.

## Methods

The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [6] ensure the quality and transparency of the present report. The PRISMA checklist is available in Supplementary Material 1. The protocol has been previously registered on the PROSPERO International Prospective Register of Systematic Reviews website (reference CRD42024565103). The issue of interest was defined using the following PICOS strategy: Population: Adults with a confirmed diagnosis of lung cancer—Intervention: High-dose radiation therapy and its cardiac dose-volume metrics—Comparator: Not applicable—Outcomes: Cardiac events (any type) following radiation therapy possibly combined with

other cancer treatment—Study design: Longitudinal, prospective or retrospective, observational studies, and randomized controlled trials.

## Literature search strategies

The literature search was launched on March 26, 2024, applying a specific search strategy on MEDLINE, Cochrane CENTRAL, and Embase (via Ovid), available in Supplementary Material 2. Additionally, we manually searched the reference lists of the included studies and the Google Scholar search engine. An update was conducted on August 26, 2024. The search strategy comprised four key concepts: (1) lung cancer, (2) radiation therapy, (3) cardiac events, and (4) cardiac dose-volume predictors.

## Inclusion and exclusion criteria

We established predefined eligibility criteria to determine the inclusion of abstracts and articles. In summary, we included peer-reviewed original studies from MEDLINE indexation (1946) to 2024, involving at least 30 adults (≥ 18 years old) with a confirmed diagnosis of NSCLC or SCLC who received high-dose radiation therapy (≥ 45 Gy; the minimum prescribed dose for treating lung cancer considered higher than standard protocols for other thoracic radiotherapies such as for breast cancer) regardless of the modality. Studies had to report on cardiac events of any type, with the clinical manifestation of the cardiac event being mandatory for inclusion. Eligible study designs could include longitudinal, prospective, or retrospective observational studies published in the English language [7]. Comprehensive eligibility criteria are available in Table 1.

<table><caption>**Table 1** Eligibility criteria of references to be included in the systematic review</caption><thead><tr><th></th><th></th></tr></thead><tbody><tr><td>Inclusion criteria</td><td>- Adults (≥ 18 years old) with confirmed diagnosis of non-small cell lung carcinoma or small-cell lung carcinoma<br>- High-dose of radiation therapy (≥ 45 Gy) (any technique, any modality, any dose-volume predictors)<br>- Cardiac events (any type) (clinical manifestation of the cardiac event is mandatory to be included)<br>- Original studies: Longitudinal, prospective or retrospective, observational studies, randomized controlled trials</td></tr><tr><td>Exclusion criteria</td><td>- Animal studies<br>- Dose-volume predictors not studied<br>- Original studies including less than 30 patients<br>- Case reports, reviews, systematic reviews, letters to the editors<br>- Non-English language studies<br>- Protocol of research study<br>- No report of dose-volume metrics as potential predictors of radiation therapy treatment<br>- Palliative radiation therapy</td></tr></tbody></table>
## Selection of studies

Titles and abstracts of references identified by the search strategy were independently screened by two reviewers (ML and CB) according to the above eligibility criteria. The full-text review stage followed, and eligible studies were identified by the two reviewers (ML and CB). At each stage, disagreements were resolved by discussion between reviewers (ML and CB) with the intervention of a third peer (XG), if needed, to arbitrate in final inclusion. Clinicians and other experts were consulted to ensure the comprehensive inclusion of relevant references. This entire procedure was performed using the Covidence® systematic review management software suggested by the Cochrane Collaboration (Covidence systematic review software, Veritas Health Innovation, Melbourne, Australia. Available at www.covidence.org.).

## Data extraction

A standardized data extraction form was developed. An initial pilot extraction of the first reference evaluated the form's relevance. Following this, ML extracted relevant data. The extraction was performed according to the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS) [8]. Following the systematic review process, this checklist was selected a posteriori due to the final inclusion of only retrospective observational studies aiming to evaluate the predictive power of dose-volume metrics about the occurrence of cardiac events after radiotherapy for lung cancer treatment. The following data were extracted: information related to the reference included study design and main characteristics, patient and tumor characteristics, radiation therapy and other cancer treatment, cardiac events, dose-volume parameters, the magnitude of the association between dose-volume predictors of cardiac events after radiation therapy for lung cancer treatment.

## Quality assessment and risk of bias

ML assessed each included study's quality and Risk of Bias (RoB) using the Prediction model study Risk Of Bias Assessment Tool (PROBAST), specifically designed for prediction modeling studies. This tool was selected as a posteriori because of the final inclusion, after the systematic review work, of only retrospective observational studies that tested the predictive power of dose-volume metrics on the occurrence of cardiac events after radiotherapy for lung cancer treatment. The RoB assessment involved questions regarding several domains: participants, predictors, outcomes, and analysis. The questions were answered with "high risk

of bias" (0 points) or "low risk of bias." (1 point). Any issue was resolved through consensus, with the intervention of a second party (CB).

## Data synthesis and statistical analyses

A descriptive analysis of the included studies was performed as a narrative report. The results were structured to provide an initial description of the general characteristics of the included studies, followed by details on the incidence of cardiac events and the dose-volume prediction model.

Several studies provide different cardiac dose parameters, and the mean heart dose is known to be a key metric in dose-response studies. Given the diversity of dose-volume parameters studied in the literature, only studies focusing on the MHD predictor were included in the meta-analysis because they were sufficiently numerous to pool the results. The other dose-volume parameters were each studied by less than three studies, not allowing a meta-analysis. The meta-analysis focused on included studies that provided results with this metric, and we pooled them using the meta-analysis, a random effects meta-analytical model assuming heterogeneity between studies was applied. The adjusted effect sizes of interest, specifically hazard ratios, were pooled using appropriate statistical packages in R (i.e., the 'meta' and 'risks' packages), resulting in an increased probability of cardiac events per additional Gy administered during RT. Heterogeneity among studies was assessed using the I² statistic. Leave-one-out (LOO) sensitivity analyses determined the stability of the results when omitting individual studies. Egger's regression asymmetry test detected any publication bias. No funnel plot asymmetry was applied because less than ten studies were included in the meta-analysis.

All results were considered statistically significant if they had a two-sided *p*-value of 0.05 or less. All analyses were conducted using R software and its relevant packages.

## Results

Of the 1,630 abstracts reviewed, we selected 250 articles for full-text screening. The list of the references excluded is available at https://osf.io/3d4be/. As shown in Fig. 1, 21 studies finally met the eligibility criteria and were included in our review.

## Description of the included studies

Table 2 gives the general characteristics of the 21 included studies. Most of the studies were performed in the USA on patients with NSCLC, except Kim et al., 2022 [9] which also included some SCLC. Retrospective cohort design was the most frequent, and only two studies had a prospective cohort design (Chen et al., 2019
<figure><img src="image_3.png" /><figcaption>**Fig. 1** PRISMA flow diagram for the inclusion of studies</figcaption></figure>

[10] and Ning et al., 2017 [11]). Retrospective and prospective data collection was the study design applied in three references (Table 2). No randomized controlled trials matched our inclusion criteria. The different follow-ups varied between 20.4 months [12] and 8.8 years [3].

Table 3 describes the exposure and outcomes definitions of the 21 included studies regarding dose-volume predictors of radiation-induced cardiac events in lung cancer patients. The outcomes of the studies included various cardiac events and exposure measures (dose-volume predictors), including MHD (in all studies except one [21]). The exposure of specific cardiac substructures, such as cardiac chambers or coronary arteries, varied significantly between studies, with limited explanations for selecting these additional cardiac structures and the corresponding dose-volume parameters. Regarding cardiac outcomes, five studies focused on major adverse cardiac events (MACE) [12, 13, 17, 20, 27], 5 studies on grade 2, 3 or higher of “common terminology criteria for adverse events” (CTCAE) [10, 15, 16, 18, 19], and other focused on specific cardiac events.

## Quality assessment

Figure 2 presents the evaluation of PROBAST signaling questions and the overall risk of bias across participants, predictors, outcomes, and analysis domains. Most studies presented medium to low quality and a high to moderate

risk of bias. The studies demonstrated a low or unclear bias risk in the predictors and analysis domains. Indeed, the selection of predictors is mainly arbitrary, except for two studies that evaluated the best predictors using statistical principles [14, 27]. None of the studies reported the intercept of the prediction models or prediction model accuracy parameters, and only one assessed the model's discriminatory power in the area under the receiver operating characteristic curve [27].

## Incidence of cardiac events after radiation therapy

Table 4 lists the incidence of post-RT cardiac events in patients treated for lung cancer, varying widely according to the studies, the cardiac outcome, and the respective follow-ups.

Overall, these cardiac events occur in up to 32% [15] in the cohort, followed by Cho et al. during a 36-month observation period. The smallest incidence was 10% [13] in Atkins et al. (b) during a 9-month observation period. The most frequent cardiac events were as follows:

- Pericardial effusion: 42.8% as observed over nine months follow-up by Ning et al. [11] (the smallest incidence was 6.2% as observed over 26 months follow-up by Wang et al. [23]).

- Arrhythmias: 17.0% as observed over 60 months follow-up by Banfill et al [4]. (the smallest incidence was
<table><caption>**Table 2** Characteristics of the 21 studies regarding dose-volume predictors of cardiac events in lung cancer patients</caption><thead><tr><th>Reference</th><th>Year</th><th>Country</th><th>Population</th><th>Study design</th><th>Number of patients</th><th>Follow-up</th></tr></thead><tbody><tr><td>Atkins (a) [12]</td><td>2019</td><td>USA</td><td>Locally advanced NSCLC</td><td>Retrospective cohort analysis</td><td>748</td><td>20.4 months</td></tr><tr><td>Atkins (b) [13]</td><td>2021</td><td>USA</td><td>Locally advanced NSCLC</td><td>Retrospective cohort analysis</td><td>701</td><td>20.4 months</td></tr><tr><td>Banfill [4]</td><td>2022</td><td>UK</td><td>Stage I to III NSCLC</td><td>Retrospective cohort analysis</td><td>967</td><td>60 months</td></tr><tr><td>Borkenhagen [14]</td><td>2019</td><td>USA</td><td>NSCLC</td><td>Retrospective cohort analysis</td><td>76</td><td>1.2 years</td></tr><tr><td>Chen [10]</td><td>2019</td><td>China</td><td>Stage III NSCLC</td><td>Retrospective and prospective cohort analysis</td><td>112</td><td>29.5 months</td></tr><tr><td>Cho [15]</td><td>2022</td><td>Republic of Korea</td><td>NSCLC</td><td>Retrospective cohort analysis</td><td>133</td><td>45 months</td></tr><tr><td>Dess [16]</td><td>2017</td><td>USA</td><td>Stage II to stage III NSCLC</td><td>Retrospective and prospective cohort analysis</td><td>125</td><td>51 months</td></tr><tr><td>Jang [17]</td><td>2020</td><td>Republic of Korea</td><td>Stage III NSCLC</td><td>Retrospective cohort analysis</td><td>53 (low risk CVD)<br>205 (high risk CVD)</td><td>27.5 months</td></tr><tr><td>Kim [9]</td><td>2022</td><td>Republic of Korea</td><td>Limited-stage SCLC and locally advanced NSCLC</td><td>Retrospective cohort analysis</td><td>560</td><td>25.7 months</td></tr><tr><td>Koutroumpakis [18]</td><td>2022</td><td>USA</td><td>NSCLC</td><td>Retrospective cohort analysis</td><td>193</td><td>24.3 months</td></tr><tr><td>Ning [11]</td><td>2017</td><td>USA</td><td>Locally advanced NSCLC</td><td>Retrospective and prospective cohort analysis</td><td>201 (prospective)<br>301 (retrospective)</td><td>31 months</td></tr><tr><td>No [19]</td><td>2023</td><td>USA</td><td>Locally advanced NSCLC</td><td>Retrospective cohort analysis</td><td>233</td><td>73.7 months</td></tr><tr><td>Tjong [20]</td><td>2022</td><td>USA</td><td>Locally advanced NSCLC</td><td>Retrospective cohort analysis</td><td>701</td><td>19 months</td></tr><tr><td>Walls (a) [21]</td><td>2024</td><td>UK</td><td>NSCLC</td><td>Retrospective cohort analysis</td><td>420</td><td>21.8 months</td></tr><tr><td>Walls (b) [22]</td><td>2024</td><td>UK</td><td>NSCLC</td><td>Retrospective cohort analysis</td><td>478</td><td>21.1 months</td></tr><tr><td>Wang (a) [23]</td><td>2022</td><td>USA</td><td>Stage III NSCLC</td><td>Retrospective and prospective cohort analysis</td><td>109</td><td>26 months</td></tr><tr><td>Wang (b) [3]</td><td>2017</td><td>USA</td><td>Stage III NSCLC</td><td>Retrospective cohort analysis</td><td>112</td><td>8.8 years</td></tr><tr><td>Wang (c) [24]</td><td>2017</td><td>USA</td><td>Stage III NSCLC</td><td>Retrospective and prospective cohort analysis</td><td>112</td><td>8.8 years</td></tr><tr><td>Xue [25]</td><td>2019</td><td>USA</td><td>Inoperable/unresectable NSCLC</td><td>Retrospective cohort analysis</td><td>94</td><td>58 months</td></tr><tr><td>Yegya-Raman (a) [26]</td><td>2018</td><td>USA</td><td>Stage II-III NSCLC or stage IV oligometastatic NSCLC</td><td>Retrospective cohort analysis</td><td>165</td><td>47.4 months</td></tr><tr><td>Yegya-Raman (b) [27]</td><td>2024</td><td>USA</td><td>Locally advanced NSCLC</td><td>Retrospective cohort analysis</td><td>335</td><td>3.3 years</td></tr></tbody></table>

Abbreviations: NSCLC Non-small cell lung cancer, SCLC Small cell lung cancer, USA United States of America, UK United Kingdom, CVD Cardiovascular disease

0.7% as observed over 36 months by Cho et al [15].). Atrial fibrillation was also observed over 24 months follow-up with an incidence rate of around 6% [18, 21].

- Heart failure: 7.3% as observed over 17 months follow-up by Walls et al [21]. (the smallest incidence 0.9% as observed over 26 months follow-up by Wang et al [3].).

- Acute coronary syndrome: 6.0% as observed over 36 months follow-up by Cho et al [15]. (the smallest incidence was 0.7% as observed over 28 months follow-up by Jang et al [20].).

Moreover, cardiac death was also observed over a 60-month follow-up by Banfill et al. [4], with an incidence rate of 11.4%.

## Dose-volume predictors of cardiac events

Table 4 summarizes all dose-volume predictors of cardiac events following RT observed in each included

study. Overall heterogeneity was observed in both the predictors and cardiac events analyzed. However, whole heart exposure, characterized by MHD or heart volumes receiving a specific dose, was most frequently and significantly associated with cardiac events and was the best predictor of such events following RT for lung cancer. The likelihood of a cardiac event increased by 1% to 7% per Gray of MHD when adjusted for confounders such as age, sex, competing risks, comorbidities, and cardiovascular risk scores. In retrospective studies, seven references analyzed the relationship between MHD (exposure) and cardiac events (outcome) after RT for lung cancer. Figure 3 shows the results of the data meta-analysis regarding MHD as a predictor of cardiac events after RT for lung cancer.

This meta-analysis demonstrated a significant positive association between the MHD and the risk of cardiac events. The pooled HR across the studies was 1.04 [95% CI: 1.03, 1.06], indicating that each Gy increase in MHD corresponded to a 4% increase in the probability of
<table><caption>**Table 3** Exposure and outcomes definitions of the 21 included studies</caption><thead><tr><th>Reference</th><th>RT technique and dose prescribed</th><th>Dose prescribed</th><th>Heart structures delineated</th><th>Dose-volume parameters</th><th>Justification for the choice of dose-volume parameters</th><th>Cardiac events</th></tr></thead><tbody><tr><td>Atkins (a) [12]</td><td>3D-CRT, IMRT</td><td>64,0 (54,9–66,0) Gy</td><td>Heart</td><td>Mean</td><td>No justification</td><td>AHA/ACC-defined MACE: cardiac death, unstable angina, myocardial infarction, heart failure hospitalization or urgent visit, and coronary revascularization</td></tr><tr><td>Atkins (b) [13]</td><td>3D-CRT, IMRT</td><td>60 Gy</td><td>Heart, coronary arteries (left main, LAD left circumflex, right, and posterior descending), LV, LA, RA, RV</td><td>Mean, DMax, V5-Gy increments]</td><td>No justification</td><td>AHA/ACC-defined MACE: cardiac death, unstable angina, myocardial infarction, heart failure hospitalization or urgent visit, and coronary revascularization</td></tr><tr><td>Banfill [4]</td><td>Not reported</td><td>Not reported</td><td>Heart</td><td>Mean, V5, V30, V50</td><td>No justification</td><td>Death with a cardiac cause</td></tr><tr><td>Borkenhagen [14]</td><td>Not reported</td><td>60 (44–69) Gy</td><td>LV, RV, LA, RA, pericardium</td><td>Mean, Dmax, V30, V45</td><td>LASSO for predictors selection</td><td>Arrhythmias, pericardial effusion, valvular disease</td></tr><tr><td>Chen [10]</td><td>Not reported</td><td>Not reported</td><td>Heart, LV</td><td>Mean, V5, V30</td><td>No justification</td><td>≥ Grade 3 cardiac event (CTCAE 4.0)</td></tr><tr><td>Cho [15]</td><td>3D-CRT, IMRT</td><td>Not reported</td><td>Heart, myocardium</td><td>Mean, V5, V30, V50</td><td>No justification</td><td>≥ Grade 2 cardiac event (CTCAE)</td></tr><tr><td>Dess [16]</td><td>3D-CRT, IMRT</td><td>70 (45–88) Gy</td><td>Heart</td><td>Mean, V5, V30, V50</td><td>No justification</td><td>≥ Grade 3 cardiac event (CTCAE 4.03)</td></tr><tr><td>Jang [17]</td><td>3D-CRT, IMRT</td><td>50 to 72 Gy</td><td>Heart, LV, RV, RA, LA</td><td>Mean, V5, V10, V20, V30, V40, V50, V60</td><td>No justification</td><td>AHA/ACC-defined MACE: cardiac death, unstable angina, myocardial infarction, heart failure hospitalization or urgent visit, and coronary revascularization</td></tr><tr><td>Kim [9]</td><td>3D-CRT (photon-based RT and proton therapy)</td><td>60 (54.0–60.8) Gy<br>63 (60.0–64.5) Gy</td><td>LV, RV, LA, RA, LAD, RCA, LCA</td><td>Mean, Dmax, V5, V60</td><td>No justification</td><td>Cardiac death, unstable anginas, myocardial infarction, coronary revascularization, heart failure, and atrial fibrillation</td></tr><tr><td>Koutroumpakis [18]</td><td>Proton therapy, IMRT</td><td>66 Gy: 16 patients (8%)<br>66–73 Gy: 64 patients (33%)<br>74 Gy: 113 patients (59%)</td><td>Heart</td><td>Mean</td><td>No justification</td><td>≥ Grade 3 cardiac event (CTCAE 5.0)</td></tr><tr><td>Ning [11]</td><td>3D-CRT, IMRT, VMAT</td><td>Not reported</td><td>Heart</td><td>Mean, V20, Vf(increment 5 Gy to V65]</td><td>Increment 5 Gray (volume)</td><td>Pericardial effusion</td></tr></tbody></table>
<table><caption>**Table 3 (continued)**</caption><thead><tr><th>Reference</th><th>RT technique and dose prescribed</th><th>Dose prescribed</th><th>Heart structures delineated</th><th>Dose-volume parameters</th><th>Justification for the choice of dose-volume parameters</th><th>Cardiac events</th></tr></thead><tbody><tr><td>No [19]</td><td>3D-CRT, IMRT</td><td>Not reported</td><td>Heart, LV, LAD, LMCA, LCx, RCA, combined 3-vessel arteries (LAD, LMCA, and LCx, referred to as TotalLeft), and all combined coronary arteries (TotalCor)</td><td>Mean, V15</td><td>No justification</td><td>≥ Grade 3 cardiac event (CTCAE 4.0)</td></tr><tr><td>Tjong [20]</td><td>3D-CRT, IMRT</td><td>Not reported</td><td>Heart, LAD</td><td>Mean, V15, V30</td><td>Based on prior studies</td><td>AHA/ACC-defined MACE: cardiac death, unstable angina, myocardial infarction, heart failure hospitalization or urgent visit, and coronary revascularization</td></tr><tr><td>Walls (a) [21]</td><td>3D-CRT, IMRT, VMAT</td><td>55 Gy</td><td>Right pulmonary vein (RPV), Left pulmonary vein (LPV)</td><td>Mean, Dmax, V10, V20, V55</td><td>Based on prior studies</td><td>Atrial fibrillation</td></tr><tr><td>Walls (b) [22]</td><td>3D-CRT, IMRT, VMAT</td><td>52–55 Gy: 461 patients (96%)<br>60–66 Gy: 14 patients (3%)<br>72–79 Gy: 14 patients (3%)</td><td>Heart base</td><td>Dmax</td><td>No justification</td><td>Atrial fibrillation, acute heart failure, and acute coronary syndrome</td></tr><tr><td>Wang (a) [23]</td><td>3D-CRT</td><td>70–74 Gy: 84 (77%)<br>78–90 Gy: 25 (23%)</td><td>Heart, LV</td><td>Mean, V5, V30</td><td>No justification</td><td>Symptomatic pericardial effusion, pericarditis, unstable angina, myocardial infarction, significant arrhythmia, and/or heart failure</td></tr><tr><td>Wang (b) [3]</td><td>3D-CRT</td><td>74,0 Gy</td><td>Heart, LV, LA, RA</td><td>Mean, V5, V30, V60</td><td>No justification</td><td>Symptomatic pericardial effusion, pericarditis, ischemic cardiac events, myocardial infarction, unstable angina, significant arrhythmia</td></tr><tr><td>Wang (c) [24]</td><td>3D-CRT</td><td>74,0 Gy</td><td>Heart, LV</td><td>Mean, V5, V30</td><td>No justification</td><td>Symptomatic pericardial effusion, myocardial infarction, unstable angina, pericarditis, significant arrhythmia, heart failure</td></tr><tr><td>Xue [25]</td><td>3D-CRT, others</td><td>Not reported</td><td>Heart, pericardium</td><td>Mean, V5, V30, V55</td><td>V5 and V30 were significant predictors in the trials</td><td>Pericardial effusion</td></tr></tbody></table>
<table><caption>**Table 3 (continued)**</caption><thead><tr><th>Reference</th><th>RT technique and dose prescribed</th><th>Dose prescribed</th><th>Heart structures delineated</th><th>Dose-volume parameters</th><th>Justification for the choice of dose-volume parameters</th><th>Cardiac events</th></tr></thead><tbody><tr><td>Yegya-Raman (a) [26]</td><td>3D-CRT, IMRT, both</td><td>61,2 (60–66)</td><td>Heart, LV, RV, LAD</td><td>Mean, V5, V30, V50</td><td>The metrics are based on RTOG 0617</td><td>Acute coronary syndrome, significant arrhythmia, symptomatic pericardial effusion, pericarditis, congestive heart failure</td></tr><tr><td>Yegya-Raman (b) [27]</td><td>Pencil beam scanning PBT<br>Passive scatter PBT<br>IMRT<br>3D-CRT</td><td>66.6 (66.6–70)</td><td>Heart, LV, LAD</td><td>Mean, Dmin, Dmax, V[increment 5 Gy to V95]</td><td>Based on statistical properties</td><td>AHA/ACC-defined MACE: cardiac death, unstable angina, myocardial infarction, heart failure hospitalization or urgent visit, and coronary revascularization</td></tr></tbody></table>

Abbreviations: 3D-CRT 3-dimensional conformal radiation therapy, IMRT Intensity modulated radiation therapy, Gy Gray, LV Left ventricle, RV Right ventricle, RA Right atrium, LA Left atrium, LAD Left anterior descending artery, MACE Major adverse cardiac event, PBT Proton beam therapy
<figure><img src="image_4.png" /><figcaption>**Fig. 2** Signaling questions from the Prediction model Risk of Bias Assessment Tool (PROBAST)</figcaption></figure>

cardiac events. There was a low heterogeneity across the studies ($I^2=23\%$).

The leave-one-out (LOO) analysis (Fig. 4) confirmed the robustness of the association. The HR remained consistent at 1.04 across all iterations, with a slight variation to 1.05 when the study by Yegya-Raman et al. (b) [27] was omitted but remained within the confidence interval [1.03, 1.06]. Furthermore, the $I^2$ statistic varied slightly across the iterations, ranging from 0% (when omitting Koutroumpakis et al. [18]) to 35% (when omitting Atkins et al. [28] or Wang et al. (b) [24]). Sensitivity analysis confirmed the observation of the association when omitting the study, potentially duplicating the study population from the works of Wang et al. (b) (2022) [16] (Supplementary Material 3).

Egger's test for asymmetry did not reveal statistically significant evidence of publication bias ($t=-0.10, p-value=0.93$), which was unlikely.

## Discussion

This systematic review and meta-analysis provide new insights into the relationship between cardiac exposure and the incidence of radiation-induced cardiac events in patients undergoing high-dose thoracic RT for lung cancer. Throughout all these studies, significant dose-response relationships between cardiac exposure (characterized by heart exposure or cardiac structure exposure metrics) and cardiac events were observed, with higher doses to cardiac structures inducing significantly increased risk of cardiac adverse events, such as pericardial effusion, arrhythmias, congestive heart failure, and acute coronary syndromes.

A strong predictor identified across studies was the MHD. Our meta-analysis revealed that for each

additional Gy of MHD, the risk of cardiac events increased by approximately 4% (95% CI: 3% to 6%). This finding aligns with existing literature, such as the study by Darby et al., which reported a 7.4% increase in major coronary events per Gy in breast cancer patients undergoing RT [5]. However, the slightly lower risk observed in our analysis could be explained by differences in patient populations (i.e., the lung cancer population is already at higher risk of cardiac events, mainly due to tobacco exposure), treatment protocols, and shorter follow-up periods.

Furthermore, our review identified that while MHD is a significant predictor, doses to specific cardiac substructures, particularly the left ventricle and the left anterior descending (LAD) artery, also play a crucial role. Some studies included in our review reported that exceeding 20 Gy to the LAD was associated with a marked increase in the incidence of ischemic heart disease, corroborating findings from the RTOG 0617 trial, which highlighted the importance of limiting cardiac doses to reduce cardiotoxicity [29]. However, the variability in dose metrics across studies indicates the need for more standardized reporting and a deeper understanding of the dose-response relationship for these substructures.

Our findings are consistent with previous studies on radiation-induced cardiotoxicity in lung and breast cancer populations. For example, Gagliardi et al. found that patients receiving doses exceeding 25 Gy to the heart had a significantly higher incidence of pericarditis than those receiving lower doses [30]. Similarly, the CHARTED trial demonstrated that patients with MHD above 15 Gy had a nearly two-fold increase in cardiac mortality compared to those with lower MHD [31].
<table><caption>**Table 4** Incidence of cardiac events after radiation therapy for lung cancer</caption><thead><tr><th></th><th>Incidence</th><th>Event</th><th>Time for the CE to occur or FU period*</th><th>Risk</th><th>Predictor</th><th>Adjusted HR and 95%CI</th><th>p-value</th></tr></thead><tbody><tr><td>Atkins (a) [12]</td><td>10.3%</td><td>MACE</td><td>18,5 (5,4–33,6) months</td><td>Increased risk of MACE</td><td>Mean heart dose</td><td>1.05 (1.02–1.08)</td><td>&lt;0.001</td></tr><tr><td>Atkins (b) [13]</td><td>10.0%</td><td>MACE</td><td>20,6 (8,8–43,3) months</td><td>Increased risk of MACE</td><td>LAD coronary artery V15 Gy ≥ 10%</td><td>13.90 (1.23–157.21)</td><td>0.03</td></tr><tr><td>Banfill [4]</td><td>21.9%<br>17.0%<br>11.4%<br>3.1%<br>1.0%</td><td>Ischemic heart disease<br>Arrhythmias<br>Cardiac death<br>Valve disease<br>Peri/myocardial disease</td><td>60 months*</td><td>Increased risk of death with a cardiac cause</td><td>Mean heart dose<br>Heart V5<br>Heart V30</td><td>1.07 (1.01–1.13)<br>1.01 (1.00–1.03)<br>1.04 (1.00–1.07)</td><td>0.02<br>0.05<br>0.04</td></tr><tr><td>Borkenhagen [14]</td><td>21.0%<br>6.6%<br>1.3%</td><td>Pericardial effusion<br>Arrhythmia<br>Valve disease</td><td>14 months*</td><td>Increased risk of cardiotoxicity (PE, arrhythmias, valve disease)</td><td>LV V45</td><td>1.50</td><td>0.03</td></tr><tr><td>Chen [10]</td><td>5.3%<br>3.6%<br>0.9%</td><td>Acute coronary syndrome<br>Heart failure<br>Myocardial infarction</td><td>29.5 months*</td><td>Increased risk of cardiac events (CTCA)</td><td>Heart V30</td><td>3.73 (1.06–6.90)</td><td>0.04</td></tr><tr><td>Cho [15]</td><td>32.0%<br>26.3%<br>6.0%<br>3.0%<br>0.7%</td><td>Cardiac events<br>Pericardial effusion<br>Acute coronary syndrome<br>Congestive heart failure<br>Arrhythmia</td><td>36 (9–119) months</td><td>Increased risk of cardiac events (CTCA)</td><td>Mean heart dose &gt; 11.1 Gy</td><td>3.65 (1.79–7.42)</td><td>&lt;0.001</td></tr><tr><td>Dess [16]</td><td>15.2%</td><td>≥ Grade 3 cardiac events</td><td>11.0 (0.4–63.0) months</td><td>Increased risk of cardiac events (CTCA)</td><td>Mean heart dose</td><td>1.07 (1.02–1.13)</td><td>0.01</td></tr><tr><td>Jang [17]</td><td>10.5%<br>1.8%<br>1.1%<br>0.7%</td><td>Cardiac events<br>MACE<br>Heart failure<br>Acute coronary syndrome</td><td>27.5 months*</td><td>Increased risk of acute coronary syndrome</td><td>LV V60 &gt; 0</td><td>9.49 (1.28–70.53)</td><td>0.03</td></tr><tr><td>Kim [9]</td><td>SCLC cohort/<br>NSCLC cohort<br>3.8%/ 5.3%<br>2.1%/ 1.9%</td><td>Arrhythmia<br>Non-arrhythmia<br>cardiac events</td><td>SCLC cohort/<br>NSCLC cohort<br>25.7 (16.5–47.2) months/<br>36.2 (26.9–60.2) months</td><td>Increased risk of arrhythmias</td><td>SAN<br>Dmax &gt; 53.5 Gy</td><td>14.91 (4.00–55.56)</td><td>&lt;0.001</td></tr><tr><td>Koutroumpakis [18]</td><td>15.0%<br>5.7%<br>6.2%<br>3.1%</td><td>≥ Grade 2 cardiac event (CTCA)<br>Coronary/vascular event<br>Atrial fibrillation<br>Heart failure</td><td>24.3 months*</td><td>Increased risk of cardiac events (CTCA)</td><td>Mean heart dose</td><td>1.00 (0.96–1.05)</td><td>0.95</td></tr><tr><td>Ning [11]</td><td>42.8%</td><td>Pericardial effusion</td><td>8.9 (0.7–40.2) months</td><td>Increased risk of pericardial effusion</td><td>Heart V20 &gt; 21%<br>Heart V25 &gt; 21.7%<br>Heart V30 &gt; 18.9%<br>Heart V35 &gt; 10.2%<br>Heart V40 &gt; 9.2%<br>Heart V45 &gt; 8.0%<br>Heart V50 &gt; 7.0%<br>Heart V55 &gt; 5.4%<br>Heart V60 &gt; 4.9%<br>Heart V65 &gt; 3.0%<br>Mean heart dose &gt; 12 Gy</td><td>1.72 (1.17–2.65)<br>1.72 (1.13–2.62)<br>1.77 (1.16–2.71)<br>2.02 (1.26–3.23)<br>1.88 (1.19–2.97)<br>1.95 (1.23–3.10)<br>1.93 (1.23–3.02)<br>1.98 (1.25–3.14)<br>1.74 (1.13–2.68)<br>1.76 (1.14–2.73)<br>1.79 (1.16–2.77)</td><td>0.01<br>0.01<br>0.009<br>0.004<br>0.007<br>0.005<br>0.004<br>0.01<br>0.01<br>0.01<br>0.008</td></tr></tbody></table>
<table><caption>**Table 4** (continued)</caption><thead><tr><th></th><th>Incidence</th><th>Event</th><th>Time for the CE to occur or FU period*</th><th>Risk</th><th>Predictor</th><th>Adjusted HR and 95%CI</th><th>p-value</th></tr></thead><tbody><tr><td>No [19]</td><td>22.3%<br>11.6%<br>8.1%<br>1.3%<br>1.3%</td><td>Cardiac events<br>Conduction events<br>Myocardial events<br>Constrictive events<br>Valvular events</td><td>21.5 (1.7–118.9) months</td><td>Increased risk of cardiac events</td><td>Total left heart V15</td><td>1.38 (1.11–1.72)</td><td>0.004</td></tr><tr><td>Tjong [20]</td><td>13.7%</td><td>MACE</td><td>21.8 months*</td><td>Increased risk of MACE</td><td>LAD V15</td><td>1.04 (1.03–1.06)</td><td>&lt;0.001</td></tr><tr><td>Walls (a) [21]</td><td>6.0%</td><td>Atrial fibrillation</td><td>21.1 months*</td><td>Increased risk of atrial fibrillation</td><td>Left pulmonary dose<br>Right pulmonary dose</td><td>1.02 (1.00–1.03)<br>1.01 (1.00–1.02)</td><td>0.005<br>0.03</td></tr><tr><td>Walls (b) [22]</td><td>17.0%<br>7.3%<br>6.1%<br>3.1%</td><td>Cardiac events<br>Heart failure<br>Atrial fibrillation<br>Acute coronary syndrome</td><td>16.3 (9.5–33.9) months</td><td>Increased risk of cardiac events</td><td>Heart base DMax</td><td>1.75 (1.03–2.97)</td><td>0.04</td></tr><tr><td>Wang (a) [23]</td><td>11.0%<br>6.4%<br>4.6%<br>2.7%<br>1.8%<br>0.9%</td><td>Arrhythmia<br>Pericardial effusion<br>Myocardial infarction<br>Unstable angina<br>Pericarditis<br>Heart failure</td><td>26.0 (1.0–84.0) months</td><td>Increased risk of cardiac events</td><td>Mean heart dose</td><td>1.05</td><td>&lt;0.001</td></tr><tr><td>Wang (b) [3]</td><td>10.7%<br>8.0%<br>6.2%</td><td>Arrhythmic events<br>Pericardial events<br>Ischemic events</td><td>Arrhythmic: 23 (1–190) months<br>Pericardial: 28 (7–58) months<br>Ischemic: 26 (9–68) months</td><td>Increased risk of:<br>Arrhythmic events<br>Pericardial events<br>Ischemic events</td><td>LA V30<br>LA Mean dose<br>Heart V60<br>RA V60<br>LV V5<br>LV V30<br>LV Mean<br>Heart V5<br>Heart V5<br>RA V60<br>Heart V30<br>Mean heart dose</td><td>1.03<br>1.04<br>1.04<br>1.02<br>1.03<br>1.03<br>1.05<br>1.03<br>1.02<br>1.02<br>1.02<br>1.02</td><td>0.001<br>0.002<br>0.004<br>0.005<br>0.008<br>0.012<br>0.014<br>0.014<br>0.042<br>0.047<br>0.014<br>0.054</td></tr><tr><td>Wang (c) [24]</td><td>23.0%<br>10.7%<br>6.2%<br>4.4%<br>2.7%<br>1.8%<br>0.9%</td><td>Cardiac events<br>Arrhythmia<br>Pericardial effusion<br>Myocardial infarction<br>Unstable angina<br>Pericarditis<br>Heart failure</td><td>26.0 (1.0–84.0) months</td><td>Increased risk of cardiac events</td><td>Mean heart dose<br>Heart V5<br>Heart V30<br>LV mean dose<br>LV V5<br>LV V30</td><td>1.04<br>1.02<br>1.02<br>1.03<br>1.02<br>1.02</td><td>0.001<br>0.001<br>0.01<br>0.08<br>0.001<br>0.01</td></tr><tr><td>Xue [25]</td><td>40.4%</td><td>Pericardial effusion</td><td>5.4 (1.0–24.7) months</td><td>Increased risk of pericardial effusion</td><td>Pericardial V30<br>Pericardial V35</td><td>1.02 (1.00–1.03)<br>1.03 (1.01–1.05)</td><td>0.01<br>0.01</td></tr><tr><td>Yegya-Raman (a) [26]</td><td>28.6%</td><td>Cardiac events</td><td>15.3 (1.0–75.3) months</td><td>Increased risk of cardiac events</td><td>Mean heart dose<br>LV Mean dose<br>RV Mean dose<br>LAD Mean dose</td><td>1.07 (1.03–1.10)<br>1.04 (1.02–1.07)<br>1.06 (1.03–1.10)<br>1.04 (1.02–1.07)</td><td>0.0003<br>0.0013<br>0.003<br>0.0005</td></tr><tr><td>Yegya-Raman (b) [27]</td><td>10.4%</td><td>MACE</td><td>3.3 (3.1–3.5) years</td><td>Increased risk of MACE</td><td>LAD V15<br>Mean heart dose</td><td>%1.962 (1.00–1.02)<br>1.03 (1.01–1.06)</td><td>0.01<br>0.03</td></tr></tbody></table>

Abbreviations: MACE Major adverse cardiac event, FU Follow-up, HR Hazard ratio, CI confidence interval, LV Left ventricle, Gy Gray, SAN Sino-atrial node, LAD Left anterior descending artery, LV Left ventricle, PE Pericardial effusion

The consistency of these findings across different cancer types and treatment protocols underscores the critical importance of cardiac dose constraints in RT planning.

However, the heterogeneity in the definitions of cardiac events and the varying follow-up durations across studies

<footnote>* FU period</footnote>
<figure><img src="image_5.png" /><figcaption>**Fig. 3** Forest plot pooling the results of 7 seven studies regarding the impact of mean heart dose on cardiac events risk after radiation therapy for lung cancer</figcaption></figure>

<figure><img src="image_6.png" /><figcaption>**Fig. 4** Leave-one-out analysis when considering the 7 seven studies regarding the impact of mean heart dose on cardiac events risk after radiation therapy for lung cancer</figcaption></figure>

complicate direct comparisons and highlight the need for more uniform criteria in future research.

Several limitations must be acknowledged. First, the methodological differences of the included studies implied a significant challenge. The variability in RT techniques, protocol intent, and the definition of cardiac events did not allow for pool estimates. For instance, some studies used three-dimensional conformal RT (3D-CRT). In contrast, others employed intensity-modulated RT (IMRT) or proton therapy, each with different implications for cardiac dose distribution, therefore not reflected in the MHD metric.

Additionally, the varied definitions of cardiac events across studies could impact the conclusions drawn regarding the dose-volume parameter, potentially introducing inconsistencies or biases in interpreting results; each type of cardiac event likely has distinct prognostic implications. However, there was no heterogeneity in pooled studies, yielding a robust HR. Moreover, the LOO analysis showed consistency, suggesting that no single research overly influences the overall result, indicating the robustness of the findings despite different follow-up periods, number of cardiac events, or sample size. Finally, our results suggested that publication bias was unlikely in this meta-analysis, supporting the reliability of the conclusions regarding the association between MHD and the

risk of cardiac events following radiotherapy in patients with lung cancer.

A second limitation could be residual confounding. Notably, there was little or no information in the included studies about CV risk factors such as age, smoking status, and pre-existing cardiovascular conditions. However, our conclusions would probably not have been impacted. Indeed, in 2013, Darby et al. demonstrated that the proportional increase in the rate of major coronary events per Gy was similar in women with and women without cardiac risk factors at the time of RT for breast cancer, which was further demonstrated in other breast cancer and Hodgkin lymphoma survivors treated with RT [5].

The third limitation of this meta-analysis is the inclusion of only retrospective studies. Retrospective studies, while valuable for providing comprehensive data, are more prone to biases, which can affect the reliability of the findings. Additionally, they limit the ability to establish causality. Future research incorporating prospective studies would help validate and strengthen our conclusions. Residual confounding could also arise from the lack of information in the references about radiation dose fractionation concurrent with chemotherapy. Without detailed data on these aspects, it becomes difficult to control the effects of these variables on the results thoroughly, leading to incomplete conclusions.
The findings of this review have significant clinical implications. Given the apparent association between cardiac dose and radiation-induced cardiac events, it is essential that clinicians carefully warrant heart exposure as low as possible during RT planning for lung cancer patients. Advanced RT techniques, such as proton therapy, which can more precisely target tumors while sparing surrounding cardiac tissue, should be explored to minimize cardiotoxicity [32].

Future research should focus on establishing a more precise dose-response association and possible thresholds for cardiac substructures, particularly the LAD and left ventricle, and developing predictive models incorporating patient-specific factors. Prospective studies with extended follow-up periods are also needed to understand better the long-term cardiac risks associated with thoracic RT (e.g., the RAPID-RT study) [33].

In conclusion, this systematic review and meta-analysis underscore the critical importance of dose-volume parameters in predicting radiation-induced cardiac events in lung cancer patients. While MHD remains a crucial predictor, the role of specific substructures warrants further investigation. Future research should standardize dose reporting and explore strategies to mitigate cardiotoxicity, ultimately improving patient outcomes.

## Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s12885-024-13281-8.

Supplementary Material 1.

Supplementary Material 2.

Supplementary Material 3.

## Authors' contributions

Conceptualization: ML; Methodology: CB; Software: CB; Validation: ML, CB, SJ, XG; Formal analysis: ML, CB, SJ; Investigation: ML, CB; Resources: CB; Data cura-
tion: ML, CB; Writing – Original Draft: ML, Writing – Review & Editing: ML, SJ, CB; Vizualization: ML, SJ, XG, CB; Supervision: CB; Project administration: ML.

## Funding

None.

## Data availability

Data is provided within the manuscript or supplementary information files.

## Declarations

### Ethics approval and consent to participate

Not applicable.

### Consent for publication

Not applicable.

### Competing interests

The authors declare no competing interests.

## Author details

Received: 30 September 2024 Accepted: 2 December 2024

Published online: 20 December 2024

## References

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<footnote n="1">¹Department of Biomedical Sciences, Namur Research Institute for Life Sciences, (NARILIS), Faculty of Medicine, University of Namur, Namur, Belgium.</footnote>

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