Abstract
Purpose
Several studies show associations between cardiac radiation dose and cardiac morbidity or overall survival. To evaluate cardiac toxicity of radiation therapy in the absence of another cardiotoxic agent, we set up a prospective pilot study evaluating cardiac function using a wide range of diagnostic modalities in early-stage non-small cell lung cancer (NSCLC) patients with a tumor in close proximity to the heart.
Methods and Materials
The HALO study was a prospective, single-arm, multicenter observational pilot study. Patients scheduled for stereotactic body radiation therapy for stage 1A to 2B NSCLC, or a solitary lung metastasis, with a tumor <3 cm from the heart were included. Cardiac function was evaluated using electrocardiography (ECG), laboratory exams, echocardiography, cardiac magnetic resonance imaging (CMR), and questionnaires at pretreatment and 3 and 12 months poststereotactic body radiation therapy. To assess dose effects, generalized linear models were fitted between segmental radiation dose and strain difference between time points, for longitudinal, circumferential, and radial myocardial strain.
Results
Ten patients were included in the study, of whom 8 were included for analysis, yielding 90 cardiac segments for analysis. No significant differences were found in any of the ECG, laboratory exams, echocardiography, CMR, or questionnaire measurements. The dose effects were small and translated to a possible worsening of myocardial strain in the highest cardiac dose segments, with an absolute difference of 2.8%.
Conclusions
In these early-stage NSCLC patients with mean cardiac doses of 4 Gy, no clinically relevant dose-related cardiac adverse events nor significant changes in global cardiac function were observed after multimodal cardiac evaluation during 12 months of follow-up. Dose-dependent effects of radiation therapy on myocardial strain were not observed in this small pilot study.
Introduction
Cardiac toxicity in non-small cell lung cancer (NSCLC) patients after radiation has been a subject of interest since the results of the Radiation Therapy Oncology Group 0617 trial described an association between cardiac radiation therapy dose and worse overall survival.1 Many studies have since shown similar associations between cardiac dose and survival,2, 3, 4, 5, 6 or cardiac dose and cardiac events.7, 8, 9, 10, 11, 12, 13 The association of mean cardiac dose with the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3 cardiac adverse events7 was reported in a prospective study. In retrospective studies or posthoc analyses, mean cardiac dose was associated with major adverse events and all-cause mortality13 and pericardial effusion,8 left atrial wall dose with electrocardiography (ECG) changes,11 and sinoatrial node dose with atrial fibrillation.12
These studies show associations between cardiac (substructure) dose and negative outcomes as measured by multiple diagnostic modalities, both in patients treated with stereotactic body radiation therapy (SBRT),2,4,5 as in patients treated with conventional fractionation.1,3,7, 8, 9, 10, 11, 12, 13 These findings point in the same direction: there is an effect of radiation therapy on the heart.14,15 However, there are several limitations to these studies. First, retrospective or posthoc collection of cardiac toxicity is less reliable, for example, because symptoms of shortness of breath can be attributed to either pulmonary or cardiac toxicity (eg, dyspnea or pulmonary hypertension). Moreover, cardiac toxicity is often underreported16 and could well be prevalent in NSCLC patients with an average of over 15 pack-years of smoking.17 To evaluate cardiac toxicity after radiation therapy, cardiac evaluations pretreatment and posttreatment, and a comparison between those, are warranted. Second, the types of toxicity reported vary between studies and seem to be dependent on the diagnostic tool. By using multiple diagnostic modalities—electrocardiography (ECG), laboratory exams, echocardiography, cardiac magnetic resonance imaging (CMR)—as well as patient-reported outcome measures, the overall assessment of cardiac toxicity due to radiation therapy dose may be improved. Last, in most of these studies, chemotherapy was involved, which is known to be cardiotoxic, thereby influencing the evaluations of cardiac toxicity caused by radiation therapy alone. To evaluate cardiac toxicity of radiation therapy, we proposed to perform diagnostic cardiac evaluations in the absence of other simultaneous cardiotoxic agents. Therefore, we started a prospective pilot study evaluating cardiac function in early-stage NSCLC patients treated with only SBRT for a tumor in close proximity to the heart.
Methods and Materials
Study design and participants
The HALO (Heart-Lung) study was a prospective, single-arm, multicenter, observational pilot study that opened in January of 2020 (NCT03984019),18 and aimed to include 25 patients treated with SBRT for stage 1A to 2B NSCLC, or a solitary lung metastasis of a solid tumor. Patients were eligible if the shortest distance between the edge of the tumor and the pericardium was <3 cm in all planes, as measured on the diagnostic computed tomography (CT) using lung window setting (W = 1600 and L = −600) and the Feng atlas for guidance, as first described by Feng et al.19 The 3 cm threshold was based on a retrospective cohort treated in the NKI-AvL between January 2018 and March 2019, where patients with a tumor <3 cm from the heart had an average maximum heart dose of 36 GyEQD2. If a patient had a pacemaker or implantable cardioverter-defibrillator, or could not receive MR contrast due to poor renal function (glomerular filtration rate <30 mL/min/1.7 m2), they were excluded from participation. The study was approved by the medical ethics committee of all participating institutes, and all patients provided written informed consent. Due to the COVID-19 pandemic, resources (eg, scan time, scan technicians) were limited for study patients. Subsequently, participant accrual remained slow. In 2023, the study was prematurely terminated due to slow accrual.
Planning, treatment and follow-up
All patients received the standard-of-care treatment and follow-up. Pretreatment work-up consisted of a CT thorax, FDG–positron emission tomography/CT scan and pulmonary function tests, and documentation of pre-existing (cardiac) comorbidities. The gross tumor volume was delineated on a midposition CT scan and expanded to a planning target volume based on the peak-to-peak breathing amplitude (NKI-AvL), or delineated on all phases of the 4-dimensional CT (Amsterdam UMC) or the midexpiration CT scan (LUMC), to create an internal target volume which was expanded to the planning target volume. Patients received SBRT to the primary tumor in 3 fractions of 18 Gy, 5 fractions of 11 Gy in case of chest wall proximity, or 8 fractions of 7 to 7.5 Gy in case of a centrally located tumor. No specific cardiac dose constraints were advised in the study, other than what was clinically used (D0.35cm3 < 36 Gy). All patients were treated with intensity modulated radiation therapy or volumetric arc therapy on a cone beam CT-guided or magnetic resonance imaging (MRI)-guided linear accelerator.
Standard-of-care follow-up consisted of clinical consultation at 1 and 2 months after treatment, every 3 months thereafter for the first 2 years, and biannually thereafter. At each follow-up appointment, cardiac and pulmonary toxicity was assessed by evaluating adverse events according to CTCAE v5.0. Minimum diagnostic follow-up consisted of a CT scan at 6 months after treatment, and every 6 months thereafter, or upon clinical indication.
Cardiac evaluation
Cardiac function was evaluated using ECGs, laboratory exams, echocardiography, CMR, and quality of life questionnaires pretreatment, and 3 and 12 months after treatment.
Electrocardiography
ECGs were evaluated by a single observer. PR intervals (time from the start of the P wave to the start of the QRS comple), QRS durations (length of QRS complex), and QT intervals (time from QRS to end of T wave) were measured in lead II or lead V5 by measuring and averaging 3 consecutive beats using ImageJ v1.50i software (National Institute of Mental Health). QT intervals were measured using the tangent method and QTc intervals (corrected QT interval) were calculated using Bazett’s formula.20
Laboratory exams
In addition to standard laboratory exams, serum N-terminal pro-B-type natriuretic peptide, hs-troponin T, and lymphocyte counts were routinely collected.
Echocardiography
Echocardiographic measures consisted of left ventricular (LV) ejection fraction (LVEF), valvular function, and pericardial effusion. For deformation imaging, echocardiograms were analyzed using 2-dimensional speckle tracking (GE Healthcare) by a single experienced echocardiographer. Subsequently, LV longitudinal strain was measured both globally and segmentally according to the American Heart Association (AHA) 17-segment model.21 Myocardial strain is the percentage of shortening or lengthening in myocardial fibers during the cardiac cycle in a given direction, ie, radial, circumferential or longitudinal. On echocardiography, only the longitudinal strain was assessed.
CMR imaging
CMR cine and late gadolinium enhancement (LGE) images were obtained on a single 3.0 Tesla scanner (Philips Ingenia Elition, Philips Medical Systems) (n = 22) or a 1.5 Tesla Siemens Avanto Fit (Siemens Healthineers) (n = 1, because the 3.0 scanner was unavailable). LVEF, right ventricular ejection fraction, and LGE were evaluated as part of local clinical workflow. Feature tracking myocardial strain was analyzed using Cvi42 v5.12 (Circle Cardiovascular Imaging) by 2 observers independently. Short-axis slices, 4-chamber view, 3-chamber view, and 2-chamber view were used, where available. Short-axis slices wherein the ventricular outflow tract was visible were excluded. In the end-diastolic phase, the LV endocardial and epicardial borders were automatically contoured and manually adjusted where needed. Subsequently, longitudinal, radial, and circumferential strain were calculated by the software both globally and segmentally according to the AHA 17-segment model.21 The apex (segment 17) was by default excluded from CMR strain analysis. Only segments with pretreatment values with a relative interobserver variation <25% and within the normal range ±75% of the normal reference range,22 were included. This was: (1) because the contouring could be sensitive, and (2) to exclude severely abnormal baseline segments unlikely to exhibit further radiation functional changes.
Questionnaires
National Cancer Institute (NCI) patient-reported outcomes of the CTCAE (PRO-CTCAE) and EORTC QLQ-C30 and QLQ-LC13 were given to patients after they had provided informed consent, or sent to the home address before the cardiac function measurements. From the PRO-CTCAE, the cardiac toxicity-related items (shortness of breath, cough, wheezing, swollen limbs, palpitations, dizziness, and fatigue) were combined for analysis.
Dose extraction
To enable an evaluation of the association between regional cardiac deformation and planned radiation therapy dose, the mean dose to each cardiac segment was obtained as follows: first, the planning CT was semiautomatically angulated to the cardiac axes using an in-house developed angulation tool.23 The LV was delineated on the angulated scan and subsequently segmented according to the AHA 17-segment model.21 Second, the delineations of the LV segments were propagated back to the planning CT to calculate the mean planned dose per segment. Physical dose distributions from the clinical plans were corrected to biologically equivalent doses as given in fractions of 2 Gy (EQD2) using an α/β = 3 Gy.
Statistical analyses
Categorical data are presented as number and percentage. Continuous data are presented as mean and standard deviation or median and range. Differences between pretreatment and posttreatment measurements were assessed using paired t tests or Wilcoxon signed rank tests.
To assess dose effect, generalized linear models and linear mixed models with the patient as random intercept were fitted between the dose and the strain difference between time points, for the different types of strains (longitudinal, circumferential, radial) with a forced intercept at 0. Normal values for longitudinal and circumferential strain are negative, indicating shortening of the myocardial fibers, and a negative dose-effect slope indicates a reduction in the shortening capacity (ie, worsening) with higher doses. A normal radial strain has a positive value, which indicates thickening of the myocardial fibers, and a positive slope indicates a reduction in the thickening of the myocardial fibers with higher doses. The generalized linear and linear mixed effect models were compared for performance using Akaike information criterion. All P values were 2-sided and considered statistically significant when <.05. All analyses were performed using R software v4.3.2.
Results
Between January 2021 and December 2022, 10 patients were included in this study. Two patients were nonevaluable (before first study follow-up; one died of a noncardiac, nontreatment-related cause, and one withdrew consent). Eight patients were included in this analysis, of whom 7 completed 12 months follow-up (as the study was closed before the eighth could complete 12 months follow-up). Three patients underwent chemotherapy between 1 and 3 years prior to inclusion in this study (low-dose cisplatinum, pembrolizumab-pemetrexed-carbo and Capox-B). Patient and treatment characteristics are presented in Table 1.
Table 1.
Patient and treatment characteristics
| Variable | N = 8 |
|---|---|
| Patient characteristics | |
| Age, y, median (range) | 66 (58-81) |
| Sex | |
| Male, n (%) | 4 (50.0) |
| Female, n (%) | 4 (50.0) |
| WHO performance status | |
| 0, n (%) | 6 (75.0) |
| 1, n (%) | 1 (12.5) |
| 3, n (%) | 1 (12.5) |
| Cardiovascular comorbidities | |
| Prior cardiac surgery (coronary artery bypass grafting), n (%) | 1 (12.5) |
| Atrial fibrillation, n (%) | 2 (25.0) |
| Left ventricular ejection fraction,* %, median (range) | 61.1 (39.8-75.0) |
| FEV1, % of predicted, median (range) | 74 (40-108) |
| Treatment characteristics | |
| Dose prescription (physical dose) | |
| 8 × 7.5 Gy, n (%) | 5 (62.5) |
| 8 × 7 Gy, n (%) | 1 (12.5) |
| 5 × 11 Gy, n (%) | 1 (12.5) |
| 3 × 18 Gy, n (%) | 1 (12.5) |
| Distance tumor-heart, cm, median (range) | 0.46 (0.00-2.76) |
| GTV, cm3, median (range) | 9.93 (0.24-34.98) |
| Tumor stage | |
| T1, n (%) | 2 (25) |
| T2, n (%) | 2 (25) |
| Solitary metastasis of a solid tumor, n (%) | 4 (50) |
| Mean lung dose, Gy, median (range) | 4.35 (1.19-6.20) |
| Mean heart dose, Gy, median (range) | 4.00 (0.20-11.4) |
| Mean left ventricle dose, Gy, median (range) | 6.60 (0.13-17.9) |
Abbreviations: CMR = cardiac magnetic resonance; FEV1 = forced expiratory volume in the first second; GTV = gross target volume; WHO = World Health Organization.
Left ventricular ejection fraction as measured on CMR.
Figure 1 shows the anatomic locations and relative size of the treated tumors in a 3-dimensional average anatomy. During study follow-up, no possibly, probably, or definitely treatment-related cardiac adverse events were observed. One patient was referred for Holter examination for palpitations during the pretreatment measurements (3 days before the start of treatment), and received a diagnosis of paroxysmal atrial fibrillation during follow-up with a cardiologist (treatment had since finished). Mean heart dose for this patient was low: 0.2 Gy. ECG, laboratory results, echocardiography, CMR, and questionnaire parameters are presented in Table 2.
Figure 1.
Three-dimensional rendering of the average heart anatomy (white) of the 8 study patients with the tumor locations and relative size.
Table 2.
Laboratory results, ECG measurements, and echocardiography and CMR metrics
| Modality | Moment in study |
||
|---|---|---|---|
| Pretreatment | 3 months | 12 months* | |
| Laboratory results | |||
| Median lymphocyte counts, per 10⁻9 L⁻1, (range) | 1.58 (1.18-3.27) | 1.47 (0.71-2.68) | 1.34 (0.80-2.59) |
| Median troponin T, ng/L, (range) | 9.0 (6.0-20.0) | 9.0 (5.0-11.0) | 8.0 (6.0-14.0) |
| Median NT-proBNP, pg/mL, (range) | 109 (50-932) | 129.5 (50-1255) | 155 (50-1108) |
| Questionnaires | |||
| Median of cardiac toxicity-related items (shortness of breath, cough, wheezing, swollen limbs, palpitations, dizziness and fatigue) (range) | 1.57 (1.14-2.71) | 1.86 (1.00-2.86) | 2.14 (1.00-2.71) |
| ECG | |||
| Median heart rate, bpm, (range) | 80 (43-123) | 69 (44-120) | 67 (61-88) |
| Median PR interval, ms, (range) | 150 (126-208) | 151.5 (127-219) | 142 (130-209) |
| Median QRS duration, ms, (range) | 82 (67-109) | 82 (70-166) | 82 (74-111) |
| Median QTc Bazett, ms, (range) | 424 (376-456) | 403 (380-425) | 414 (380-432) |
| Echocardiography | |||
| Median LVEF, %, (range)† | 56.5 (32.0-63.0) | 52.5 (46.0-60.0) | 56.0 (38.0-65.0) |
| Median GLS, %, (range) | −17.7 (−19.2 to −11.4) | −16.7 (−20.6 to −8.7) | −17.9 (−21.6 to −9.3) |
| Pericardial effusion, n/total | 0/8 | 0/8 | 0/7 |
| CMR | |||
| Ejection fraction | |||
| Median LVEF, %, (range)† | 64.5 (39.8-75.0) | 59.1 (31.5-76.4) | 64.3 (31.0-73.0) |
| Median RVEF, %, (range) | 59.6 (56.0-65.3) | 59.0 (55.0-66.0) | 57.6 (53.0-74.0) |
| Strain | |||
| Median GLS, %, (range) | −15.1 (−19.9 to −8.9) | −14.3 (−18.0 to −8.3) | −13.4 (−17.9 to −6.4) |
| Median GRS, %, (range) | 27.6 (10.9-60.3) | 27.4 (9.1-43.7) | 27.5 (8.3-40.7) |
| Median GCS, %, (range) | −17.1 (−26.1 to −8.5) | −17.0 (−22.3 to −7.2) | −17.1 (−21.7 to −6.5) |
Abbreviations: bpm = beats per minute; CMR = cardiac magnetic resonance; CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; ECG = electrocardiography; GCS = global circumferential strain; GLS = global longitudinal strain; GRS = global radial strain; LVEF = left ventricular ejection fraction; NT-proBNP = N-terminal pro-B-type natriuretic peptide; RVEF = right ventricular ejection fraction.
In 7 evaluable patients.
Lowest LVEF values for patient with myocardial infarction years prior.
The combined NCI patient-reported outcomes of the CTCAE questionnaire items are: shortness of breath, cough, wheezing, swollen limbs, palpitations, dizziness and fatigue.
Electrocardiography
No significant differences between pretreatment and 3 or 12 months posttreatment were found in any of the ECG measurements. Individual patient QRS duration and QTc interval are shown in Fig. E1.
Laboratory exams
No significant differences were found between pretreatment values and 3 or 12 months posttreatment values in any of the laboratory exams. One patient had lymphopenia grade 2 and 1 after treatment; 0.71 × 10⁻9L⁻1 and 0.80 × 10⁻9L⁻1 at 3 and 12 months posttreatment, respectively. The dynamics of the values per patient are shown in Fig. E2.
Echocardiography
No significant differences were found between pretreatment values and 3 or 12 months posttreatment values in any of the echocardiography measurements.
Cardiac magnetic resonance
There was no significant difference in global longitudinal, circumferential, and radial strain between pretreatment and 3 and 12 months posttreatment (Table 2). Two patients had a relative reduction in global longitudinal strain (GLS) >15% at 12 months posttreatment. Visually, no LGE was observed.
Of segments, 23% were excluded for having an interobserver variation >25%. The interclass correlation was 0.801. Of segments, 10% were excluded because the pretreatment strain in these segments was outside of predefined limits of normal range ±75%. Excluded segments were evenly distributed over segments and patients except for 1 patient who had had a myocardial infarction and coronary artery bypass grafting 16 years prior. Ninety segments were included in the analysis for pretreatment versus 3 months posttreatment, and 78 in the analysis for pretreatment versus 12 months posttreatment. No significant differences were found between pretreatment and 3 or 12 months posttreatment LVEF, right ventricular ejection fraction, and strains in any of the CMR values. Also no correlation was found between the difference in GLS and the difference in ECG measurements (Fig. E5).
Dose-effect relation
The slopes of the dose-effect relation as modeled by the linear model for the difference between pretreatment and posttreatment are shown in Table 3. All slopes show a worsening of the strain with higher doses, but these were not significant. The linear mixed models did not perform significantly better than the linear models. The difference in strain as measured on the CMR and echocardiography is shown in Fig. 2 (pretreatment vs 12 months follow-up) and Fig. E3 (pretreatment vs 3 months follow-up).
Table 3.
Slopes and their theoretical impact in the segment with highest dose for each patient; difference between pretreatment and posttreatment
| Time difference | Parameter | Longitudinal strain (echocardiography) | Longitudinal strain (CMR) | Circumferential strain (CMR) | Radial strain (CMR) |
|---|---|---|---|---|---|
| Normal values, % | −15.9 to −22.1 | −15.9 to −22.1 | −20.9 to −27.8 | 35.1 to 59.0 | |
| Pretreatment to 3 months posttreatment | Slope, Gy⁻1(95% CI) | −0.06 (−0.13 to 0.01) | −0.01 (−0.14 to 0.13) | −0.03 (−0.10 to 0.05) | 0.07 (−0.17 to 0.31) |
| Absolute worsening in segments with high dose, % | 1.3 | 0.2 | 0.6 | 2.1 | |
| Pretreatment to 12 months posttreatment | Slope, Gy⁻1 (95% CI) | −0.04 (−0.12 to 0.04) | −0.13 (−0.26 to 0.01) | −0.01 (−0.09 to 0.06) | 0.05 (−0.21 to 0.32) |
| Absolute worsening in segments with highest dose, % | 0.9 | 2.8 | 0.2 | 0.6 |
Abbreviation: CMR = cardiac magnetic resonance.
Figure 2.
Strain as measured on CMR and echocardiography for the difference between pretreatment and 12 months posttreatment.
Abbreviation: CMR = cardiac magnetic resonance.
For the segments with the highest dose per patient, the average mean dose was 29.7 Gy (EQD2). The dose effect in the high-dose segments as measured on the CMR equates to an average longitudinal strain decrease of 2.8% at 12 months (Table 3).
Questionnaires
Compared to pretreatment, there were no significant differences in PRO-CTCAE outcome measures, as collected in all patients. Dynamics per patient are shown in Fig. E4. Quality of life questionnaires were filled out for 1 patient and could, therefore, not be analyzed.
Discussion
This was a prospective pilot study evaluating the toxic effects of radiation therapy on cardiac function in patients receiving SBRT for lung tumors in close proximity to the heart, using multiple diagnostic modalities and in the absence of other simultaneous cardiotoxic agents. Due to insufficient accrual, the study was prematurely terminated after the inclusion of 10 out of the 25 intended patients. During 12 months of follow-up, no clinically significant treatment-related cardiac adverse events were observed. In this small cohort analysis, there were no statistically significant differences in global cardiac function comparing pretreatment with 3 and 12 months after radiation therapy. Last, there was no statistically significant dose-effect relationship observed in segmental radial, circumferential, and longitudinal myocardial strain before and after treatment.
Previously, associations between cardiac radiation therapy dose and overall survival in early-stage NSCLC patients have been observed.2 By including patients who were not simultaneously using other cardiotoxic agents such as chemotherapy, we aimed to analyze the influence of dose to the heart. Although 3 patients had received chemotherapy in the years before their current treatment, these chemotherapies are very unlikely to affect the analyses; any possible deterioration of cardiac function from the chemotherapy would have been before the current treatment started, and thus, the baseline measurement before the current treatment combined with the follow-up measurements should reflect the pure radiation therapy effect. A reduction in GLS has been shown to be an early predictor for chemotherapy-related cardiotoxicity,24 indicating that chemotherapy confounds effects of radiation therapy on cardiac function. We found no significant differences in GLS in this small cohort with relatively low doses to the heart. Combined with the possibility that a negative effect may be too small to be clinically relevant with these relatively low doses, this hints that cardiac toxicity may not have been the cause of the decreased survival in the early-stage lung cancer patients. Importantly, when the heart is irradiated, the blood inside the heart inadvertently receives the dose as well. Negative influences on the immune system, or more specifically lymphopenia, have been shown to be associated with survival in patients with locally advanced stage lung cancer,25 although these patients receive much higher doses to the heart. Because lymphocyte data are generally not collected in early-stage lung cancer patients, no association in this patient population has yet been observed. In this paper, 6 of 8 patients had a lower nonsignificant lymphocyte count 3 months posttreatment than pretreatment.
We found some differences between echocardiography and CMR. These are in line with previous reports on intertechnique variability between CMR feature tracking and echocardiography speckle tracking.26,27 Additionally, the CMR feature tracking and echocardiography speckle tracking were performed by different observers; hence, the addition of interobserver variability cannot be entirely ruled out. Given the small sample size, we think the nonsignificant decrease in GLS observed on CMR should be interpreted with caution, as it may also be noise.
Echocardiography, CMR, and dose-effect relation
Myocardial strain can be used as a surrogate for early deterioration of cardiac function, where a worsening in GLS specifically can be observed before a worsening in LVEF.28 Therefore, it is advised to include GLS in echocardiographic screening in cancer patients receiving cardiotoxic cancer treatment,29 where a relative reduction in GLS of >15% compared to pretreatment is considered mild cancer therapy-related cardiac dysfunction. In this study, 2 patients experienced a >15% relative reduction in GLS. Our findings regarding global cardiac function are consistent with a recent pilot study evaluating both cardiac and aortic parameters in patients with locally advanced lung cancer treated with conventional radiation therapy (median LV mean dose = 7.4 Gy) and concurrent chemotherapy.30 Conversely, Omidi et al30 did describe several segmental changes, including regional longitudinal, circumferential, and radial strain, but did not find a correlation between segmental strain and dose. The latter also accords with our observations in the absence of other simultaneous cardiotoxic cancer therapy, even with a follow-up duration that was 6 months longer. In a second study with mostly locally advanced stage NSCLC patients treated with conventionally fractionated radiation therapy, LVEF declined after radiation therapy, but mostly recovered after 12 months.31 This is in line with our results (Table 2), although these were not significant in this small cohort. This supports the findings that radiation therapy did not result in important changes in cardiac function in the dose range as given in early-stage NSCLC patients.
In a posthoc analysis from a small prospective trial in patients with esophageal cancer, an increase (ie, reduction in shortening capacity) in GLS was observed. In the LV segments with a planned mean radiation therapy dose of >30 Gy, a moderate correlation between dose and change in longitudinal strain per segment was reported.32 Interestingly, this effect was observed in a short mean time of 37 days. This difference may be explained by the higher planned dose to the heart. Mean LV dose was 18.7 ± 3.5 Gy and 34 (out of 324) segments received 30 Gy or more, compared to 6.6 Gy and no segments in our cohort. This may suggest that the low mean doses to the heart in our study are not high enough to influence cardiac function.
We opted for a broad range of tests to assess multiple aspects of cardiac function. We can thoroughly compare cardiac toxicity found in locally advanced stage patients in the literature, taking into account that the mean heart dose is much higher: 11.0 Gy7 in locally advanced stage patients versus 4.0 Gy in our early-stage patients. Moreover, in locally advanced stage patients, concurrent chemotherapy is standard of care. First, pericardial effusion was not observed in any of the patients in our cohort. Ning et al8 found that pericardial effusion was common after radiation therapy, with 31.4% of patients experiencing pericardial effusion ≥grade 2 (CTCAE), and that a heart volume receiving ≥35 Gy of >10% was a strong predictor for pericardial effusion. In our cohort, none of the patients were exposed to this dose-volume histogram parameter. Second, we did not see any major adverse cardiac events in our 12 months of follow-up. In locally advanced stage patients, major adverse cardiac events were correlated to LAD (left anterior descending artery) dose (LAD-V15).9 Because of the lower LAD-V15 dose in early-stage NSCLC patients, we do not expect this to parameter to be important in these patients. We also did not find any atrial fibrillation de novo. Our dose is comparable to the low-dose group represented in Fig. 1 of Kim et al,12 where atrial fibrillation was absent as well.
This study has several important limitations. First, the low number of patients due to the early termination of the trial makes it difficult to draw any firm conclusions. However, we believe that because of the thoroughness of the evaluation of cardiac function, these results are still meaningful. This is the first prospective study evaluating cardiac function in early-stage NSCLC patients by using multiple modalities to obtain insight into the functional cardiac consequences in patients with low heart doses and in the absence of other simultaneous cardiotoxic agents. Second, although no clinically relevant treatment-related cardiac adverse events or significant changes in global cardiac function were observed, the follow-up duration of 12 months was limited. Although it was longer than similar studies reporting on the effects of radiation therapy on cardiac function, radiation-induced toxicity can still occur years later. Third, the interobserver variation in myocardial strain measurements may lead to a difference between the actual and the measured strain. We minimized the risk of measurement error by having 2 independent observers perform the CMR measurements, but some deviation may still exist. Because of the measurement uncertainty, we also opted to do all analyses with absolute differences, to not magnify any error when using relative differences. Fourth, we assumed that all segments of the LV would respond similarly to the dose. Additionally, measuring the planned dose and the strain on separate modalities may have caused slight anatomic differences, although the 17 LV segments are anatomically well defined. Fifth, T2 mapping was not available. Sixth, medication was not collected at the time; hence, the effect of cardioprotection for the patient with prior cardiac surgery from, for eg, ACEi could not be established. Lastly, the cohort was heterogeneous in cardiovascular baseline function, which is representative of an average early-stage NSCLC cohort, but the performance status was better than the average cohort.
Conclusions
This was a prospective pilot study that aimed to evaluate the effects of radiation therapy dose on cardiac function in patients with a lung tumor treated with SBRT in the absence of other cardiotoxic agents. We did not observe any clinically relevant treatment-related cardiac adverse events nor significant changes in global or local cardiac function after multimodal cardiac evaluation within 12 months after treatment. Regionally, no dose-dependent effects of radiation therapy on longitudinal, radial, and circumferential strain were observed. Importantly, this was a relatively small pilot study with a relatively low mean heart dose of 4 Gy, small volumes of the heart irradiated, and limited follow-up; hence, these results should be interpreted accordingly.
Disclosures
Wiert F. Hoeksema reports: EHRA Educational Grant 2023 and Heart Rhythm Society Travel Scholarship 2025. Pieter G. Postema reports: institutional support from the Dutch Heart Foundation grant 03-003-2021-T061; and board membership of Praetorian-DFT, National Health Regulatory Authority, EHRA, EMA, and Cardionetworks. Jan-Jakob Sonke reports: institutional support from the Dutch Cancer Society, the Dutch Ministry of Health, Elekta AB, the Dutch Science Organization, KWF, Health Holland, RVO, institutional royalties for cone beam CT-guided software; and is a member of the international advisory board of PMB. Barbara Stam reports financial support was provided by KWF Dutch Cancer Society. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgment
We thank Shermarke Hassan for statistical discussion.
Footnotes
Sources of support: KWF Dutch Cancer Society Alpe Du’zes grant 11964 to Barbara Stam and Dutch Heart Foundation grant 03-003-2021-T061 to Pieter G. Postema.
The study data are available from the corresponding authors upon reasonable request.
Supplementary material associated with this article can be found in the online version at doi:10.1016/j.adro.2026.102158.
Contributor Information
Jan-Jakob Sonke, Email: j.sonke@nki.nl.
Barbara Stam, Email: b.stam@nki.nl.
Appendix. Supplementary materials
References
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