Effects of trimetazidine on cardiac function in patients undergoing pulmonary stereotactic body radiotherapy evaluated by speckle-tracking echocardiography: A randomized, double-blind study

doi:10.21203/rs.3.rs-4846863/v1

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Effects of trimetazidine on cardiac function in patients undergoing pulmonary stereotactic body radiotherapy evaluated by speckle-tracking echocardiography: A randomized, double-blind study

https://doi.org/10.21203/rs.3.rs-4846863/v1

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Radiation-induced heart damage (RIHD) has become an important factor affecting the long-term prognosis of cancer patients, and there are still no effective prevention or treatment measures. The purpose of this study was to evaluate the prevention and treatment effect of trimetazidine (TMZ) on early subclinical cardiac damage. We conducted a prospective, single-centre, randomized controlled study in the Department of Radiation Oncology of Peking University Third Hospital from May 2021 to April 2022. Patients who planned to receive pulmonary stereotactic body radiotherapy (SBRT) were randomly divided into a TMZ group and a control group. The TMZ group was treated with TMZ 2 weeks before SBRT (20 mg/time, 3 times a day, for 12 weeks). The control group received SBRT 2 weeks after admission. The primary outcomes were myocardial strain indices. Safety was analysed in all treated patients. We enrolled 73 patients, of whom 36 were assigned to the TMZ group and 37 to the control group. One patient in each of the two groups was lost to follow-up. The main outcome index, global longitudinal strain (GLS), was better in the TMZ group than the control group (-11.8 ± 3.7% vs. -10.1 ± 3.4%, P=0.042). There was no significant difference between the two groups in any secondary outcome indicators, including cardiac injury markers, cardiac structure, left ventricular ejection fraction and diastolic function indices. No drug-related adverse reactions occurred. In patients who plan to undergo pulmonary SBRT, TMZ can improve the myocardial strain parameter GLS after pulmonary SBRT, suggesting that TMZ has preventive and therapeutic effects on RIHD.

Trial registration: ClinicalTrials.gov: NCT04939857 (25/06/2021).

Health sciences/Cardiology

Health sciences/Oncology

Radiation-induced heart disease

Stereotactic body radiotherapy

Trimetazidine

Speck-tracking echocardiography

Global longitudinal strain

Radiation therapy can significantly improve the long-term prognosis of patients, making it an important means of treating lung cancer [1]. The heart is exposed to radiation during transthoracic radiotherapy, which causes radiation-induced heart damage (RIHD), leading to an increased risk of cardiovascular death in lung tumour patients [2][3]. Compared to patients who did not receive radiation, patients receiving transthoracic radiotherapy had a 27% higher risk of cardiac-related death[4]. In patients with non-small-cell lung cancer, the risk of cardiac events significantly increases within 2 years after radiotherapy, and a higher cardiac dose leads to a shorter overall survival period [5], seriously limiting the survival benefits of radiotherapy. RIHD can affect any structure of the heart and has become one of the main complications threatening the survival of cancer patients after radiotherapy [6].

The course of RIHD is often hidden, and the best treatment window may have been missed by the time symptoms appear. Early intervention is expected to reduce or delay the occurrence of RIHD, but there are no effective drugs for preventing or treating RIHD in clinical practice [7]. Transthoracic radiotherapy can cause cardiac damage by inducing inflammatory reactions, oxidative stress, energy metabolism disorders, and myocardial fibrosis. Energy metabolism disorders are important causes of RIHD. Trimetazidine (TMZ) is a widely used drug that improves myocardial energy metabolism by inhibiting the fatty acid oxidative enzyme 3-ketoacyl-CoA thiolase and increasing glucose oxidation, thereby improving myocardial energy metabolism and cardiac function [8]. TMZ can alleviate cardiac inflammatory reactions in rats after irradiation and inhibit radiation-induced myocardial fibrosis [9][10]. Our research group have found that TMZ can exert myocardial-protective effects by inhibiting oxidative stress and myocardial fibrosis, but there is still no clinical evidence supporting the use of TMZ for preventing and treating RIHD. The purpose of this study was to evaluate the preventive and therapeutic effects of TMZ on early subclinical cardiac damage.

Patient Characteristics

Between May 1, 2021 and April 30, 2022, 86 patients who underwent pulmonary SBRT were screened in this study. According to the inclusion and exclusion criteria, 73 patients were ultimately enrolled, including 36 patients in the TMZ group and 37 patients in the control group. One patient in each group did not have myocardial strain measured 10 weeks after SBRT due to the impact of the COVID-19 epidemic (Fig. 1). The baseline characteristics of the enrolled patients are provided in Table 1.

Table 1

Demographics and baseline characteristics
	TMZ group (n = 36)	Control group (n = 37)
Age, in years	55.6 ± 18.4	56.3 ± 19.6
Male sex, no. (%)	17(47.2)	19(51.4)
BMI, kg/m²	23.9 ± 3.9	24.2 ± 3.8
Systolic pressure, mmHg	125.6 ± 8.5	126.9 ± 8.8
Diastolic pressure, mmHg	74.3 ± 7.8	74.8 ± 7.0
Heart rate, bpm	78.5 ± 14.7	79.6 ± 14.4
Tumor classification, no.(%)
Lung cancer	18(50.0)	22(59.5)
Pulmonary metastasis tumor	18(50.0)	15(40.5)
Tumor Stage, no.(%)
I	11(30.6)	13(35.1)
II	1(2.8)	0
III	2(5.6)	0
IV	22(61.1)	24(64.9)
CAD, no.(%)	2(5.6)	2(5.4)
Hypertension, no.(%)	7(19.4)	9(24.3)
Diabetes, no.(%)	5(13.9)	7(18.9)
Dyslipidaemia, no.(%)	23(63.9)	21(56.8)
Smoking, no.(%)	9(25.0)	8(21.6)
Medication, no.(%)
Chemotherapy history	22(61.1)	22(59.5)
Anthracycline	11(30.6)	10(27.0)
Targeted drugs	16(44.4)	18(48.6)
Immunocheckpoint inhibitor	6(16.7)	5(13.5)
β Receptor blocker	4(11.1)	4(10.8)
ACEI/ARB	3(8.3)	2(5.4)
Statins	5(13.9)	5(13.5)
ALT(U/L)	18.0(15.0,28.8)	20.0(12.5,32.5)
AST(U/L)	23.0(17.3,29.8)	21.0(17.0,29.5)
Cr(µmol/L)	74.5 ± 17.0	75.1 ± 15.1
FBG(mmol/L)	5.6(5.1,6.2)	5.5(5.0,6.7)
TC(mmol/L)	4.7 ± 1.2	4.7 ± 1.0
TG(mmol/L)	1.5(1.1,2.3)	1.6(1.1,2.4)
LDL-C(mmol/L)	3.0 ± 0.9	3.0 ± 0.8
HDL-C(mmol/L)	1.1(0.9,1.3)	1.1(1.0,1.3)
US-CRP(mg/L)	1.4(0.6,4.3)	1.5(0.6,6.1)
BMI: body mass index; CAD: Coronary Artery Disease; ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; ALT: alanine transaminase; AST: aspartate transaminase; Cr: creatinine; FBG: fasting blood glucose; TC: total cholesterol; TG: triglyceride; LDL-C: low density lipoprotein cholesterol; HDL-C: high density lipoprotein cholesterol; US-CRP: ultrasensitive C-reaction protein.

Stereotactic body radiotherapy

The TMZ group and the control group did not differ in radiotherapy site, prescription dose, fractionations, biologically effective dose (BED), equivalent dose in 2 Gy per fraction (EQD2), planned target volume (PTV), gross tumour volume (GTV), or cardiac dose-related indicators (minimum heart dose, average heart dose, maximum heart dose, percentages of heart volume receiving ≥ 5 Gy, ≥ 10 Gy and ≥ 20 Gy) (P > 0.05) (Table 2).

Table 2

Stereotactic body radiotherapy parameters
	TMZ group (n = 36)	Control group (n = 37)
Radiotherapy location, n (%)
Upper lobe of left lung	9(25.0)	7(18.9)
Lower lobe of left lung	5(13.9)	8(21.6)
Upper lobe of right lung	9(25.0)	5(13.5)
Middle lobe of right lung	1(2.8)	3(8.1)
Lower lobe of right lung	4(11.1)	3(8.1)
Multiple lung lobes	8(22.2)	11(29.7)
Prescription dose (Gy)	40.0(36.0, 45.0)	36.0(28.5, 45.0)
Fractionation, times	3.0(3.0, 5.0)	3.0(3.0, 4.0)
BED(Gy)	180.0(147.0, 270.0)	216.0(157.5, 270.0)
EQD2(Gy)	108.0(88.0, 162.0)	130.0(97.0, 162.0)
PTV(cm³)	13.0(6.4, 28.6)	11.3(5.6, 33.5)
GTV(cm³)	2.9(0.5, 14.3)	2.9(0.6, 18.6)
Minimum heart dose (Gy)	0.4(0.2, 0.8)	0.5(0.2, 0.7)
MHD (Gy)	3.4(1.2, 6.7)	3.4(1.5, 5.8)
Maximum heart dose (Gy)	18.5(9.2, 32.8)	18.0(8.1, 31.9)
V5(%)	31.4(4.3, 54.0)	24.1(3.6, 52.4)
V10(%)	2.3(0, 15.0)	4.2(0, 15.6)
V20(%)	0(0, 2.1)	0(0, 1.7)
BED: biologically effective dose; EQD2: equivalent dose in 2Gy per fraction; PTV: planned target volume; GTV: gross tumor volume; MHD: mean heart dose; V5, V10 and V20: percentages of heart volume receiving ≥ 5Gy, ≥ 10Gy and ≥ 20Gy.

Primary and secondary outcomes

Before pulmonary SBRT, there were no significant differences in GLS, GCS or GRS between the two groups (Table 3). After SBRT, the left ventricular strain function of patients in the two groups was re-evaluated. The results showed that the GLS in the TMZ group was higher than that in the control group (-11.8 ± 3.7% vs. -10.1 ± 3.4%, P = 0.042). GCS and GRS were also higher in the TMZ group, but the differences were not statistically significant (Table 3 and Fig. 2). In the TMZ group, no significant differences were found in left ventricular myocardial strain indicators, including GLS, GCS and GRS, from after SBRT to baseline. The GLS and GCS did decrease after SBRT from baseline in the control group (Table 3 and Fig. 3)

Table 3

Primary outcomes
	Baseline		post-SBRT		P₁	P₂
	TMZ group (n = 36)	Control group (n = 37)	TMZ group (n = 36)	Control group (n = 37)	P₁	P₂
GLS(%)	-12.1 ± 4.4	-12.0 ± 3.3	-11.8 ± 3.7	-10.1 ± 3.4	0.906	0.042*
GCS(%)	-13.9 ± 6.0	-13.7 ± 3.7	-13.3 ± 5.5	-11.5 ± 3.9	0.832	0.101
GRS(%)	19.5 ± 8.0	19.5 ± 9.0	19.4 ± 11.6	18.3 ± 10.6	0.976	0.662
GLS: global longitudinal strain; GCS: global circumferential strain; GRS: global radial strain; P₁: Baseline date comparison of P-values between TMZ group and control group; P₂: post-SBRT date comparison of P-values between TMZ group and control group.

In this study, early RIHD was defined as a decrease in GLS ≥ 15% from baseline. Eighteen patients in the control group and 11 patients in the TMZ group experienced RIHD (30.6% vs. 48.6%, P = 0.113). The relative risk of RIHD was 1.592 (95% CI 0.880–2.882) between the control group and the TMZ group, and there was no significant difference in the incidence of RIHD between the two groups.

Secondary outcomes

Before pulmonary SBRT, no significant differences were found in cardiac injury markers or echocardiographic indices. When we compared the secondary outcome indicators again 10 weeks after SBRT, there was still no difference between the two groups (Table 4).

Table 4

Secondary outcomes
	Baseline		post-SBRT
	TMZ group (n = 36)	Control group (n = 37)	TMZ group (n = 36)	Control group (n = 37)
Cardiac injury markers
CK, U/L	75.5(59.0, 90.8)	65.0(52.5,88.0)	75.5(56.0,94.8)	62.0(46.0,89.0)
CKMB, U/L	8.5(7.0, 10.0)	8.0(6.0,11.0)	9.0(6.3,11.0)	8.0(7.0,11.0)
TnT, ng/mL	0.009 (0.005, 0.011)	0.008 (0.006, 0.011)	0.008 (0.006,0.011)	0.008 (0.005,0.012)
NT-proBNP, pg/mL	64.5 (33.8, 113.3)	68.0 (22.0, 114.0)	74.5 (31.3,149.3)	68.0 (31.5,162.0)
Echocardiographic indexes
LAD, mm	34.5(29.0,36.0)	33.0(30.5, 35.5)	32.7(31.1,35.0)	32.0(29.9,35.0)
LAA, cm²	18.0(16.0,19.0)	17.0(15.8, 19.0)	17.0(15.0,19.8)	17.0(15.0,18.0)
IVST, mm	8.0(7.2,8.5)	7.8(7.3,8.9)	7.8(7.1,8.2)	8.1(7.2,8.7)
LVEDD, mm	46.2 ± 3.3	45.8 ± 4.0	46.5 ± 3.9	45.7 ± 5.0
LVESD, mm	28.0(27.0,29.8)	27.0(26.0,29.0)	28.0(25.8,30.0)	27.0(25.0,29.5)
LVEF, %	69.0(67.0,71.8)	70.0(68.0,72.0)	69.5(67.0,73.0)	70.0(68.0,72.5)
E/A	0.7(0.7,1.1)	0.8(0.7,1.0)	0.8(0.7,1.0)	0.8(0.6,1.2)
E/Em	6.0(4.3,7.8)	6.0(5.0,8.0)	5.0(5.0,7.0)	6.0(5.0,8.0)
CK: creatine kinase; CKMB: creatine kinase-MB; TnT: troponin T; NT-proBNP: N-terminal pro-B-type natriuretic peptide; LAD: left atrial diameter; LAA: left atrial area; IVST: interventricular septum thickness; LVEDD: left ventricular end-diastolic dimension; LVESD: left ventricular end-systolic dimension; LVEF: left ventricular ejection fraction; E: early diastolic transmitral velocity; Em: early diastolic mitral annular velocity.

Safety and adverse event outcomes

Thirty-five patients in the TMZ group had follow-up data available, and one patient was lost to follow-up due to the impact of COVID-19. They all took TMZ according to the prescribed medication regimen, and no drug-related adverse reactions occurred within 12 weeks.

Sensitivity Analysis

One patient in the TMZ group and one in the control group were lost to follow-up. After those 2 patients were removed, the remaining patients made up the per-protocol set, in which we analysed the sensitivity of TMZ in the prevention and treatment of RIHD. We found that the GLS was higher in the TMZ group than in the control group after SBRT (-11.8 ± 3.8% vs. -10.0 ± 3.4%, P = 0.036) (Fig. 4). GCS and GRS in the TMZ group also showed a trend toward improvement compared with those in the control group, but the difference was not statistically significant (P > 0.05).

The dose of radiation received by the heart is positively correlated with RIHD [11]. With the continuous advancement of radiotherapy technology, the risk of developing RIHD has gradually decreased, but even low-dose radiotherapy can raise the risk of developing RIHD. Only controlling the heart dose cannot completely prevent cardiac damage [12]. Therefore, drug treatment is crucial for the prevention and treatment of RIHD. Our previous study found a significant decrease in GLS after pulmonary SBRT, indicating that SBRT can lead to impaired cardiac systolic function [13].

The mitochondrial DNA of myocardial cells is highly sensitive to radiation and is an important target for myocardial cell damage. In addition, long-term damage to mitochondrial DNA can lead to mitochondrial dysfunction and further disrupt the metabolic homeostasis of myocardial cells [14]. Xu et al. [15] found that after irradiation, the expression of proteins related to energy metabolism in the myocardial tissue of mice significantly increased, mitochondria swelled and vacuolized, and the number of proteins expressed decreased. At the same time, the production of adenosine triphosphate decreased. Regulating energy metabolism may be a potential therapeutic target for RIHD.

TMZ is a commonly used clinical drug for regulating energy metabolism. It improves myocardial energy metabolism efficiency by reducing free fatty acid oxidation, increasing glucose oxidation and protecting against mitochondrial structural and functional abnormalities [16]. TMZ can also improve endothelial function, inhibit oxidative stress [17], reduce intracellular calcium overload, and inhibit inflammatory reactions [18].

Animal experiments have shown that TMZ can regulate the mRNA and protein expression of TNF-α, thereby reducing the cardiac inflammatory response in rats after irradiation [9]. TMZ can also reduce the expression of genes related to cardiomyocyte apoptosis and fibrosis, including CTGF, TGF-β₁, Smad2 and Smad3[10]. Clinical studies have shown that TMZ can reduce the incidence of electrocardiographic abnormalities, oxidative stress, and inflammatory reactions in patients receiving transthoracic radiotherapy [19]. A previous study by our group found that TMZ can exert myocardial-protective effects by inhibiting oxidative stress and myocardial fibrosis [20], but there is still no clinical evidence indicating that TMZ can be used to prevent and treat RIHD.

This randomized controlled trial evaluated the preventive and therapeutic effects of TMZ on RIHD caused by SBRT. We found that GLS in the TMZ group was better than that in the control group, confirming that TMZ has preventive and therapeutic effects on RIHD. The improvement of cardiac function by TMZ has been widely confirmed. A meta-analysis of 17 randomized controlled trials showed that TMZ significantly increased the ejection fraction in patients with heart failure [21]. A randomized controlled study by Donne et al. [22] showed that TMZ may prevent the cardiotoxicity of anthracycline chemotherapy drugs.

There are no good prevention and treatment measures for RIHD in clinical practice. This study adopted a randomized controlled trial design to objectively evaluate the preventive and therapeutic effects of TMZ on RIHD through two-dimensional speckle tracking echocardiography. We found that TMZ has certain preventive and therapeutic value, laying a foundation for large-scale research and providing a new avenue for the exploration of preventive and therapeutic drugs for RIHD.

Limitations

There are some limitations to this study. First, the intervention of TMZ was done at a single centre in a small number of patients, and the randomization was not blinded to the patients, so the results might have some bias. Its preventive and therapeutic effects still need to be verified by numerous large-scale multicentre and hard endpoint clinical studies. Second, the patients were not blinded to the study groups, which in turn might have influenced the evaluation of the efficacy of TMZ.

The randomized controlled intervention trial evaluated the preventive and therapeutic effects of TMZ on RIHD using primary outcome indicators, GLS, and secondary outcome indicators (cardiac injury markers, cardiac structure, and functional indicators). TMZ treatment improved the myocardial strain parameter GLS after pulmonary SBRT, suggesting that TMZ has a certain preventive and therapeutic effect on RIHD.

Study design and participants

This was a single-centre, prospective, randomized, double-blind study conducted in Beijing, China. Patients who were admitted to the Third Hospital of Peking University between May 2021 and April 2022, who were scheduled to receive pulmonary stereotactic body radiotherapy (SBRT), and who met the following inclusion and exclusion criteria were included in this study (Table 5). The follow-up time was 12 weeks (12 ± 1 week). The baseline data were collected within 2 weeks before SBRT in this study. The study protocol of our study was approved by the Medical Science Research Ethics Committee of Peking University Third Hospital, and all patients signed informed consent forms. All methods were performed in accordance with the relevant guidelines and regulations. An internal monitoring committee was used for this trial.

Table 5

Inclusion and exclusion criteria
Inclusion criteria	Exclusion criteria
≥ 18 years old;	Satisfactory echocardiographic images could not be obtained
With indications for radiotherapy	Acute coronary syndrome
Will receive pulmonary SBRT	Heart failure (NYHA III-IV)
The heart is exposed to radiation	Heart valve disease (moderate and severe valve regurgitation and/or stenosis)
Baseline cardiac function was normal (LVEF > 50%)	Arrhythmias requiring intervention
	Congenital heart disease
	Cardiomyopathy
	Pericardial effusion
	pulmonary artery systolic pressure ≥ 50mmHg
	Severe liver and kidney dysfunction
	Autoimmune diseases
	Participate in other clinical studies
Arrhythmias requiring intervention: requiring medication, radiofrequency ablation or pacemaker treatment; Severe liver and kidney dysfunction: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥ 3 times the upper limit of reference value; Creatinine (Cr) > 130mol/L; LVEF: left ventricular ejection fraction.

Randomization and masking

Random grouping was performed using SAS 9.4 software, with a block size of 4. The random grouping result information was sealed and hidden in an opaque envelope. All randomization envelopes were kept by a single investigator who was not involved in the data measurement, entry, or analysis. According to the subjects’ order, the envelopes were sequentially opened, and the corresponding treatment was given based on the randomly assigned information in the envelopes. The echocardiographic measurement personnel, myocardial strain analysis personnel, and radiotherapy planners were blinded to the grouping, but the patients were not. Unblinding was performed after all the experimental data were locked.

Procedures

Patients who met the inclusion/exclusion criteria were randomly assigned to the TMZ group or the control group at a 1:1 ratio. The TMZ group was treated orally with TMZ at a dose of 20 mg/time, 3 times per day, for 12 weeks. After 2 weeks of medication, pulmonary SBRT was performed. The control group received pulmonary SBRT treatment 2 weeks after enrolment and was followed for up to 10 weeks after SBRT.

Outcomes

Ten weeks after SBRT, a dedicated follow-up visit was conducted by an oncologist and a cardiologist. The main outcome indicators were myocardial strain parameters, global longitudinal strain (GLS), global circumferential strain (GCS) and global radial strain (GRS), while the secondary outcome indicators included cardiac injury markers and echocardiography indicators. Drug-related adverse events were evaluated every 4 weeks after starting the drug. The occurrence time, characteristics, severity, duration, treatment measures, and outcomes of various adverse reactions or events during the trial were recorded in detail, and their causal relationships with the use of the drug were judged by the follow-up doctor.

Statistical analysis

Only one study [19] had used TMZ for the treatment of patients with RIHD, but that study did not evaluate the protective effect of TMZ on cardiac function after radiation. Therefore, according to the data in the literature, we used the ST-T change in the electrocardiogram as the occurrence standard for RIHD. The incidence of RIHD in the TMZ group was 25%, and that in the radiotherapy group was 58%. The statistical power was 80%, and the alpha-risk was 5%. The ratio of the TMZ group to the control group was 1:1. Assuming a 10% loss rate, the sample size was 36 for each group.

The data analysis in this study adopted the full analysis set and strictly followed the intention-to-treat principle. Safety analyses were done on the TMZ group, all patients who received at least one dose of TMZ being included in the safety population. Expectation maximization was used to fill in the missing data. The independent-sample t test, chi-squared test, Fisher’s exact test or Mann‒Whiney U test was used for intergroup comparison, as appropriate. The paired-sample t test or Wilcoxon test was used for intragroup comparison. P < 0.05 was considered significant. Statistical analyses were performed with SPSS 22.0.

Ethics approval and consent to participate

This study had been approved by the Medical Science Research Ethics Committee of Peking University Third Hospital (M2021119).

Consent for publication

Not applicable.

Data availability statement

Research data are stored in Peking University Third Hospital and will be available from the corresponding author on request with justification.

Competing interests

The authors declare that they have no competing interests.

Funding

This work was supported by the Peking University Third Hospital [grant numbers BYSYLXHG2020003]

Authors’ contributions

Data was collected by TCL, YXW and HQZ. Statistical analyses were performed by TCL and YXW. Overall activities were coordinated and supervised by MC and DZ. Writing was performed by TCL and DZ. All authors approved the final manuscript.

Acknowledgements

We thank the patients, their families, the laboratory, and research staff who contributed to the trial. Together, we would like to express our gratitude to doctor Liyuan Tao of the Research Center of Clinical Epidemiology, as well as Yang Yu and Zhipeng Liu from the Echocardiogram Room for their assistance in this study. Furthermore, we thank the Peking University Third Hospital’s support for this study.

Data sharing statement

Research data are stored in Peking University Third Hospital and will be shared upon request to the corresponding author.

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No competing interests reported.

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Effects of trimetazidine on cardiac function in patients undergoing pulmonary stereotactic body radiotherapy evaluated by speckle-tracking echocardiography: A randomized, double-blind study

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Abstract

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Introduction

Results

Patient Characteristics

Stereotactic body radiotherapy

Primary and secondary outcomes

Secondary outcomes

Safety and adverse event outcomes

Sensitivity Analysis

Discussion

Limitations

Conclusions

Methods

Study design and participants

Randomization and masking

Procedures

Outcomes

Statistical analysis

Declarations

References

Additional Declarations

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