Quantitative assessment of early changes in myocardial extracellular volume during postoperative adjuvant chemotherapy in patients with breast cancer via dual-layer spectral detector computed tomography: a cohort study

Introduction

With the diversification of anticancer treatment regimens, the survival time of patients with breast cancer has been extended, and the survival rate has increased. Cancer therapy-related cardiac dysfunction caused by anticancer treatments has become a common cause of death among cancer survivors (1-4), severely impacting patient prognosis and quality of life. Therefore, the early detection and monitoring of the cardiotoxicity induced by anticancer agents are essential.

Research suggests that chemotherapy-induced cardiotoxicity is a process that begins with subclinical myocardial damage, leads to an asymptomatic decline in left ventricular ejection fraction (LVEF), and finally progresses to symptomatic heart failure (5). As the most commonly used diagnostic and monitoring indicator, LVEF measured by ultrasound cardiography (UCG) has poor repeatability and is not sufficiently sensitive for the monitoring of subclinical myocardial injury (6,7). Myocardial extracellular volume (ECV) may have the potential to quantify chemotherapy-induced cardiotoxicity, in which acute myocardial edema or subsequent fibrosis due to cardiotoxicity can increase the ECV (8,9). ECV measured by cardiac magnetic resonance (CMR) has recently been developed for quantifying cardiotoxicity caused by anticancer drugs, as recommended in many guidelines (10,11). Computed tomography (CT)-derived ECV correlates well with CMR-derived ECV and histology (12-14). Compared with CMR, cardiac computed tomography (CCT) by dual-layer spectral detector CT, as a new technology for quantifying ECV, can simultaneously evaluate cardiac function and myocardial ECV; this technique is faster, easier to implement, and has particular advantages for patients with contraindications to magnetic resonance imaging (MRI) (15).

Only a few studies have been conducted on CT-derived ECVs for detecting cardiotoxicity, most of which used chest enhanced scanning (16-19) and lacked electrocardiogram-gated scanning, resulting in possible motion artifacts and high intraindividual variability. Only Egashira et al. (20) used cardiac CT scanning to analyze late-phase cardiotoxicity in patients with breast cancer. The cardiotoxicity assessed by CT-derived ECV in the early phase after chemotherapy remains to be defined, and are no reports on CT-derived ECV myocardial segmental analysis or on the correlation between ECV measured by CT and cardiac function parameters.

Anthracycline-based chemotherapy is the mainstay of breast cancer treatment, but it involves dose-dependent cardiotoxic side effects. Therefore, our primary objectives in this study were to quantify the changes in myocardial ECV on CCT and cardiac function parameters by CCT and UCG in the early stage of chemotherapy (with epirubicin) in patients with breast cancer. We further analyzed the correlations between the changes in cardiac function parameters and the changes in ECV. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-777/rc).

Methods

Study participants

Adult women with stage I to III breast cancer who were scheduled to undergo postoperative adjuvant epirubicin-containing chemotherapy (Table S1) were prospectively recruited from January 12, 2022, to November 2, 2023 from Fudan University Shanghai Cancer Center. CCT, two-dimensional (2DE) UCG performed on a Vivid E90 device (GE HealthCare, Chicago, IL, USA), serum biomarker measurements, and electrocardiography were performed both before and 3 months after treatment. The exclusion criteria were as follows: (I) general contraindications to the administration of iodinated contrast agents; (II) a life expectancy of less than 24 months; (III) prior exposure to chemotherapy or radiotherapy; (IV) current or prior congenital heart disease, myocardial infarction, or heart failure; (V) absence of 3-month follow-up or incomplete data (lacking data for UCG, serum biomarkers, or CCT at baseline or at 3 months); (VI) a change in antitumor treatment plans or discontinued treatment; and (VII) poor image quality. To reduce selection bias, clinicians screened patients strictly according to preset inclusion and exclusion criteria to ensure sample consistency; in addition, the purpose of the study was explained in full to patients through popular science videos to improve the participation rate and understanding of patients. To reduce observer bias, all examinations and parameter measurements were double-blinded. In order to reduce loss of access bias, patients were regularly followed up by dedicated staff.

This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the Ethics Committee of Fudan University Shanghai Cancer Center (No. 2111245-25; approved on November 30th, 2021). Written informed consent was obtained from all participants in the study.

CCT acquisition protocols

All images were acquired with the patient in the supine position with a dual-layer spectral detector CT (IQon; Philips Healthcare, Best, the Netherlands). The contrast agent used was iodinated (320 mg/mL iodine; Jiangsu Hengrui Pharmaceuticals Co., Ltd., Lianyungang, China). The CCT protocol involved a coronary CT angiography (CCTA) scan and a delayed phase of 7 minutes after injection. Details of the CCT acquisition are summarized in Appendix 1.

CCT data analysis

All images were reconstructed via a dedicated workstation (IntelliSpace Portal 10.0, Philips Healthcare). In the CCTA images, cardiac parameters were automatically analyzed by the workstation. The spectral-based image data of the delayed phase were postprocessed to generate a myocardial ECV map (14), and the average ECV was calculated (Figure 1A,1B) (21). The global ECV was derived from an average of 17 myocardial segments (22,23). To obtain the iodine value of the myocardium, six regions of interest (ROIs) were drawn in the middle of the left ventricular short axis at the systolic phase. To obtain the iodine value of the blood pool, a ROI was placed in the left ventricular cavity at the same level as the myocardial ROIs. The ECV map was calculated with the following formula (12,24):

ECV=(1−HCT)×IodineconcentrationinthemyocardiumIodineconcentrationintheblood[1]

Figure 1 ROI placement in a 28-year-old female patient. (A) ECV map at baseline. (B) ECV map at the 3-month follow-up. In the middle part of the left ventricular short axis, six ROIs were drawn on the ECV map, including the midinferoseptal, midanteroseptal, midanterior, midanterolateral, midinferolateral, and midinferior regions. The midaverage ECV increased from baseline to 3 months (25.3% vs. 28.3%). ROI, region of interest; ECV, extracellular volume.

where HCT is the hematocrit level. The iodine concentration was measured on iodine images in milligrams per milliliter (mg/mL).

All ventricular volumes and masses were normalized to body surface area (BSA) as calculated using the Mosteller formula (25).

Definition of cancer therapy-related cardiac dysfunction

Symptomatic or asymptomatic cancer therapy-related cardiac dysfunction was defined based on the 2022 European Society of Cardiology (ESC) guidelines (26).

Statistical analysis

Statistical analysis was performed with SPSS 26 (IBM Corporation, Armonk, NY, USA) software. The Shapiro-Wilk test was used to evaluate the normality of the data. Variables with a normal distribution are expressed as the mean ± standard deviation (SD), whereas nonnormally distributed variables are expressed as the median and 25th and 75th percentiles. Categorical variables are expressed as numbers and percentages. The paired t-test or Wilcoxon signed-rank test was used to compare the differences in variables (baseline vs. 3 months). Significant differences were assessed via analysis of variance followed by the Fisher least significant difference test for multiple comparisons. Bivariate correlation was assessed with Pearson method or Spearman method. A P value less than 0.05 was considered to indicate a significant difference.

Based on a previous literature (16), we estimated that a minimum of 25 patients was required to ensure the robustness of our statistical analysis, with an 80% power and 5% significance.

Results

Study participants

Initially, 96 patients were included, among whom 56 were excluded due to contraindications to iodinated contrast agents (n=2), lack of follow-up (n=38), or incomplete data for analysis (n=16). Therefore, 40 patients remained for enrollment in this study (Figure 2). The baseline characteristics and cancer treatment details of the 40 patients (age 47.5±10.8 years) who completed the study are summarized in Table 1. The median time of CCT between baseline and the 3-month follow-up was 98 (range, 72–134) days.

Figure 2 Flowchart of patient inclusion. Ninety-six patients with breast cancer were recruited, and 40 patients remained after the application of the exclusion criteria.

Changes in UCG and electrocardiography parameters

LVEF on UCG (UCG-LVEF) and left ventricular fractional shortening on UCG (UCG-LVFS) did not significantly change between baseline and the 3-month follow-up. After normalization to BSA, the parameters measured by UCG, including left ventricular end-systolic volume/BSA ratio (UCG-LVESV indexed), left ventricular end-diastolic volume/BSA ratio (UCG-LVEDV indexed), left ventricular stroke volume/BSA ratio (UCG-LVSV indexed), and cardiac output/BSA ratio (UCG-CO indexed), showed no significant changes. Among the diastolic function parameters, only the mean mitral annular peak early diastolic velocity (e') significantly decreased (P=0.01). Early peak diastolic mitral inflow velocity (E), late peak diastolic mitral inflow velocity (A), the E/A ratio, mean mitral annular peak late diastolic velocity (a'), the e'/a' ratio, and the E/e' ratio did not significantly change between baseline and 3 months (Table 2). According to electrocardiography, new sinus tachycardia occurred in four patients and one patient developed a new grade I atrioventricular block at the 3-month follow-up.

Changes in cardiac function parameters on CCT

There were no significant changes in LVEF CCT (CCT-LVEF). Heart rate increased over the 3 months of follow-up (P<0.01). When normalized to BSA, CO on CCT/BSA ratio (CCT-CO indexed) (P=0.01) and left ventricular late (active) filling volume/BSA ratio (LVLFV indexed) (P<0.01) were significantly increased at the 3-month follow-up, while left ventricular early (passive) filling volume/BSA ratio (LVEFV indexed) (P=0.01) and the ratio of LVEFV to LVLFV (LVEFV/LVLFV) (P<0.01) significantly decreased on CCT. LVESV/BSA ratio (CCT-LVESV indexed), LVEDV/BSA ratio (CCT-LVEDV indexed), LVSV/BSA ratio (CCT-LVSV indexed), left ventricular mass index (LVMI), left ventricular regurgitation volume/BSA ratio (LVRV indexed), and left ventricular regurgitation fraction index (LVRFI) on CCT did not change between baseline and the 3-month follow-up (Table 3).

Changes in ECV on CCT

As detailed in Table 4, the midventricular and global ECVs were elevated. From baseline to 3-month follow-up, these increases were significant for the midanterior ECV (24.0%±4.5% vs. 25.6%±3.1%; P=0.04), midaverage ECV (25.6%±2.5% vs. 27.0%±2.9%; P=0.01), and global ECV (25.4%±2.4 vs. 27.3%±2.7%; P<0.01). The midinferoseptal ECV, midanteroseptal ECV, midanterolateral ECV, midinferolateral ECV, and midinferior ECV were increased at 3 months although these changes did not reach statistical significance (P>0.05). There were no significant differences in the changes in the ECVs between the six myocardial segments.

Changes in serum biomarkers

The levels of HCT, creatine kinase MB (CK-MB), and high-density lipoprotein cholesterol (HDL-C) decreased significantly from baseline to the 3-month follow-up (P<0.01); C-reactive protein (CRP), glucose (GLU), and triglyceride (TG) levels increased significantly (P<0.05); and the levels of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP), high-sensitivity cardiac troponin T (hs-cTnT), myohemoglobin (MYO), cholesterol (CHOL), and low-density lipoprotein cholesterol (LDL-C) did not change significantly (Table S2).

Cancer therapy-related cardiac dysfunction

Cancer therapy-related cardiac dysfunction occurred in two patients at the 3-month follow-up. One patient had a new NT-pro-BNP abnormality, and NT-pro-BNP was significantly elevated in one patient at the 3-month follow-up.

Concurrent association between changes in UCG and CCT parameters and myocardial ECV changes

Changes in the UCG parameters and CCT-LVEF did not correlate with any of the changes in the ECVs between baseline and the 3-month follow-up. The changes in CCT-LVEDV indexed were moderately correlated with the changes in the midanteroseptal ECV (r=0.43; P=0.006), midaverage ECV (r=0.45; P=0.004), and global ECV (r=0.52; P<0.001) (Figure 3A-3C). Changes in CCT-LVSV indexed were correlated with the changes in the midinferoseptal ECV (r=0.51; P<0.001), midaverage ECV (r=0.49; P=0.001), and global ECV (r=0.56; P<0.001) (Figure 3D-3F). Changes in CCT-CO indexed also correlated with the changes in the midinferoseptal ECV (r=0.62; P<0.001), midinferolateral ECV (r=0.41; P=0.008), midaverage ECV (r=0.48; P=0.002), and global ECV (r=0.40; P=0.010) (Figure 3G-3J). The changes in LVEFV indexed was correlated with the changes in the global ECV (r=0.41; P=0.009) (Figure 3K).

Figure 3 Correlation between changes in cardiac function parameters and ECVs on cardiac computed tomography. ∆, the difference between the third month value and the baseline value (3 months-baseline); ECV, extracellular volume fraction; CCT, cardiac computed tomography; LVEDV indexed, left ventricular end-diastolic volume/body surface area (BSA) ratio; LVSV indexed, left ventricular stroke volume/BSA ratio; CO indexed, cardiac output/BSA ratio; LVEFV indexed, left ventricular early (passive) filling volume/BSA ratio.

Discussion

Our study used CCT scans to evaluate myocardial tissue changes in a population of 40 patients with early-stage breast cancer who were undergoing chemotherapy. We observed a significant increase in global ECV in the early stage of chemotherapy, which was correlated with changes in CCT-LVEDV indexed, CCT-LVSV indexed, CCT-CO indexed, and LVEFV indexed. In this study, the ECVs of six myocardial segments had similar degrees of ECV elevation in the early stages of chemotherapy, indicating that the impact of chemotherapy on myocardial tissue is consistent across different regions of the heart.

Although UCG-LVEF is a well-established measure used in clinical practice and has been incorporated within the cancer therapy-related cardiac dysfunction definition, there was no significant decrease in UCG-LVEF or CCT-LVEF during the early stage of chemotherapy in our study. This finding is consistent with a previous study (18) and suggests that myocardial injury in the early stages of treatment may not be sufficiently severe to induce a decline in left ventricular systolic function. There were significant reductions in LVEFV indexed, LVEFV/LVLFV ratio, and e' and an increase in LVLFV indexed at the 3-month follow-up. These parameters reflect changes in cardiac diastolic function earlier than the changes in LVEF in the early stage of chemotherapy. Our findings are consistent with those of Nagiub et al.’s (27) study on doxorubicin, where decreases in e' were observed earlier than were the changes in LVEF. Furthermore, abnormal and worsening diastolic dysfunction has been associated with a risk of later systolic dysfunction (28). However, further research is needed to determine whether changes in diastolic function early after chemotherapy are associated with future cancer therapy-related cardiac dysfunction.

In patients with cancer, heart rate has been independently associated with all-cause mortality (29) and reported to be a prognostic factor (30) and significantly increased after anthracycline chemotherapy (31). An increase in heart rate has been independently associated with a subsequent decrease in LVEF (32). Similar to previous studies (31,32), we found in our study that heart rate significantly increased from 75.2±11.5 to 81.7±12.3 bpm 3 months after anthracycline chemotherapy (P<0.01). The effect of heart rate-lowering therapy in the early antitumor period on lowering the rate of cardiac adverse events is worth exploring.

In our study, the global ECV increased significantly at the 3-month follow-up, earlier than the change in LVEF, which is line with other research (12). Tu et al. (18) similarly reported a significant change in ECV 3 months after the initiation of treatment, whereas there were no significant changes in LVEF. Hong et al. (33) also found that ECV changed significantly earlier than did the observed changes in LVEF, suggesting that ECV changes are more sensitive and have higher diagnostic value than does LVEF in monitoring early anthracycline-induced cardiotoxicity. ECV might reflect subclinical myocardial injury induced by anthracycline cardiotoxicity before reduced LVEF during early chemotherapy. Our results indicate that ECV can assess early myocardial injury changes with preserved LVEF. Additionally, studies have demonstrated a correlation between ECV and left ventricular diastolic function (34-37). Both myocardial edema and fibrosis, as quantified by ECV, contribute to left ventricular diastolic dysfunction by increasing myocardial stiffness and reducing left ventricular compliance (35). Consequently, changes in ECV are expected to precede the onset of left ventricular diastolic dysfunction, enabling ECV to identify potential cardiotoxicity at an earlier stage. Notably, ECV can still increase despite the administration of dexrazoxane, suggesting that other cardioprotective strategies may be needed. Although changes in ECVs did not correlate with LVEF in our study, they were moderately correlated with partial function parameter. These findings underscore the potential of ECV as an early marker of chemotherapy-induced cardiotoxicity.

UCG is likely to remain the core method for monitoring patients receiving potentially cardiotoxic cancer therapy given its accessibility and extent of information provided. A decrease from baseline in global longitudinal strain (GLS) is used to detect subclinical cardiotoxicity (7). A prospective study reported that declines in GLS can occur in the absence of significant changes in LVEF and can then predict subsequent LV dysfunction (38). GLS monitoring is recommended by the major guidelines despite a lack of trial data supporting a clinically useful benefit, and a number of factors limit the practical utilization of GLS in the real-world oncology setting (39). Therefore, we recommend echocardiographic monitoring including GLS in all patients receiving potentially cardiotoxic cancer therapy (39).

CMR can detect subtle changes that predate clinical symptoms from cancer therapy-related cardiac dysfunction. Anthracyclines first cause an increase in myocardial edema followed by interstitial fibrosis (40); the former can be detected and quantified via T2 mapping, while the latter can be detected via ECV. GLS can also be assessed using CMR (41). However, the limitations of CMR in patients, such as claustrophobia and the risks associated with ferromagnetic devices, need to be considered. Longer imaging times may also be more difficult to endure for some patients. Therefore, CMR may be more suitable for further examination in cases of echocardiography or CCT abnormalities.

In contrast to CMR, CCT provides a more widely available, less expensive, and faster method of ECV quantification and allows for ECV calculation in patients with contraindications to MRI (23). Myocardial ECV quantification with CCT strongly correlates with ECV derived from MRI (23,42). The global ECV in our study (baseline: 25.4%±2.4%; 3 months: 27.3%±2.7%) is nearly consistent with that obtained with CMR reported by Thavendiranathan et al. (42) (baseline: 25.3%±2.4%; 53 days: 26.7%±2.7%). It is difficult to convince cancer patients without cardiovascular disease to undergo multiple CMR examinations. If patients are scheduled to undergo chest CT examination regularly before and after treatment, it is easier to add a late enhancement scan (for dual energy acquisitions) to a chest CT scan to acquire ECV as the incremental information (23). This can improve the feasibility and efficiency of the examination and the compliance of the patient. CCT one-stop examination (addition of a late enhancement scan) can simultaneously monitor coronary artery conditions and myocardial ECV changes. A recent study found that coronary artery stenosis and CT fractional flow reserve may serve as imaging markers for predicting cancer therapy-related cardiac dysfunction and recommended the evaluation of coronary parameters in patients (22). Therefore, CCT examination can be regarded as a critical supplement, especially for patients with suspected or preexisting coronary artery disease.

Limitations

Our study involved several limitations which should be discussed. First, the small sample size, mostly a result of the loss to follow-up (38/56 patients), reduced the statistical power of our analysis. Second, GLS values were not recorded on UCG. Third, as we employed longitudinal observation, the observation time was relatively short. Finally, we included cancer patients with preexisting cardiovascular disease, which reflects the real-world situation of this patient population.

Conclusions

During the early phase after adjuvant chemotherapy, the myocardial ECVs from CCT scans increased significantly before LVEF decreased significantly. The increases in ECV were not correlated with LVEF. The changes in myocardial ECVs were moderately correlated with cardiac function parameters. An early increase in ECV may indicate cardiotoxicity associated with antitumor therapy. It remains to be further determined how certain imaging modalities (UCG, CCT, and CMR) can be integrated into the detection of subclinical cancer therapy-related cardiac dysfunction.

Acknowledgments

We would like to thank nurse Beiyun Xu and Dr. Xiyu Liu for their clinical support and the Philips engineer Ke Chen for his support of the research.

Funding: This work was supported by the Key Project of National Natural Science Foundation of China (No. NSFC82430061), the Special Research Fund for Clinical Studies of Innovative Drugs after Market Launch (No. WKZX2024CX103301), and the Shanghai Pudong Science and Technology Development Fund for Livelihood Scientific Research (No. PKJ2024-Y55).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-777/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-777/coif). W.D. and Y.W. are full-time employees of Clinical & Technical Support Department, Philips Healthcare, during the conduct of the study; and they receive consulting fees from AMCA. The other authors have no conflicts of interest to declare.

Ethics Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the Ethics Committee of Fudan University Shanghai Cancer Center. Informed consent was obtained from all individual participants (No. 2111245-25; approved on November 30th, 2021).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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