As survival continues to improve following treatment for cancer, there is an increasing concern for long-term treatment-related toxicity. In the management of thoracic malignancies, systemic therapy and radiation are associated with cardiotoxicity. Radiation therapy (RT) is an important component of curative treatment in about half of patients with cancer (1). However, thoracic RT may be associated with a significant risk of cardiovascular (CV) toxicity and is of great concern, particularly in breast and lung cancer patients (2, 3). Ischemic heart disease, valvular disease, non-ischemic cardiomyopathy, pericardial disease, arrhythmias, and conduction abnormalities are each potential adverse cardiovascular sequelae of chest radiation (4–7). Despite improvements in RT techniques and modalities that decrease the total radiation dose administered, radiation-induced heart disease (RIHD) remains a common cause of morbidity and mortality among cancer survivors. The impact of cardiotoxicity with current RT techniques on cardiac function, cardiomyocyte inflammation, and necrosis is unknown (8).

The etiology of RIHD is not well-understood (9) although multiple pathophysiologic mechanisms exist for long-term RIHD, including micro- and macrovascular injury, fibrosis, and endothelial cell dysfunction (10, 11). Currently, available biomarkers such as troponin and brain natriuretic peptide have not been validated in predicting the development of RIHD (12–14). These biomarkers are known to play an important role in the prediction of cardiotoxicity in patients receiving cardiotoxic cancer therapy, particularly with sequential anthracycline and trastuzumab therapy (15). Multiple cardiac imaging modalities play important roles in pretreatment risk assessment, early detection of cardiotoxicity, and in the identification of long-term cardiotoxicity after receiving potentially cardiotoxic treatment. Cardiovascular magnetic resonance imaging (CMR) provides an accurate assessment of cardiac volumes, systolic function and can non-invasively characterize myocardial tissue and allow early detection of subclinical cardiac injury (16).

Cardiovascular magnetic resonance utilizes a multiparametric approach for myocardial evaluation. Left ventricular (LV), global longitudinal strain (GLS), and circumferential strain (GCS) by CMR feature tracking is a more sensitive measure of systolic function and can be used to identify sub-clinical LV dysfunction (17). Elevated native T1 values correlate with fibrosis or increased interstitial expansion (18). Native and post-contrast T1 mapping are used to calculate myocardial extracellular volume (ECV) which correlates with extracellular volume fraction and its elevation maybe a result of fibrosis, edema, protein deposition, or other pathologic processes (19). Myocardial edema can be assessed quantitatively with T2 mapping. T1ρ or spin-locking relaxation time is a promising non-contrast sequence that is sensitive to edema and necrosis in the acute setting and scar in chronic myocardial infarction (20). We sought to study the myocardial changes (volume, function, strain, fibrosis/edema) with CMR in patients undergoing RT after chemotherapy.

A total of 18 patients met eligibility criteria and underwent baseline CMR (Figure 1). One patient was excluded due to diagnosis of metastatic disease after enrollment and one patient due to suboptimal baseline imaging. The final cohort included 16 patients of which 11 patients underwent follow-up CMR 6 months after completion of RT.

Of the 16 patients, 10 patients underwent treatment with anthracycline (AC) based chemotherapy and six patients with non-AC based chemotherapy. Five patients received chemotherapy (all were non-AC-based) during radiation. At baseline, when compared to controls, patients who underwent RT had reduced LV GCS at baseline (15.3 ± 2.2% vs. 18.4 ± 2.1%, p = 0.004) and a trend toward lower LV ejection fraction (EF) (56.3 ± 6.6% vs. 59.7 ± 2.8%, p = NS). The T2 and T1ρ values were elevated in these patients compared with controls at baseline (47.9 ± 4.8 ms vs. 45.0 ± 1.5 ms, p = 0.04 and 78.4 ± 5.9 ms vs. 66.9 ± 4.6 ms, p < 0.001). No significant difference in the average T1 values was observed in these patients (1018.4 ± 30.7 ms) compared to the control group (998.0 ± 22.9 ms, p = NS). No significant differences were found in the right ventricle for ventricular volumes, function, and RV longitudinal strain (Table 1).

Eleven of the 16 patients completed follow-up CMR. The mean age was 48.3 ± 18.6 years and 55% were female. Contemporary radiation techniques to minimize radiation to the heart while ensuring full dose to the tumor were used. These include intensity-modulated radiation therapy (IMRT), 3-dimensional conformal RT (3DCRT) in 25 and 44% of the patients, respectively. 3D CRT was exclusively used in the setting of breast cancer and lymphoma. Proton therapy was used in 31% of the patients with either passive scattering (12% of the patients) which produces a broad beam of proton delivery or with active scanning (19% of the patients) which uses several small pencil beams throughout the target volume (Table 2). The average radiation dosage was 45.1 ± 15.7 Gy. The maximum and mean heart dose of this cohort were averaged at 38.2 Gy (range 21.6–69.1 Gy) and 6.45 Gy (range 0.6–30.7 Gy). Of these, seven patients received a mean heart dose of less than 5 Gy, two patients between 5 and 10 Gy and one patient at a dose greater than 10 Gy and one patient at a dose greater than 20 Gy. The maximum and mean dose to the LV of this cohort averaged 26.6 Gy (range 0.2–67.8 Gy) and 5.5 Gy (range 0–31.6 Gy). Patients were then divided into those who received minimal radiation and partial/full radiation. Patients who received minimal radiation are breast cancer patients with radiation primarily to the breast and right side of the heart in the radiation field (Figure 2). The partial/full radiation patients had LV in the radiation field (Figure 3). There was no significant difference in LV or RV EF, LV or RV volumes, strain (LV GLS, LV GCS, and RV GLS), T1, T2, and T1ρ values after RT compared to pre-RT in these two cohorts (Table 3). Two patients had positive LGE which did not change after RT.

There was excellent intra and inter-observer reproducibility with the ICC ranging from 0.892–0.964 for T1, T2, and T1ρ values (Table 4).

We prospectively evaluated for early cardiac toxicity following RT using CMR to identify subclinical functional and structural changes. Prior to chest RT, we have found reduced GCS, elevated T2 and T1ρ values in patients compared to controls indicating myocardial edema and subclinical functional changes after chemotherapy. After RT, a 6-month follow-up CMR showed no change in LV and RV EF, LV and RV GLS, LV GCS, T1/ECV, T2, and T1ρ values.

All patients in this study received chemotherapy prior to RT and 11/17 patients received anthracycline-based chemotherapy. When compared to controls, patients who underwent chemotherapy had elevated T2 and T1ρ values at baseline, which were possibly related to chemotherapy and active inflammation/fibrosis (23). Both T2 and T1ρ mapping are sensitive to myocardial edema with T1ρ also sensitive to fibrotic changes. T1ρ is a novel imaging parameter and has been shown to be elevated in myocardial infarction and hypertrophic cardiomyopathy (20, 24). These findings along with reduced LV GCS indicate the myocardial effect of chemotherapy prior to initiation of RT. The SUCCOUR (Strain Surveillance of Chemotherapy for Improving Cardiovascular Outcomes) trial, an international multicenter prospective randomized controlled trial, showed that changes in echocardiographic GLS in patients undergoing cardiotoxic chemotherapy predict incident LV systolic dysfunction (25). In our study, LV GLS trended toward significance, but LV GCS was more sensitive to detect subclinical LV dysfunction after chemotherapy using CMR. However, neither GCS nor GLS was further reduced in 6 months after RT in our cohort. These strain markers for subclinical functional changes and myocardial tissue characterization showed no significant change in the short-term with RT, but the long-term effect of these changes would need longer studies to elucidate.

A few studies in patients receiving anthracycline-based chemotherapy have shown elevated T1 and ECV which can occur as early as 3 months after initiation of therapy (26–28). However, other studies have shown an acute decrease in T1 values 48 h after anthracycline administration (29). A porcine model of doxorubicin toxicity showed an early increase in T1 values (2 weeks after three doses of doxorubicin) with unchanged T2 and ECV values (30). Takagi et al. (31) prospectively assessed changes in LV volumes, native T1, and ECV in 24 patients with esophageal cancer receiving RT with CMR at baseline, 6-month, and 1.5 years using a 3 Tesla MRI scanner. Their study showed early myocardial changes with elevated native T1 and ECV in the septum at 6-month compared to baseline (1257.0 ± 6.4 ms vs. 1183.0 ± 6.5 ms; 32.0 ± 6.3% vs. 26.0 ± 6.3%; p < 0.01 for both) and LV stroke volume index reduced and more patients had LGE at 1.5 years compared to baseline (36 ± 9 mL/m² vs. 41 ± 11 mL/m²; p = 0.046; 78% [11/14] vs. 7% [1/14]; p < 0.01) (31). The mean radiation dose to the septum and apical lateral wall was 43 ± 4 Gy and 3 ± 4 Gy respectively which is higher compared to our cohort. Patients in our study cohort underwent CMR 6 months post-RT which did not show an elevation in native T1/ECV compared to baseline. This difference might be explained by the newer radiation techniques with lower mean radiation dose to the heart and the lack of esophageal cancer patients who tend to receive higher cardiac doses.

Several other studies utilized LGE/T1 sequences to detect fibrosis post-RT. Ricco et al. (32) studied 28 patients with chest tumors who underwent CMR on average 46.4 months post-RT on a 1.5 Tesla MRI scanner. The average heart dose in this cohort was 50.9 Gy (maximum heart dose) and 8.2 Gy (mean heart dose). LGE was present in 9 (32%) patients and there was no significant difference in cardiac radiation doses between patients who had LGE and those who did not. The average T1 value of the LV septum in this study was 1,009 ms (range 933–1,117 ms), similar to our study. However, patients in this study did not have a baseline CMR, so it is unclear if LGE developed post-RT (32). Another study by Umezawa et al. (33) evaluated 24 esophageal cancer patients who were treated with concurrent radiation therapy and found that 50% of the patients had LGE at a median time of 23.5 months to CMR after completion of RT. The LGE was present only within the segments of 40 Gy or 60 Gy isodose distribution (33). Another study by Tuohinen et al. (34) in 20 left breast cancer patients on a 3 Tesla MRI scanner showed elevated T1 values of 6 years after RT within the inferoseptal walls of the LV with mean heart dose being a predictor of elevated T1 values. All these studies examined the cardiac effects of RT later than our study.

The time to development of fibrosis with RT is not well-known but based on previous studies and our current study, it does not seem to develop until after 6 months of radiation therapy and is heart-dose dependent. Additional tissue characterization markers such as T2 and T1ρ may indicate ongoing myocardial edema that was a consequence of chemotherapy, but the long-term implications of these findings will need to be studied in the future.

Our study has several limitations. First, our sample size is small with a few different types of cancers/chemotherapy regimens and radiation fields. Second, patients did not have baseline CMR prior to chemotherapy. The mean cardiac dose in our cohort is low considering that less than 5% of lung cancer patients have mean cardiac doses below 10 Gy. To further study myocardial tissue changes in RT, a larger population study is needed.

Six-month follow-up CMR in patients undergoing chest radiation therapy showed no change in LV and RV EF, LV and RV GLS, LV GCS, LGE, T1/ECV, T2, and T1ρ values. Prior to chest RT, we found reduced GCS, and elevated T2 and T1ρ values in patients after chemotherapy as compared to controls. Contemporary chest radiation with a low heart dose may not have short-term effects on the heart although future studies are needed to confirm these findings.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by IRB at University of Pennsylvania. The patients/participants provided their written informed consent to participate in this study.

All authors participated in the writing and/or final review and approval of this manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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