Discovery of novel imaging biomarkers for cardiotoxicity in a prospective longitudinal study of cancer patients receiving anthracyclines and chest radiotherapy

Abstract

Background/Introduction: Cancer treatments with anthracyclines (AC) or chest radiotherapy (RT) are associated with cardiotoxicity. However, there is a lack of prospective mechanistic studies to determine the acute and long-term effects of therapy on the heart. Purpose(s): To understand the structural, functional and molecular changes that may occur within 1 year of AC and RT, and investigate their association with cardiac radiation doses. Method(s): In a single centre prospective study, patients with mediastinal lymphoma, oesophageal or lung cancer had simultaneous cardiac 18F-FDG PET/MRI scans, serum biomarkers and 12-lead ECGs taken at these timepoints: baseline, 2 weeks post AC (lymphoma only), 2 weeks post RT, and 6 months (m) post RT. Cardiac MRI assessed biventricular volumes and ejection fraction (EF%), global strain, native myocardial T1, T2 and late gadolinium enhancement (LGE). 18F-FDG PET was used to assess cardiac inflammation visually and quantitatively by obtaining segmental standardized uptake values (SUV) in the myocardium. Serum biomarkers included Troponin I and T and NT-proBNP. The data was analysed using mixed-effects models and Spearman's Rank Correlation. Patient advocates contributed to the study design and evaluation. Result(s): 24 patients (11 females) were recruited between Nov 21 - Jun 23, mean age 57y (23-80). The mean AC dose for 8 lymphoma patients was 244 mg/m2 and mean RT cardiac doses were 11.1 Gy, 9.3 Gy and 8.0 Gy for whole heart (WH), left ventricle (LV) and right ventricle (RV), respectively. We observed a significant reduction in both LV and RV EF% in the post AC and RT scans. The LV recovered by 6m but the RV EF % remained reduced (Table 1). Notably, there was significant correlation between cardiac radiation doses and EF% drop, with the most significant between WH and RVEF% drop (rho=0.70, p=0.01). Global strain increased significantly at all timepoints. In 6 patients, who received >10Gy WH dose, new abnormal focal 18F-FDG uptake was observed in the basal LV myocardial segments in the 6m post RT scans (Figure 1), with SUV increased by an average of 4.2 from baseline confirming the visual findings. Heart rate was significantly increased post-RT and Troponin I and T were significantly elevated at both post AC and RT timepoints and all recovered at 6m. LGE, T1, T2, and NT-proBNP did not change significantly from baseline. Conclusion(s): To our knowledge, this is the first study to report a significant reduction in RV systolic function immediately following AC and RT, which persists at 6m post RT. The reduction in RVEF% was associated to radiation doses. Abnormal myocardial 18F-FDG uptake was seen in the basal regions that received the highest RT doses suggesting an acute inflammatory component to radiation-related cardiac dysfunction that manifests months after treatment. Both may be useful imaging biomarkers of cardiotoxicity for initiation of preventative cardio-oncology follow up.