Abstract
Background: Apoptosis plays an important role in anthracycline-induced cardiotoxicity. Apoptosis has been detected with 99mTc labeled Annexin V imaging in rats prior to a decrease in left ventricular (LV) ejection fraction with echocardiography suggesting that annexin scanning may be a sensitive technique for early detection of anthracycline cardiotoxicity. Objectives: To determine the safety and feasibility of 99mTc-rhAnnexin V-128 imaging of apoptosis in the evaluation of possible doxorubicin-induced cardiotoxicity in patients with early stage breast cancer. Methods: Patients with early stage breast cancer (n = 9) undergoing adjuvant doxorubicin chemotherapy at the Ottawa Hospital Cancer clinic were eligible for this study. Annexin imaging, cardiac magnetic resonance imaging and bloodwork for troponin levels , routine hematology and biochemistry was performed at baseline, after the second and fourth cycles of chemotherapy and 12 weeks after the last dose of chemotherapy. Patients underwent planar and SPECT imaging (GE Hawkeye SPECT/CT) at 1 and 2 hours following intravenous injection of ~ 350 MBq of 99mTc-rhAnnexin V-128. Planar images were quantitatively assessed by placing regions of interest on the myocardium, right axilla and lung. Independent sample t-testing was used to compare baseline myocardial uptake, ratios of myocardium/axilla and myocardium/lung uptake at one and two hours between patients with positive troponin levels and those with negative levels. Two-way repeated-measures ANOVA was used with troponin status (positive or negative) as the between-subjects independent variable and time as the within-subjects independent variable. The hypothesis of interest was the two way troponin x time interaction. This study was approved by the Ottawa Hospital Science Network Research Ethics Board and Health Canada. Results: Small but significant troponin rises were seen in 2 of 9 patients. No significant changes in LV ejection fraction or global longitudinal strain measured with cardiac magnetic resonance imaging were observed. No serious adverse events were reported or observed. There were no significant changes in bloodwork related to annexin imaging. At baseline, there were no significant differences in radiotracer uptake between patients with positive vs negative troponin levels as measured with myocardial uptake or myocardium/axilla and myocardium/lung uptake ratios. The ANOVA analysis showed a significant interaction between troponin status and myocardial uptake and both myocardium/axilla and myocardium/lung uptake ratios at 1 hour (p = 0.086 (trend), 0.008 and 0.054, respectively). Similar trends were observed at 2 hours but were not significant. Conclusions: Apoptosis imaging with 99mTc-rh Annexin-V 128 in patients undergoing doxorubicin chemotherapy with early stage breast cancer is safe and feasible. Increased myocardial annexin uptake measured with planar imaging as myocardial uptake and as myocardium/axilla and myocardium/lung uptake ratios was related to abnormal troponin elevations. No significant changes occurred in cardiac LV ejection fraction and global longitudinal strain. Further studies in larger patient groups are necessary to better define the prevalence and time course of annexin uptake in these patients and subsequent relationship to development of LV dysfunction.