Doxorubicin Effect on Myocardial Metabolism as a Prerequisite for Subsequent Development of Cardiac Toxicity: A Translational ¹⁸F-FDG PET/CT Observation

Abstract

The present translational study aimed to verify whether serial F-FDG PET/CT predicts doxorubicin cardiotoxicity. Fifteen athymic mice were treated intravenously with saline ( = 5) or with 5 or 7.5 mg of doxorubicin per kilogram ( = 5 each) and underwent dynamic small-animal PET beforehand and afterward to estimate left ventricular (LV) metabolic rate of glucose (MRGlu). Thereafter, we retrospectively identified 69 patients who had been successfully treated with a regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine for Hodgkin disease (HD) and had undergone 4 consecutive F-FDG PET/CT scans. Volumes of interest were drawn on LV myocardium to quantify mean SUV. All patients were subsequently interviewed by telephone (median follow-up, 30 mo); 36 of them agreed to undergo electrocardiography and transthoracic echocardiography. In mice, LV MRGlu was 17.9 ± 4.4 nmol × min × g at baseline. Doxorubicin selectively and dose-dependently increased this value in the standard-dose (27.9 ± 9 nmol × min × g, < 0.05 vs. controls) and high-dose subgroups (37.2 ± 7.8 nmol × min × g, < 0.01 vs. controls, < 0.05 vs. standard-dose). In HD patients, LV SUV showed a progressive increase during doxorubicin treatment that persisted at follow-up. New-onset cardiac abnormalities appeared in 11 of 36 patients (31%). In these subjects, pretherapy LV SUV was markedly lower with respect to the remaining patients (1.53 ± 0.9 vs. 3.34 ± 2.54, respectively, < 0.01). Multivariate analysis confirmed the predictive value of baseline LV SUV for subsequent cardiac abnormalities. Doxorubicin dose-dependently increases LV MRGlu, particularly in the presence of low baselineF-FDG uptake. These results imply that low myocardial F-FDG uptake before the initiation of doxorubicin chemotherapy in HD patients may predict the development of chemotherapy-induced cardiotoxicity, suggesting that prospective clinical trials are warranted to test this hypothesis.

Relationship between Changes in Myocardial F-18 Fluorodeoxyglucose Uptake and Radiation Dose after Adjuvant Three-Dimensional Conformal Radiotherapy in Patients with Breast Cancer

“…Cardiotoxic chemotherapeutic agents such as anthracycline and trastuzumab are also known to induce increase of myocardial FDG uptake on post-chemotherapy PET/CT in patients with breast cancer and lymphoma [32,36]. In the present study, the myocardial-to-blood pool uptake ratios on PET2 showed higher values than those on PET1 both in patients with left and with right breast cancer.…”

Evidence for a cardiac metabolic switch in patients with Hodgkin's lymphoma

“…Interestingly, these findings were not explained by differences in serum glucose levels or prior chemotherapy, which were in turn associated with a significant decrease in cardiac FDG uptake. 15,16 This increase was associated with a decrease in left ventricular function. Of note, 'metabolic remodelling' and substrate utilization characterize the transition to heart failure.…”

“…3 In line with findings on heart failure, two studies analysing the effects of anthracyclines on FDG uptake in a total of 113 Hodgkin's lymphoma patients found a gradual increase in FDG uptake over time while on anthracycline treatment. 15,16 This increase was associated with a decrease in left ventricular function. 15 Furthermore, a low left ventricular FDG uptake before doxorubicin treatment was associated with the development of chemotherapy-induced cardiotoxicity.…”

“…Of note, 'metabolic remodelling' and substrate utilization characterize the transition to heart failure. 16 The reason why a low cardiac left ventricular FDG uptake at baseline is associated with the development of chemotherapy-induced cardiotoxicity is yet not quite understood. 3 In line with findings on heart failure, two studies analysing the effects of anthracyclines on FDG uptake in a total of 113 Hodgkin's lymphoma patients found a gradual increase in FDG uptake over time while on anthracycline treatment.…”

“…15 Furthermore, a low left ventricular FDG uptake before doxorubicin treatment was associated with the development of chemotherapy-induced cardiotoxicity. 16 The reason why a low cardiac left ventricular FDG uptake at baseline is associated with the development of chemotherapy-induced cardiotoxicity is yet not quite understood.…”