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

The present translational study aimed to verify whether serial ¹⁸F-FDG PET/CT predicts doxorubicin cardiotoxicity. Methods: Fifteen athymic mice were treated intravenously with saline (n = 5) or with 5 or 7.5 mg of doxorubicin per kilogram (n = 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 ¹⁸F-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. Results: In mice, LV MRGlu was 17.9 ± 4.4 nmol × min⁻¹ × g⁻¹ at baseline. Doxorubicin selectively and dose-dependently increased this value in the standard-dose (27.9 ± 9 nmol × min⁻¹ × g⁻¹, P < 0.05 vs. controls) and high-dose subgroups (37.2 ± 7.8 nmol × min⁻¹ × g⁻¹, P < 0.01 vs. controls, P < 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, P < 0.01). Multivariate analysis confirmed the predictive value of baseline LV SUV for subsequent cardiac abnormalities. Conclusion: Doxorubicin dose-dependently increases LV MRGlu, particularly in the presence of low baseline ¹⁸F-FDG uptake. These results imply that low myocardial ¹⁸F-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.