Doxorubicin effect on myocardial metabolism as a prerequisite for subsequent development of cardiac toxicity

A translational 18F-FDG PET/CT observation

Matteo Bauckneht, Giulia Ferrarazzo, Francesco Fiz, Silvia Morbelli, Matteo Sarocchi, Fabio Pastorino, Alberto Ghidella, Elena Pomposelli, Maurizio Miglino, Pietro Ameri, Laura Emionite, Flavia Ticconi, Eleonora Arboscello, Ambra Buschiazzo, Elena Augusta Massimelli, Salvatore Fiordoro, Anna Borra, Vanessa Cossu, Annalisa Bozzano, Adalberto Ibatici & 6 others Mirco Ponzoni, Paolo Spallarossa, Andrea Gallamini, Paolo Bruzzi, Gianmario Sambuceti, Cecilia Marini

Research output: Contribution to journalArticle

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Abstract

The present translational study aimed to verify whether serial 18FFDG 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 = = 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 • min21 × g21 at baseline. Doxorubicin selectively and dose-dependently increased this value in the standard-dose (27.9 ± 9 nmol × min21 × g-1, P < 0.05 vs. controls) and high-dose subgroups (37.2 6 7.8 nmol × min21 × 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 dosedependently 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.

Original languageEnglish
Pages (from-to)1638-1645
Number of pages8
JournalJournal of Nuclear Medicine
Volume58
Issue number10
DOIs
Publication statusPublished - Oct 1 2017

Fingerprint

Fluorodeoxyglucose F18
Doxorubicin
Observation
Hodgkin Disease
Glucose
Drug Therapy
Dacarbazine
Vinblastine
Bleomycin
Cardiotoxicity
Telephone
Nude Mice
Echocardiography
Myocardium
Electrocardiography
Multivariate Analysis
Clinical Trials

Keywords

  • Doxorubicin
  • FDG PET/CT
  • Myocardial metabolism

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this

Doxorubicin effect on myocardial metabolism as a prerequisite for subsequent development of cardiac toxicity : A translational 18F-FDG PET/CT observation. / Bauckneht, Matteo; Ferrarazzo, Giulia; Fiz, Francesco; Morbelli, Silvia; Sarocchi, Matteo; Pastorino, Fabio; Ghidella, Alberto; Pomposelli, Elena; Miglino, Maurizio; Ameri, Pietro; Emionite, Laura; Ticconi, Flavia; Arboscello, Eleonora; Buschiazzo, Ambra; Massimelli, Elena Augusta; Fiordoro, Salvatore; Borra, Anna; Cossu, Vanessa; Bozzano, Annalisa; Ibatici, Adalberto; Ponzoni, Mirco; Spallarossa, Paolo; Gallamini, Andrea; Bruzzi, Paolo; Sambuceti, Gianmario; Marini, Cecilia.

In: Journal of Nuclear Medicine, Vol. 58, No. 10, 01.10.2017, p. 1638-1645.

Research output: Contribution to journalArticle

Bauckneht, M, Ferrarazzo, G, Fiz, F, Morbelli, S, Sarocchi, M, Pastorino, F, Ghidella, A, Pomposelli, E, Miglino, M, Ameri, P, Emionite, L, Ticconi, F, Arboscello, E, Buschiazzo, A, Massimelli, EA, Fiordoro, S, Borra, A, Cossu, V, Bozzano, A, Ibatici, A, Ponzoni, M, Spallarossa, P, Gallamini, A, Bruzzi, P, Sambuceti, G & Marini, C 2017, 'Doxorubicin effect on myocardial metabolism as a prerequisite for subsequent development of cardiac toxicity: A translational 18F-FDG PET/CT observation', Journal of Nuclear Medicine, vol. 58, no. 10, pp. 1638-1645. https://doi.org/10.2967/jnumed.117.191122
Bauckneht, Matteo ; Ferrarazzo, Giulia ; Fiz, Francesco ; Morbelli, Silvia ; Sarocchi, Matteo ; Pastorino, Fabio ; Ghidella, Alberto ; Pomposelli, Elena ; Miglino, Maurizio ; Ameri, Pietro ; Emionite, Laura ; Ticconi, Flavia ; Arboscello, Eleonora ; Buschiazzo, Ambra ; Massimelli, Elena Augusta ; Fiordoro, Salvatore ; Borra, Anna ; Cossu, Vanessa ; Bozzano, Annalisa ; Ibatici, Adalberto ; Ponzoni, Mirco ; Spallarossa, Paolo ; Gallamini, Andrea ; Bruzzi, Paolo ; Sambuceti, Gianmario ; Marini, Cecilia. / Doxorubicin effect on myocardial metabolism as a prerequisite for subsequent development of cardiac toxicity : A translational 18F-FDG PET/CT observation. In: Journal of Nuclear Medicine. 2017 ; Vol. 58, No. 10. pp. 1638-1645.
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T1 - Doxorubicin effect on myocardial metabolism as a prerequisite for subsequent development of cardiac toxicity

T2 - A translational 18F-FDG PET/CT observation

AU - Bauckneht, Matteo

AU - Ferrarazzo, Giulia

AU - Fiz, Francesco

AU - Morbelli, Silvia

AU - Sarocchi, Matteo

AU - Pastorino, Fabio

AU - Ghidella, Alberto

AU - Pomposelli, Elena

AU - Miglino, Maurizio

AU - Ameri, Pietro

AU - Emionite, Laura

AU - Ticconi, Flavia

AU - Arboscello, Eleonora

AU - Buschiazzo, Ambra

AU - Massimelli, Elena Augusta

AU - Fiordoro, Salvatore

AU - Borra, Anna

AU - Cossu, Vanessa

AU - Bozzano, Annalisa

AU - Ibatici, Adalberto

AU - Ponzoni, Mirco

AU - Spallarossa, Paolo

AU - Gallamini, Andrea

AU - Bruzzi, Paolo

AU - Sambuceti, Gianmario

AU - Marini, Cecilia

PY - 2017/10/1

Y1 - 2017/10/1

N2 - The present translational study aimed to verify whether serial 18FFDG 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 = = 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 • min21 × g21 at baseline. Doxorubicin selectively and dose-dependently increased this value in the standard-dose (27.9 ± 9 nmol × min21 × g-1, P < 0.05 vs. controls) and high-dose subgroups (37.2 6 7.8 nmol × min21 × 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 dosedependently 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.

AB - The present translational study aimed to verify whether serial 18FFDG 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 = = 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 • min21 × g21 at baseline. Doxorubicin selectively and dose-dependently increased this value in the standard-dose (27.9 ± 9 nmol × min21 × g-1, P < 0.05 vs. controls) and high-dose subgroups (37.2 6 7.8 nmol × min21 × 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 dosedependently 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.

KW - Doxorubicin

KW - FDG PET/CT

KW - Myocardial metabolism

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