Evaluation of Myocardial Injury After Anthracycline Chemotherapy in Osteosarcoma Patients Using CMR

using a contrast-enhanced (CE) cardiac magnetic resonance imaging(CMR) which included the measurement of T1 mapping, T2 mapping, T2\* mapping and late gadolinium enhancement(LGE) sequences, as well as LVEF and extracellular volume(ECV) to evaluate the respective changes before and after anthracycline chemotherapy.

Osteosarcoma is the most common primary malignant bone tumor in children and young adults and accounts for 5% of all pediatric malignancies. The long-standing chemotherapy regimen of doxorubicin and cisplatin with or without methotrexate remains a standard treatment of osteosarcoma.But anthracyclines such as doxorubicin have a notorious cardiotoxic side effect, which causes chemotherapy-related cardiac dysfunction(CTRCD). The American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) defines it as a decrease in left ventricular ejection fraction (LVEF) of more than 10% to below the lower limit of normal, which is considered an LVEF of 53%, despite symptoms.

Cardiac magnetic resonance imaging is the gold standard for detection of ventricular volume and function. The parametric mapping techniques provide a non-invasive tool for quantifying tissue alterations in myocardial disease and is capable of in vivo tissue characterization.

In this study, the investigators used a contrast-enhanced (CE) cardiac magnetic resonance imaging(CMR), which included the measurement of T1 mapping, T2 mapping, T2\* mapping and late gadolinium enhancement(LGE) sequences, as well as LVEF and extracellular volume(ECV) to evaluate the respective changes before and after anthracycline chemotherapy.

Study Population:

This prospective study was conducted at the Second Affiliated Hospital, School of Medicine, Zhejiang University. All chemotherapy naive patients whose biopsy results show high grade osteosarcoma were considered. Patients with underlying heart disease, severe hypertension, diabetes mellitus and previous history of gadolinium contrast agent allergy were excluded.Patients were treated with a standard chemotherapy protocol containing anthracyclines.

Study Protocol:

All patients underwent a contrast-enhanced (CE) cardiac magnetic resonance imaging(CMR), including measurement of LVEF, T1mapping, T2mapping, T2\*mapping, ECV, LGE before starting chemotherapy (baseline), after neoadjuvant chemotherapy treatment, at the end of treatment (within 1 month), or whenever required by the clinical situation. These times points corresponded to scheduled oncological controls.

The CMR protocol included a standard segmented cine steady-state free-precession sequence, a T2 gradient spin-echo mapping sequence, a T2\* gradient spin-echo mapping sequence, native and post-contrast T1 mapping sequences, and late gadolinium enhancement (LGE) sequence. The imaging parameters for the standard segmented cine steady-state free-precession sequence were as follows: field of view (FOV) 340 X340 mm², slice thickness 8 mm , repetition time (TR) 34.84ms, echo time (TE) 1.14ms, flip angle 67°, voxel size 1.8 X1.8 mm, and number of excitation. The imaging parameters for the T2-gradient-spin-echo mapping sequence were FOV 340X 340 mm², acquisition voxel size 1.8 X1.8 mm², slice thickness 8 mm, 8 echo times ranging from 6.7 to 53.6ms, and flip angle 70°. The T2\* mapping sequence parameter were FOV 340X340 mm², acquisition voxel size 1.3X1.3mm², slice thickness 8mm, 8 echo times ranging from 2.22 to 17.48 (2.22,4.4,6.58,8.76,10.94,13.12,15.3,17.48), and flip angle 20°. The T1 mapping sequence (Modified Look-Locker Inversion recovery \[MOLLI\]) was acquired before and 10 min after contrast administration. All MOLLI sequences were based on a 5(3)3 scheme using a single shot steady-state free precession readout sequence (TR/TI/TE/flip angle 291.84ms/183ms/1.22ms/35°) with an in-plane acquisition resolution of 1.2 X1.2 mm² and an 8mm slice thickness. LGE imaging was performed 8 min after intravenous administration of 0.2mmol/kg gadopentetate dimeglumine contrast agent using a 3-dimensional inversion-recovery spoiled turbo field echo sequence (TR/TE/flip angle 813.6ms/1.09ms/40). Inversion time was adjusted before acquisition using a look-locker scout sequence with different inversion times to ensure proper nulling of the healthy myocardium signal.

The primary end point of the study was completion of chemotherapy with anthracycline drugs.

The secondary end point was cardiotoxicity. The time of occurrence of cardiotoxicity was recorded. Cardiotoxicity was defined as an LVEF reduction \>10% from baseline, or LVEF \<53%.

The following cardiac events were also considered as secondary end points: cardiac death, acute coronary syndromes, acute pulmonary edema, overt HF, and life-threatening arrhythmias.

Eligibility Criteria:
Inclusion Criteria:

* All chemotherapy naive patients whose biopsy results show high grade osteosarcoma undergoing an anthracycline agent as part of their chemotherapy regimen
* Informed consent has been signed

Exclusion Criteria:

* Strict contraindications to contrast-enhanced cardiac magnetic resonance imaging
* Underlying heart disease:myocardial infarction, heart failure, valvular disease or cardiomyopathy
* Acute or chronic kidney failure