ABSTRACT

BACKGROUND: Lifetime cumulative doses of conventional doxorubicin (>450 mg/m2) are associated with dose-dependent cardiotoxicity. In sarcoma and breast cancer, conventional doxorubicin is often utilized in the adjuvant setting, whereas pegylated liposomal doxorubicin (PLD) is typically reserved for recurrent and metastatic disease. PLD is believed to be associated with reduced cardiotoxicity compared to conventional doxorubicin. Limited data exists evaluating the cardiotoxicity associated with PLD treatment after conventional doxorubicin, especially when doxorubicin lifetime doses approach the established cumulative total lifetime dose of 450-550 mg/m2. This study aims to further qualify the cardiac safety of PLD use in patients who have had prior exposure to conventional doxorubicin.

METHODS: This was a single-center, observational, retrospective cohort study conducted in patients ≥18 years with sarcoma or breast cancer who were exposed to conventional doxorubicin from an earlier line of treatment before PLD between January 2010 to May 2022. Patients were evaluated for the presence of cardiac toxicity at any point in their treatment course. Cardiac toxicity was defined as ≥ 10% decrease in left ventricle ejection fraction (LVEF) or a new diagnosis of heart failure within six months after PLD cessation. The time interval between the last conventional doxorubicin exposure and PLD initiation and the time interval between PLD initiation and LVEF monitoring were also analyzed.

RESULTS: 494 patients were screened, and 50 met inclusion criteria: eight with sarcoma and 42 with breast cancer. The median lifetime cumulative conventional doxorubicin dose in patients with sarcoma was 450 mg/m2 with a maximum dose of 825 mg/m2 and 240 mg/m2 with a maximum dose of 300 mg/m2 in breast cancer patients. The median lifetime cumulative PLD dose was 105 mg/m2 (range: 35-150 mg/m2) in the sarcoma group and 105 mg/m2 (range: 35-510 mg/m2) in the breast cancer group. A decrease of ≥ 10% in LVEF was not observed in the sarcoma group. Patients with breast cancer had available LVEF data on PLD, and three of these patients experienced ≥ 10% in LVEF drop, with one of these patients diagnosed with heart failure. The average cumulative dose of PLD administered in patients with > 10% decrease in LVEF was 177 mg/m2 and had an average of 3.5 cycles. Five sarcoma patients initiated PLD treatment within two years after conventional doxorubicin exposure, while most breast patients initiated PLD treatment at least 10 years following conventional doxorubicin exposure. The average time from PLD initiation to first and second available LVEF monitoring was one and five months in the sarcoma group and three and eight months in the breast cancer group, respectively.

CONCLUSION: PLD administration in patients with prior exposure to conventional doxorubicin appears to be safe, with limited cardiotoxicity in patients with sarcoma and breast cancer. Future research is needed to determine if and how often routine cardiac monitoring is needed for patients on PLD without existing cardiac risk.

PMID:37809186 | PMC:PMC10559758 | DOI:10.7759/cureus.44837

20:18

PubMed articles on: Cardio-Oncology

Angiotensin IV ameliorates doxorubicin-induced cardiotoxicity by increasing glutathione peroxidase 4 and alleviating ferroptosis

Toxicol Appl Pharmacol. 2023 Oct 12;479:116713. doi: 10.1016/j.taap.2023.116713. Online ahead of print.

ABSTRACT

BACKGROUND: Doxorubicin (DOX)-induced cardiotoxicity is an important cause of poor prognosis in cancer patients treated with DOX. Angiotensin IV (Ang IV) has multiple protective effects against cardiovascular diseases, including diabetic cardiomyopathy and myocardial infarction, but its role in DOX-induced cardiotoxicity is currently unclear. In this study, we investigated the effects of Ang IV on DOX-induced cardiotoxicity.

METHODS: The viability of primary cardiomyocytes was measured by Cell Counting Kit-8 assays and Hoechst 33342/propidium iodide staining in vitro. ELISAs (serum cTnT and CK-MB) and echocardiography were performed to assess myocardial injury and cardiac function in vivo. Phalloidin staining, haematoxylin and eosin staining and wheat germ agglutinin staining were conducted to detect cardiomyocyte atrophy. We also performed C11 BODIPY staining, measured the levels of Ptgs2 and malondialdehyde and detected the concentrations of ferrous ions, glutathione and oxidized glutathione to indicate ferroptosis.

RESULTS: Ang IV not only attenuated DOX-induced atrophy and cardiomyocyte injury in vitro but also alleviated myocardial injury and improved cardiac function in DOX-treated mice in vivo. Moreover, Ang IV reversed DOX-induced downregulation of glutathione peroxidase 4 (GPX4) and inhibited ferroptosis both in vitro and in vivo. Knockdown of GPX4 by siRNA abolished the cardioprotective effects of Ang IV. Furthermore, Ang IV increased GPX4 levels and ameliorated ferroptosis in RAS-selective lethal 3-treated primary cardiomyocytes.

CONCLUSIONS: Ang IV ameliorates DOX-induced cardiotoxicity by upregulating GPX4 and inhibiting ferroptosis. Ang IV may be a promising candidate to protect against DOX-induced cardiotoxicity in the future.

PMID:37838222 | DOI:10.1016/j.taap.2023.116713

20:18

PubMed articles on: Cardio-Oncology

Development and Validation of a Nomogram Model for the Risk of Cardiac Death in Patients Treated with Chemotherapy for Esophageal Cancer

Cardiovasc Toxicol. 2023 Dec;23(11-12):377-387. doi: 10.1007/s12012-023-09807-4. Epub 2023 Oct 7.

ABSTRACT

The primary cause of mortality in esophageal cancer survivors is cardiac death. Early identification of cardiac mortality risk during chemotherapy for esophageal cancer is crucial for improving the prognosis. We developed and validated a nomogram model to identify patients with high cardiac mortality risk after chemotherapy for esophageal cancer for early screening and clinical decision-making. We randomly allocated 37,994 patients with chemotherapy-treated esophageal cancer into two groups using a 7:3 split ratio: model training (n = 26,598) and validation (n = 11,396). 5- and 10-year survival rates were used as endpoints for model training and validation. Decision curve analysis and the consistency index (C-index) were used to evaluate the model's net clinical advantage. Model performance was evaluated using receiver operating characteristic curves and computing the area under the curve (AUC). Kaplan-Meier survival analysis based on the prognostic index was performed. Patient risk was stratified according to the death probability. Age, surgery, sex, and year were most closely related to cardiac death and used to plot the nomograms. The C-index for the training and validation datasets were 0.669 and 0.698, respectively, indicating the nomogram's net clinical advantage in predicting cardiac death risk at 5 and 10 years. The 5- and 10-year AUCs were 0.753 and 0.772 for the training dataset and 0.778 and 0.789 for the validation dataset, respectively. The accuracy of the model in predicting cardiac death risk was moderate. This nomogram can identify patients at risk of cardiac death after chemotherapy for esophageal cancer at an early stage.

PMID:37804372 | DOI:10.1007/s12012-023-09807-4

20:18

PubMed articles on: Cardio-Oncology

Clinical Utility and Prognostic Value of Coronary Computed Tomography Angiography in Patients With Cancer

Am J Cardiol. 2023 Oct 3;207:448-454. doi: 10.1016/j.amjcard.2023.08.121. Online ahead of print.