1st April 2023, Dr Chee L Khoo
Two months ago, we explored heart failure in cancer survivors exposed to anthracyclines in a dose dependent manner. Anthracyclines are a common agents used in chemotherapy against breast cancer and lymphomas. Heart failure may appear as early as within 12 months of receiving anthracyclines and the incidence continues to grow over time. There have been a lot of work done on the possible molecular pathways in the development of the cardiotoxicity, the prevention strategies explored and the development of “safer” anthracycline derivatives. It’s timely to explore them this week.
Anthracyclines are a class of drugs used in cancer chemotherapy that are extracted from the Streptomyces bacterium. They are used to treat many cancers including the leukaemias, lymphomas, breast, stomach, uterine, ovarian, bladder and lung cancers. The most important anthracyclines are doxorubicin, daunorubicin, epirubicin and idarubicin.
Anthracyclines has significantly contributed to marked improvements of overall survival during the last few decades and represents the most potent cytostatic drugs for cancer treatment across various histologies. Based on these results, the US FDA has approved the anthracyclines as one of the most effective and commonly used antineoplastic drugs and they have also been named on the World Health Organisation list of essential drugs.
The main cellular target of all anthracyclines is topoisomerase II (TOPO-II), an enzyme that cleaves DNA strands and generates transient double-strand breaks. Anthracyclines bind and stabilise TOPO-II DNA cleavable complexes, which leads to DNA double-strand breaks that are lethal if remain unrepaired. Two isoforms of TOPO-II have been identified: TOPO-II α and TOPO-II β. TOPO-II α is highly active in proliferating cells and is overexpressed in malignant cells but not in quiescent tissues, and inhibition of TOPO-IIα is considered the main mechanism of anthracycline-induced cell death.
Unfortunately, anthracyclines can also contribute to DNA damage by generating reactive oxygen species (ROS), which occur during the intracellular breakdown of the drug. The myocardium is particularly sensitive to ROS. Soon after the discovery of anthracyclines, it became clear that the toxic effects of these drugs were not limited to tumour cells and amongst all routinely administered antineoplastic agents the members of the anthracycline family were a significant cause of acute and chronic cardiotoxicity [1].
It is now thought that anthracycline-induced ROS and drug-induced inhibition of TOPO-II β within cardiac myocytes are the key mechanisms for the observed cardiotoxicity (2). Human cardiomyocytes do not express TOPO-II α but do express the TOPO-II β isoform, it was demonstrated that knockout of TOPO-II β in mice led to a significant reduction of doxorubicin-induced cardiomyocyte death (3).
Other mechanisms proposed to be responsible for the observed cardiotoxicity include mitochondrial iron accumulation, lipid peroxidation, protein nitrosylation, and calcium handling abnormalities (reviewed in (2,4),
Cancer therapy-related cardiovascular disease (CTRCD) risk should include repeated clinical assessment combined with cardiac biomarkers (i.e. cardiac troponin, natriuretic peptides) and transthoracic echocardiography.
Prevention strategies?
Different strategies to prevent or reduce anthracycline-induced cardiotoxicity:
Angiotensin-converting enzyme inhibitors, sartans, beta-blockers (BB)
ACE inhibitors and BB were associated with increased cardiotoxicity-free survival and fewer interruptions in cancer therapy compared to placebo among HER2 positive breast cancer patients treated with trastuzumab (± anthracyclines) [5,6]. Similarly, among patients treated for haematological cancers, concurrent use of enalapril and carvedilol with anthracyclines in the Prevention of Left Ventricular Dysfunction with Enalapril and Carvedilol in Patients Submitted to Intensive Chemotherapy for the Treatment of Malignant Hemopathies (OVERCOME) trial was associated with a lower incidence of cardiotoxicity and no significant change in LV ejection fraction compared to controls [7]. A meta-analysis of 9 RCTs showed carvedilol reduced incidence of LVSD, higher LVEF value, better diastolic function, and lower troponin I level in patients undergoing anthracyclines-based chemotherapy (8).
Angiotensin antagonists, angiotensin receptor blockers and beta‐blockers, are often poorly tolerated in these patients due to intravascular volume fluctuations, which are further escalated by the hemodynamic side effects of these agents.
Statins
Statins may exert a favourable cardio-protective effect during anthracycline and/or trastuzumab treatment owing to its pleiotropic, anti-oxidative and anti-inflammatory effects. A recent meta-analysis suggests that statin use may reduce the risk of cardiotoxicity after anthracycline exposure (9). Larger well-conducted RCTs are needed to determine whether statins decrease risk of cardiotoxicity from anthracyclines.
Novel non-cardiotoxic anthracyclines
The design and development of novel, potentially non-cardiotoxic anthracyclines that are already under clinical evaluation is sufficient proof that the approach based on structural modification leading to elimination of drug interactions with cardiotoxic pathways/targets is a valid and highly promising. Some of the “non-cardiotoxic” anthracyclines have demonstrated reduced cardiotoxicity but does have some degree of cardiotoxicity at higher doses. Others are still in Phase 1-2 clinical trials.
Recommendations for the diagnosis and management of cancer drug-induced cardio-toxicities have most recently been published in updated guidelines [20]. There are recommended monitoring protocol during anthracycline therapy according to baseline CTRCD risk. As the risk of heart failure increases over time, symptoms and signs may not be evident till patients are discharged from oncology units back to primary care. We need to be on a look out for cardiotoxicity in these patients.
In summary, anthracyclines is an important class of chemotherapeutic agents in the treatment of a wide spectrum of solid tumours and haematologic malignancies (e.g. leukaemias, malignant lymphomas, small-cell lung cancer, breast cancer, multiple myeloma, sarcomas, etc.) and has a major impact on the overall survival of these patients. However, the development of life-threatening cardiotoxicity still remains a huge challenge for physicians treating cancer patients.
References:
- Macedo AVS, Hajjar LA, Lyon AR, et al. Efficacy of dexra[1]zoxane in preventing anthracycline cardiotoxicity in breast cancer. JACC CardioOncol 2019;1:68–79
- Sobczuk P, Czerwinska M, Kleibert M, et al. Anthracycline-in[1]duced cardiotoxicity and renin-angiotensin-aldosterone system – from molecular mechanisms to therapeutic applications. Heart Fail Rev 2022;27:296–319.
- Zhang S, Liu X, Bawa-Khalfe T, et al. Identification of the mo[1]lecular basis of doxorubicin-induced cardiotoxicity. Nat Med 2012;18:1639–42
- Robinson EL, Azodi M, Heymans S, et al. Anthracycline-related heart failure: certain knowledge and open questions. Curr Heart Fail Rep 2020;17:357–64.
- Tewey KM, Rowe TC, Yang L, et al. Adriamycin-induced DNA damage mediated by mammalian topoisomerase II. Science 1984;226:446–8
- Murabito A, Hirsch E, Ghigo A. Mechanisms of anthracycline-induced cardiotoxicity: is mitochondrial dysfunction the answer? Front Cardiovasc Med 2020;7:35
- Macedo AVS, Hajjar LA, Lyon AR, et al. Efficacy of dexra[1]zoxane in preventing anthracycline cardiotoxicity in breast cancer. JACC CardioOncol 2019;1:68–79
- Zhan, T., Daniyal, M., Li, J. et al. Preventive use of carvedilol for anthracycline-induced cardiotoxicity: a systematic review and meta-analysis of randomized controlled trials. Herz 45 (Suppl 1), 1–14 (2020)
- Obasi, M., Abovich, A., Vo, J.B. et al. Statins to mitigate cardiotoxicity in cancer patients treated with anthracyclines and/or trastuzumab: a systematic review and meta-analysis. Cancer Causes Control 32, 1395–1405 (2021).
- Lyon AR, Lópéz-Fernandéz T, Couch LS, et al. 2022 ESC guidelines on cardio-oncology developed in collaboration with the European Hematology Associatin (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International cardio-Oncology Society (IC-OS). Eur Heart J 2022;43:4229–361
- Dempke WCM, Zielinski R, Winkler C, Silberman S, Reuther S, Priebe W. Anthracycline-induced cardiotoxicity – are we about to clear this hurdle? Eur J Cancer. 2023 Feb 24;185:94-104. doi: 10.1016/j.ejca.2023.02.019. Epub ahead of print. PMID: 36966697.