202411102246
Status:
Tags: Oncology, pharmacology
Anthracycline
doxorubicin
daunorubicin
epirubicin
idarubicin
Since their introduction in the 1960s, anthracyclines have been a significant breakthrough in oncology, introducing dramatic changes in the treatment of solid and hematologic malignancies
Cardiotoxicity
In clinical practice, the application of anthracyclines is limited by a dose-dependent cardiotoxicity, leading to both systolic and diastolic cardiac dysfunction and, in less common cases, overt heart failure
Anthracycline-related cardiotoxicity can be categorized based on the temporal relationship to drug administration
Acute cardiotoxicity may develop anytime during or shortly after the anthracycline treatment and is generally reversible upon drug discontinuation; it is rare, occurring in <1% of cases
Early onset cardiotoxicity can appear within the first year after treatment, which is often associated with an asymptomatic decline in left ventricular ejection fraction (LVEF); this form represents 98% of the total cardiotoxicity cases in a large cohort of anthracycline-treated patients
Late onset cardiotoxicity, which becomes clinically evident more than 1 year after exposure, typically presents as hypokinetic and/or dilated cardiomyopathy with overt HF symptoms.
Despite efforts to reduce cumulative doses in the treatment of cancer, the use of liposomal formulations, and the omission of anthracyclines from chemotherapy regimens, many cancer patients are still treated with these drugs, which increases their risk of cardiac dysfunction.
Pathophysiology
The molecular mechanisms of anthracycline cardiotoxicity can be broadly divided into 3 main areas:
- oxidative stress,
- alterations of cell death pathways,
- epigenetic changes
Oxidative stress
anthracyclines both generate reactive oxygen species (ROS) and mobilize iron, which facilitates the iron-catalyzed free radical deterioration of mitochondria and sarcoplasmic reticulum
This damage may lead to dysregulation of energy metabolism and calcium homeostasis
Alteration of cell death pathway
anthracyclines are known to induce myocyte apoptosis through both intrinsic and extrinsic pathways
anthracyclines dysregulate autophagy, resulting in the accumulation of undegraded autophagosomes and autolysosomes. This accumulation eventually leads to death rather than allowing for the physiological degradation and recycling of cellular components
Epigenetic change
Anthracyclines can down-regulate DNA methylation, which results in altered mitochondrial gene expression, and up-regulate histone deacetylation, leading to deacetylation of proteins such as α-tubulin
anthracyclines can both up-regulate and down-regulate numerous microRNAs, although the downstream consequences of these changes are only partially understood
2 pharmacokinetic determinants of cardiotoxicity rest on more solid evidence: the cumulative dose of anthracyclines and the extent of their ==accumulation in cardiac tissue
Anthracyclines are incompletely cleared from cardiomyocytes, leading to a cardiac pool that increases with each infusion and begins to induce cardiotoxicity
Morphologic and functional damage eventually occur when the cumulative dose causes the size of these cardiac anthracycline pools to exceed the detoxifying capacity of cardiomyocyte
Low cumulative doses and small anthracycline pools still induce cardiotoxicity if genetic variants, comorbidities, cardiac RT, or concomitant administration of other potentially cardiotoxic drugs magnify cardiac vulnerability
Liposomal doxorubicin formulations, because of their size, do not easily diffuse through the regular endothelium of coronary vessels, resulting in reduced delivery of anthracycline to cardiomyocytes
slow or prolonged infusions generate plasma anthracycline levels too low to promote significant anthracycline accumulation in cardiac tissue, yet tumors remain highly sensitive to continued anthracycline exposure
Definition of cardiac dysfunction
| ASE/EACVI 2014 |
ESC Position Paper 2016 |
ESMO 2020 |
|---|---|---|
| Decrease in LVEF of >10% from baseline to LVEF <53% Relative drop in GLS >15% from baseline |
Decrease in LVEF of >10% from baseline to LVEF <50% Relative decrease in GLS of >15% from baseline |
LVEF drop by ≥10%-15% or LVEF <50% HF symptoms regardless of LVEF |
Variability in defining anthracycline cardiotoxicity limits precise determinations of its incidence, progression, and prognostic value.
The definition of CTRCD, endorsed by multiple societies, now integrates LVEF and GLS decrements as well as troponin elevations and new onset HF symptoms.
Diagnosis / imaging
GLS <16% or a relative modification >15% from baseline are considered risk markers, indicating the potential need to start cardioprotective drugs before LVEF decrements eventually occur.
Diastolic dysfunction (DD) can occur in patients undergoing treatment with anthracyclines
limited but persuasive evidence suggests that the right ventricle is also prone to anthracycline damage
CMR can detect microvascular obstruction, tissue iron overload, and diffuse interstitial fibrosis (via native T1 mapping and calculation of the extracellular volume fraction), whereas myocardial edema can be quantified via T2 mapping
In clinical practice, CMR is mainly used for evaluating LVEF when echocardiography is limited by a poor acoustic window or provides borderline values or when a clinical suspicion of myocarditis requires diagnostic refinement
Cardioprotection
The optimal cardioprotective strategy for patients undergoing anthracycline therapy is yet to be clearly defined
Neurohormonal blockade is recommended for preventing CTRCD in patients who receive high-dose anthracyclines (≥250 mg/m2) and/or those with pre-existing cardiovascular conditions. Statins may be beneficial for lymphoma patients scheduled for high-dose anthracyclines.
Treatment
CTRCD can be reversible if detected early and treated appropriately.
ESC guidelines on cardio-oncology recommend managing CTRCD according to current HF recommendations.