Cardio-Oncology: Managing Cardiotoxic Effects of Cancer Therapies

Anthracyclines

The American College of Cardiology and American Heart Association HF Guidelines classify exposure to cardiotoxic therapies, such as anthracyclines, as stage A HF. Reports of the incidence of anthracycline-associated cardiotoxicity have varied widely in the literature, in part, secondary to the variability in the definition of CV outcomes across retrospective analyses and the lack of systematic and rigorously ascertained longitudinal follow-up data, particularly in adults. Historically, cardiotoxicity has been classified as acute, subacute, or chronic although recent studies have substantially challenged this paradigm.

Anthracyclines are a mainstay of therapy in childhood cancers. Cardiotoxicity, when carefully evaluated, is also observed in patients early after exposure to anthracyclines. In clinical trial participants younger than 30 years of age receiving frontline treatment for acute myelogenous leukemia, the cumulative incidence of cardiotoxicity, as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0) grade 2 or worse LV systolic dysfunction, was 12%. The standard induction and intensification treatment protocol included daunorubicin and mitoxantrone. In this study, 25% of the cardiotoxicity events were infection associated and 70% of these occurred early, with a median time to cardiotoxicity of 4.3 months (IQR, 3.1 to 5.9) after chemotherapy initiation. Both 5-year event free and overall survival were significantly worsened in patients who suffered from cardiotoxicity. These findings not only indicate an early cardiotoxicity onset, but also suggest treatment-related cardiotoxicity in children results in worse overall outcomes.

Clinical risk factors for anthracycline-induced cardiotoxicity include age of exposure, traditional, modifiable CV risk factors (HTN, diabetes, obesity, and hyperlipidemia), prior chest RT, anthracycline dose, genetic factors, and pre-existing CV disease. In adult survivors of childhood cancer, the prevalence of CM is 4.7% to 10.7%, and increases with age, with an adjusted odds of CM development 2.7 (95% CI 1.1 to 6.9) fold greater compared to patients not exposed to anthracyclines. More recent studies also suggest that the association between anthracycline dose and HF is modified by age of treatment, with a greater relative risk (RR) of CV disease among those who received high-dose anthracycline chemotherapy (≥250 mg/m ² ) at ≤13 years of age, as compared to children older than 13 years. Here, children that were ≤13 years at diagnosis had a RR of 2.4 to 4.0 fold of any CV disease compared to those older than 13 years. In addition to modifiable CV risk factors and age at anthracycline exposure, concomitant treatment exposures such as RT (>15 Gy) are associated with an increased risk of CV disease. In 1820 adult survivors of childhood cancer treated with anthracyclines, chest-directed RT, or both, there was a high prevalence of subclinical dysfunction in those with an LVEF ≥50%, with abnormal GLS in 28% and diastolic dysfunction in 8.7%, greatest in those who received both anthracyclines and RT.

While multiple studies document a dose-dependent relationship between anthracycline exposure and risk of HF and CM, it is recognized that anthracycline cardiotoxicity can occur at any dose. Older retrospective analyses suggest an incidence of HF, as defined by clinical signs and symptoms, of 1.7% at a cumulative dose of 300 mg/m ² , 4.7% at 400 mg/m ² , 15.7% at 500 mg/m ² , and 48% at 650 mg/m ² . It is notable that standard errors for many of these estimates are large, given the small sample sizes. Moreover, with respect to dose, emerging data suggest that the equivalency ratios for mitoxantrone relative to doxorubicin is 10.5 (95% CI 6.2 to 19.1), much greater than previously published (0.6 (95% CI 0.4 to 1.0) for daunorubicin, 0.8 (95% CI 0.5 to 2.8) for epirubicin). Data from childhood cancer survivors also indicate that genetic variations in single-nucleotide polymorphisms modify the association between the anthracycline dose and CM risk and confer an increased risk of cardiotoxicity at lower dosages. The genetic determinants of anthracycline cardiotoxicity is an active area of research, with ongoing studies in candidate genes and genome-wide association studies. Additional content on this topic is presented in an online supplement, “Genetics of Anthracycline Cardiotoxicity.”

Several basic mechanisms have been proposed to explain anthracycline-induced cardiotoxicity. The first is formation of reactive oxygen species (ROS) and increased oxidative stress via redox cycling of the quinone moiety of doxorubicin, formation of anthracycline-iron complexes, and topoisomerase-2β (Top2β) inhibition ( Fig. 56.2 ). Furthermore, anthracyclines have been shown to cause impaired calcium signaling and intracellular sequestration affecting myocardial relaxation, a decrease in cardiac progenitor cells, and alterations in neuregulin (NRG)/ErbB signaling. ^, Recent data also suggest a role for phosphoinositide 3-kinase γ (PI3Kγ) in the pathophysiology of anthracycline cardiotoxicity, perhaps related to the release of mitochondrial DNA by injured organelles and contained autolysosomes. The most widely cited and unifying mechanism is the formation of ROS, leading to oxidative stress and subsequent injury to cardiac myocytes and endothelial cells. ^, The quinone moiety of the anthracycline enters cells and undergoes redox cycling, generating free radicals via both an enzymatic pathway involving the mitochondrial respiratory chain and also via a nonenzymatic pathway involving direct interactions between anthracyclines and intracellular iron. Toxic hydroxyl radicals from anthracycline-iron complexes act as cytotoxic messengers. This results in impaired mitochondrial function, cellular membrane damage, and cytotoxicity. Nitric oxide synthase (NOS) also contributes to the generation of anthracycline-mediated reactive nitrogen species, worsening nitrosative stress. The formation of ROS may occur via the isozyme Top2, and, more specifically, Top2β, in cardiomyocytes. Mice lacking Top2β are protected from anthracycline-induced DNA damage, cardiomyocyte death, and declines in cardiac function. These findings need to be validated. Interestingly, dexrazoxane, an iron chelator and cardioprotectant, binds to Top2β and results in Top2βdegradation.

Data derived from in vitro and in vivo animal models support the hypothesis that anthracyclines also affect the population of cardiac progenitor cells. Anthracycline chemotherapy may also render cardiomyocytes more susceptible to alterations in NRG-1 and ErbB signaling and downstream prosurvival pathways. ^, In vitro studies have demonstrated an inhibitory effect of doxorubicin on hypoxia-inducible factor (HIF) and downstream pathways. Anthracyclines also result in impaired diastolic relaxation via calpain-dependent titin proteolysis. More recent studies have used human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) to model the predilection to anthracycline cardiotoxicity in patients, and corroborated decreased cell viability, impaired mitochondrial and metabolic function, impaired calcium handling, decreased antioxidant pathway activity, and increased ROS production as mechanisms of toxicity.

Several other traditional chemotherapeutic agents, including taxanes, alkylating and alkylating-like agents, and antimetabolites can also lead to cardiotoxicity ( see online supplement “Cardiotoxicity of Traditional Chemotherapeutic Agents”).

Taxanes

The taxanes, paclitaxel (Taxol) and its semisynthetic analogue docetaxel (Taxotere), disrupt microtubular networks as their mechanism of antitumor activity. Used alone, these drugs have relatively little cardiotoxicity; there may be predominantly asymptomatic bradycardia and atrioventricular block.

Alkylating and Alkylating-Like Agents

Cyclophosphamide, used in the treatment of breast cancer and hematologic malignancies, is typically well tolerated. At higher dosages, greater than 100 mg/kg, there have been case reports of hemorrhagic myocarditis, tachyarrhythmia, HF, and pericardial disease. Emerging data on the use of cyclophosphamide in the post-transplant setting may suggest increased CV risk.

Platinum-based agents, often considered alkylating-like agents, are commonly used in germ-cell testicular cancer, as well as ovarian, lung, and breast cancers and other solid tumors. Primary CV concerns with platinum-based therapies have been related to vasculotoxicity, which perhaps has been most well studied in the testicular cancer population. Cases of acute arterial occlusive events, including myocardial infarction and stroke, have been reported in patients receiving cisplatin. In retrospective analyses, the risk of thromboembolic events is elevated within the first year after cancer diagnosis. There is also a hypothesized late risk of cardiotoxicity. One epidemiologic study in testicular cancer survivors with a median observation time of 19 years reported a 5.7-fold increased risk of coronary artery disease and 2.3-fold increased risk of atherosclerotic disease (coronary, cerebrovascular, and peripheral arterial disease) in patients receiving platinum-based chemotherapy regimens compared with patients receiving no chemotherapy. These effects were worsened in patients who received concomitant RT. Platinum results in direct endothelial damage and increased platelet reactivity, which may potentially explain these clinical observations. Platinum levels also remain detectable in the plasma of patients up to 20 years after therapeutic exposure, raising a question as to whether or not prolonged exposure worsens toxicity, although this remains unknown.

Antimetabolites

5-Fluorouracil (5FU) and its oral analog, capecitabine (Xeloda), are used in the treatment of many solid tumors, including gastrointestinal, breast, head and neck, and pancreatic cancers. CV effects include myocardial ischemia potentially related to vasospasm, as well as cardiac arrhythmias, HTN, hypotension, HF, CM, and even cases of cardiac arrest. A review of 12 Phase II and III clinical trials of 5FU and capecitabine reported the following CV adverse events across these studies: dyspnea in up to 16% of the participants; arrhythmias in less than 1% to 6%; and angina, ischemia, and elevated troponin in less than 1% to 5%. In vitro and in vivo studies suggest that 5FU is associated with endothelial injury, vasospasm and vasoconstriction, and interstitial fibrosis. Capecitabine (Xeloda) is associated with a 6.5% incidence of cardiac events, defined by angina in 4.6%, myocardial infarction, ventricular tachycardia, and sudden death. One retrospective analysis from the SEER Medicare database of individuals greater than 65 years of age with colon cancer suggested that treatment with capecitabine was associated with an increased risk of HF compared to 5FU. Conversely, 5FU treatment was associated with a greater risk of stroke or myocardial infarction compared to capecitabine. Moreover, there was a significant interaction between HTN and chemotherapy and the development of CVD. In a prospective study of 106 patients treated with 5FU, 9% (8.5%) had symptoms of cardiotoxicity, presenting primarily as angina and electrocardiographic changes, as well as elevations in N-terminal pro hormone natriuretic peptide (NT-proBNP).

Proteasome Inhibitors

Proteasome inhibitors, including bortezomib and carfilzomib, are used in the treatment of relapsed or refractory and newly diagnosed cases of multiple myeloma. Bortezomib is a reversible nonselective inhibitor of proteasomes that blocks chymotrypsin-like activity at the 26S proteasome; carfilzomib is an irreversible selective inhibitor of proteasomes that blocks chymotrypsin activity of the 20S proteasome.

The reported incidence of all-grade and grade 3 and higher adverse CV events with these proteasome inhibitors from a meta-analysis of Phase 1 to 3 clinical trials was 18.1% and 8.2%, respectively. HF (4.1%) and HTN (12.2%) were the most common adverse CV events, followed by arrhythmias (2.4%) and ischemia (1.8%). In a multi-center, longitudinal prospective cohort study of 95 patients, the rates of adverse CV events were much greater, occurring in 50.7% in patients receiving carfilzomib and 16.7% receiving bortezomib. Most occurred during carfilzomib therapy; HF and HTN were similarly noted as most common, with grade 3 and 4 HF and HTN events occurring in 20% and 23%, respectively. Arrhythmia, acute coronary syndrome, and pulmonary HTN were also noted. In case series, both HF with preserved and reduced ejection fraction have been reported. Predictors of adverse CV events with carfilzomib include a history of HF, baseline diastolic dysfunction, higher doses of carfilzomib, and abnormal NT-proBNP levels at baseline or during therapy. It is postulated that proteasome inhibitors alter protein homeostasis and reduce phosphorylation of AMPKalpha and downstream autophagy related proteins, such as Raptor.