Cardiovascular risks of chemotherapy

KEY POINTS

Cancer therapies can be associated with a broad range of cardiovascular toxicities
The three most important cardiovascular toxicities in terms of reported incidence and severity are 1) cardiomyopathy and heart failure, 2) vascular toxicities and hypertension, and 3) QTC prolongation and arrhythmias
The absolute and relative risks of cardiovascular toxicities are drug class specific and will be presented as such in the following
As evident, one cardiovascular side effect may stand out in particular for one or two agents in any given drug class

Cardio-oncology or onco-cardiology is the discipline at the intersection between cardiovascular disease and cancer, the two leading causes of death in the United States and much of the developed world. A central focus is the cardiovascular risk of cancer therapies. Cardiotoxicity from chemotherapy can be an important source of morbidity and mortality and can limit the use of potentially life-saving cancer therapies. A wide spectrum of cardiovascular toxicities is associated with cancer chemotherapies, including cardiomyopathy, coronary artery disease, atherothrombosis, hypertension, pulmonary hypertension, arrhythmias, conduction system disease, QT prolongation, metabolic effects, peripheral arterial disease, and venous thromboembolism ( Table 3.1 ). These toxicities can result from both on-target and off-target effects; they can occur during treatment or after completion of treatment; and they can contribute to cardiovascular disease long after cancer therapy is completed.

TABLE 3.1

Common Cardiovascular Toxicities With Associated Chemotherapies

Cardiomyopathy/myocyte injury	Anthracyclines HER2 inhibitors VEGF signaling pathway inhibitors Immune checkpoint inhibitors Cyclophosphamide (high dose) Paclitaxel (with anthracycline) Bcr-Abl inhibitor (Ponatinib) BRAF + MEK1/2 inhibitor (Vemurafenib + Trametinib) Proteosome inhibitor (Carfilzomib)
Coronary artery disease/ischemia	Antimetabolites (5-Fluorouracil, Capecitabine) VEGF signaling pathway inhibitors Bcr-Abl inhibitor (Ponatinib) Immune modulators (Lenalinomide) EGFR inhibitor (Erlotinib)
Arrhythmia	Ibrutinib (atrial fibrillation) Crizotinib (bradycardia) Taxanes (bradycardia) Anthracycline (atrial fibrillation, ventricular ectopy) Alkylating agents (Ciplatin, Melphalan, Cyclophosphamide) c-MET inhibitor (Cabozantinib, bradycardia) HDAC inhibitors (Romidepsin) Proteosome inhibitor (Carfilozmib) Immunomodulators (Thalidomide)
QTc prolongation	Anthracyclines BRAF inhibitor (Vemurafenib) EGFR inhibitors (Laptinib, Vandetanib) c-MET inhibitor (Crizotinib) HDAC inhibitors (Belinostat)
Peripheral arterial disease	Bcr-Abl inhibitors (Ponatinib, Nilotinib)
Cerebrovascular accident	VEGF signaling pathway inhibitors Bcr-Abl inhibitors (Ponatinib) EGFR inhibitor (Erlotinib, Vandetanib)
Hypertension	VEGF signaling pathway inhibitors Bcr-Abl inhibitor (Ponatinib) BRAF inhibitor (Vemurafenib) MEK1/2 inhibitor (Trametinib) EGFR inhibitor (Vandetanib) Bruton’s tyrosine kinase inhibitor (Ibrutinib) c-MET inhibitor (Cabozantinib) Proteosome inhibitor (Carfilzomib)
Pulmonary hypertension	Bcr-Abl inhibitors (Ponatinib, Dasatinib) Proteosome inhibitors (Carfilzomib)
Venous thromboembolism	EGFR inhibitors (Cetuximab, Panitumumab) Cyclin-dependent kinase inhibitors (Abermaciclib) c-MET inhibitors (Cabozantinib) Immunomodulators (Lenalidomide, Thalidomide, Pomalidomide)
Metabolic	Bcr-Abl inhibitor (Nilotinib) JAK inhibitor (Tofacitinib) m-TOR inhibitors

HDAC , Histone deacetylase; VEGF , vascular endothelial growth factor.

Prompt recognition of cardiovascular toxicity can lead to appropriate mitigation and treatment and optimize health outcomes in patients with cancer. Herein we will discuss the cardiovascular risks of common chemotherapies. The reader is reminded that cardiovascular toxicities of relatively new drugs may not be fully characterized in published clinical trials or initial post-marketing surveillance. Furthermore, long-term cardiovascular risks of currently used therapies require ongoing surveillance and research. This remains a constantly evolving field.

Chemotherapy for cancer can be divided into two broad categories: standard chemotherapy and targeted therapies, which also includes immunotherapies and anti hormonal therapies ( Fig. 3.1 ). Standard or traditional chemotherapy acts on all dividing cells (cancerous and non cancerous) leading to both therapeutic effects and toxicities. Targeted therapies arose from a greater understanding of the molecular mechanisms of cancers and represent a true revolution in cancer care. Of note, however, “targeted” therapies may have both on-target and off-target effects on non cancerous cells/organs/systems and lead to toxicity.

Traditional chemotherapy

Four classes of traditional chemotherapeutics will be discussed herein: anthracyclines, alkylating agents, anti metabolites, and anti microtubule agents.

Anthracyclines

KEY POINTS

Main cardiotoxicity is cardiomyopathy with risk factors of cumulative dose, young age at treatment, and traditional cardiovascular risk factors.
Can have a long latency period from completion of therapy, particularly in childhood cancer survivors.
Current guidelines recommend screening echocardiography before and 6 to 12 months after completion of treatment in adult and every 1 to 5 years starting 1 to 3 months and up to 5 years after completion of treatment in cases of childhood cancer by various guidelines.

Anthracyclines include doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin, and mitoxantrone.

The anti cancer therapy effect of anthracyclines relates to topoisomerase II alpha inhibition, which leads to double strand breaks and disarray of the DNA structure in proliferating cells. They are also DNA intercalators, and induction of oxidative stress may further contribute to their cytotoxicity.

Anthracyclines are currently used in the treatment of leukemia, lymphoma, breast cancer, sarcomas, uterine cancer, and gastric cancer.

Cardiomyopathy

Incidence

Anthracycline cardiomyopathy is often broken down into three categories.

Acute: Occurs during active treatment. Estimated incidence is less than 1%.
Early onset: Occurs within 1 year of treatment. Incidence of 9% based on a large prospective series.
Late onset: Occurs after one year of treatment. Incidence varies, depending on series, study cohorts, and definitions used, ranging from 0 to 57%. Most of these are asymptomatic declines in cardiac function. The highest heart failure rates have been projected for childhood patients with cancer exposed to more than 250 mg/m ² doxorubicin equivalent dose. Chest radiation exposure adds to the risk (as does hypertension, with a more than additive effect in childhood cancer survivors).

Risk factors

Risk factors include cumulative dose, bolus dosing, extremes of age (very young and old), female gender, concomitant chest radiation, preexisting cardiovascular disease, obesity and genetic factors. ^,

Mechanism

The mechanisms of anthracycline-associated cardiomyopathy continue to be the focus of basic and translation research. Central pathways involved include the inhibition of topoisomerase II beta in cardiomyocytes leading to DNA instability and subsequent cell death; oxidative stress manifest by decreases in p53, peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha); and angiogenic imbalance via decreased ErbB/nrg signalling and, subsequently, decreased vascular endothelial growth factor (VEGF) activity.

Arrhythmias

The incidence of atrial fibrillation is estimated at 8% to 10%. It can occur during or immediately after administration of anthracyclines or be a latent effect after months/years. Atrial fibrillation may be a marker for cardiomyopathy and clinical heart failure.

Ventricular arrhythmias have been described during and immediately after administration. In patients qualifying for primary prevention implantable cardioverter defibrillator (ICD) the risk of ventricular arrhythmias in the setting of an anthracycline-associated cardiomyopathy appears to be similar to that seen of patients with ischemic and especially dilated cardiomyopathy.

QTc prolongation has also been described with anthracycline use. In a small study, 12% of patients with acute leukemia developed QTc greater than 450 msec in the setting of anthracycline therapy.

Coronary artery disease

Some small studies have demonstrated abnormalities in endothelial dysfunction which might precede the development of atherosclerosis, but that remains speculative. No increase in myocardial infarction was seen in survivors of childhood cancers compared with a healthy sibling cohort.

Alkylating agents

KEY POINTS

Cardiomyopathy and hemorrhagic myocarditis can be seen with high-dose cyclophosphamide.
Atrial fibrillation has been noted with melphalan, and also cisplatin and cyclophosphamide.

Akylating agents include five different categories:

Nitrogen mustards: cyclophosphamide, ifosfamide, bendamustine, chlorambucil, bendamustine, mechlorethamine, melphalan
Nitrosoureas: carmustine, lomustine, streptozocin
Alkyl sulfonates: busulfan
Triazines: dacarbazines, temozolomide
Ethylenimines: altretamine, thiotepa
Metal salts (“platinums”): carboplatin, cisplatin, and oxaliplatin

Alkylating agents promote cell death by induction of DNA instability leading to breakage. These agents, and especially nitrogen mustards and metal salts, are commonly used for a variety of solid and hematologic malignancies.

Cardiomyopathy

High-dose cyclophosphamide can cause a hemorrhagic myocarditis leading to heart failure. This was reported in 1981 using a high dose of 180 mg/kg over 4 days. The incidence of heart failure in this series was 28%. Current, dosing regimens are a fraction of this and consequently the incidence of heart failure is low. In a contemporary study investigating heart failure in the hematopoietic cell transplant (HCT) population no difference was found between patients treated with and without cyclophosphamide. Of note in this relatively small cohort there was a 22% incidence of heart failure post HCT.

Risk factors for cardiotoxicity with high-dose regimens include the following: prior anthracycline treatment, prior chest radiation, obesity, older age, left ventricular ejection factor (LVEF) less than 50%.

Arrhythmias

Cisplatin, melphalan, and high-dose cyclophosphamide have all been associated with atrial fibrillation. Intrapericardial and intrapleural administration of cisplatin is associated with a higher rate of atrial fibrillation. Both acute and late effects have been reported.

Antimetabolites

KEY POINTS

Most common cardiovascular toxicity with fluorouracil or capecitabine is chest pain, including acute coronary syndrome presentations, which are likely secondary to coronary vasospasm.
Decline in cardiac function is not common, but can be seen, including Takotsubo cardiomyopathy.
Ventricular tachycardia (VT) and sudden cardiac death (SCD) have been reported as well, but uncommonly.
Pericarditis is seen with cytarabine.

Anti-metabolites include 5-fluorouracil (5-FU) fluorouracil, capecitabine, cytarabine, gemcitabine, cladribine, clofarabine, fludarabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed.

These agents interfere with DNA and RNA synthesis to prevent cell proliferation. Current use includes leukemias, breast, ovary, and gastrointestinal cancers.

Ischemia

5-FU and capecitabine (oral prodrug of fluorouracil) are associated with a syndrome of chest pain, electrocardiographic (ECG) changes, and elevated cardiac biomarkers indicative of myocardial injury. Although not fully understood, the mechanism of cardiotoxicity is often attributed to coronary vasospasm; in vitro and animal studies suggest direct endothelial and myocardial injury may be present. The reported incidence ranges from 1% to 19%.

Cardiomyopathy

There are case reports of left ventricular dysfunction and ventricular arrhythmias often associated with the chest pain syndrome described with 5-FU and capecitabine. Based on the available literature this appears to be an uncommon toxicity. Risk factor for “cardiotoxicity” is a history of coronary artery disease.

Antimicrotubule agents

Anti-microtubule agents taxanes (paclitaxel, docetaxel) and vinca alkaloids (vincristine, vinblastine, vinorelbine).

These agents work by stabilizing microtubules and thus inhibiting cell division, ultimately leading to cell death. Taxanes are commonly used in the treatment of breast cancer, ovarian cancer, and non small-cell lung cancer.

Arrhythmias

Sinus bradycardia during infusion has been reported in up to 30% of patients receiving taxanes. This is largely asymptomatic. ECG changes have been reported, including non specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia in 30% of patients receiving paclitaxel who had normal baseline ECGs. Rarely do these ECG changes have a clinical impact.

Blood pressure effects

Hypertension and hypotension have been described as part of the infusion reaction that can be seen with paclitaxel. Serious cardiac events occur infrequently, with an incidence of 1% to 2% according to package insert and these seem to be largely related to events during the infusion period.

Cardiomyopathy

Paclitaxel has been associated with cardiomyopathy in patients treated concomitantly with an anthracycline. Paclitaxel may increase doxorubicin levels contributing to increased risk of cardiomyopathy. There are also case reports of congestive heart failure in the setting of combination therapy with gemcitabine and nab-paclitaxel.

Miscellaneous

The package insert for abraxane reports a 3% incidence of serious cardiac events, possibly related to paclitaxel. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension.

KEY POINTS

Most common cardiovascular side effect is sinus bradycardia during infusion.
Hypotension/hypertension can occur during infusion as well.
Serious side effects including myocardial infarction (MI) and cardiomyopathy/heart failure are relatively uncommon.

Targeted therapies

One of the revolutions in medicine has been driven by a better understanding of the molecular mechanisms that drive proliferation and metastasis of cancer cells. The human genome project identified approximately 538 kinases. Dysregulation of these enzymes is seen in many cancers providing an attractive target from a therapeutic perspective. The current landscape of kinase inhibitors includes many different targets. It is important for the reader to understand that this list continues to grow with many new drugs and targets in various stages of development.

HER2 inhibitors

HER2-inhibitors include trastuzumab, pertuzumab, lapatinib and trastuzumab emtansine (T-DM1)

The discovery that approximately 25% of breast tumors over-express the receptor kinase HER2 set the stage for targeted therapies that have reduced morbidity and mortality for the subset of HER2+ breast patients with cancer. Besides breast cancer, anti-HER2 therapy is used in HER2 expressing gastrointestinal stromal tumors.

Cardiomyopathy

An early clinical trial using the antibody, trastuzumab to target the HER2 receptor in conjunction with anthracyclines noted a 27% incidence of congestive heart failure (New York Heart Association III or IV). Subsequent protocols administered trastuzumab sequentially with an anthracycline and the incidence of clinical heart failure was lowered to 2% to 4% with cardiac dysfunction occurring from 3% to 19%. ^, Without concomitant anthracycline therapy the incidence of cardiomyopathy and clinical heart failure with HER2-targeted therapies is even lower. An important caveat is that, in general, clinical trials often enroll patients who are relatively younger and healthier with a lower prevalence of preexisting cardiovascular disease and traditional cardiovascular risk factors compared with the general population. As such, continued vigilance is necessary, as “real world” incidences of cardiotoxicity are often higher. Along the same lines, although clinical trials indicate that cardiac function recovers in the majority of patients with interruption of therapy and that the long-term risk is low clinical registry-based data argue that this is not guaranteed. Mechanistically, the HER2-signaling pathway is an important stress response element in cardiomyocytes with a role in sarcomere structure, cell survival, and metabolism.

The addition of pertuzumab to trastuzumab does not seem to increase the risk of cardiotoxicity at least not in published clinical trials. ^, Lapatinib, of note, is associated with a lower risk of cardiotoxicity, possibly related to effects other than HER2 inhibition which could counteract the toxicity risk potential. Intriguingly, T-DM1 is also associated with a lower risk of cardiomyopathy though this agent is a conjugate of trastuzumab and the anti-microtubule agent DM1.

Risk factors for HER2 inhibitor cardiomyopathy include concomitant anthracycline treatment, traditional cardiovascular risk factors (esp. hypertension), and age.

KEY POINTS

The main cardiovascular toxicity risk with HER2-directed therapy, and mainly trastuzumab, is cardiomyopathy.
Regular (3-monthly) screening with echocardiography is thus advised as standard of care.
Beta blockers and angiotensin-converting enzyme inhibitors–angiotensin II receptor blockers (ACEi-ARBs) are indicated in cases of LV dysfunction.
Most (but not all) patients who develop cardiomyopathy will have full or near full recovery.
If LVEF improves, HER2 inhibitors can be resumed based on careful risk/benefit discussion.

BCR-Abl inhibitors

BCR-Abl inhibitors include imatinib, dasatinib, nilotinib, bosutinib, and ponatinib.

These agents target the molecular fingerprint of Philadelphia chromosome-positive leukemias, which is the Bcr-Abl fusion protein, namely its tyrosine kinase activity. Imatinib was one of the first targeted therapies yielding normal life expectancy in those patients who responded to therapy. However, as not 100% selective, off-target effects can lead to toxicity, including a variety of cardiovascular toxicities.

Risk factors included preexisting coronary artery disease, diabetes mellitus, and hypertension, which increased the risk of cardiotoxicity, particularly with ponatinib.

Cardiomyopathy

Rare event with imatinib and bosutinib cardiovascular events increased with ponatinib, including congestive heart failure, although this may at least be partially related to the increased risk of coronary ischemic events.

Myocardial infarction

In a trial of ponatinib there was a 10% incidence of myocardial infarction (MI) during a 2+ year follow up.

Pulmonary hypertension

A 5% incidence of pulmonary hypertension was seen with dasatinib over a 5 year follow-up period in of the DASISION trial. Rarely did the degree of pulmonary hypertension estimated on echocardiography lead to a right heart catheterization, suggesting that this may not be a severe complication. Pleural effusions are also commonly observed, with a reported incidence of 28% with dasatinib, which may be a more frequent etiology of dyspnea.

Metabolic effects

Nilotinib is associated with hyperglycemia, increased weight, and dyslipidemia.

Peripheral arterial disease

Ponatinib and especially nilotinib have been associated with peripheral arterial disease events.

Cerebrovascular disease

An incidence of cerebrovascular events of 7% has been reported for ponatinib for the 2+ year follow up of the PACE clinical trial.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here