Cardiac disease and cancer are by far the two most common disease conditions in the developed world. Cardiac disease may pre-exist cancer therapy or may be caused/exacerbated by it. Cancer therapy is more effective than ever before at treating cancer, but has a price. Cardiotoxicity is a significant adverse effect of cancer treatment, and responsible for increased morbidity and mortality.
The most frequent and serious effect of chemotherapeutic agents on the cardiovascular system is heart failure with ventricular systolic dysfunction. Other toxic effects include hypertension, thromboembolic disease, pericardial disease, arrhythmias and myocardial ischemia.
Over the last years, the significance of the cardiac toxicity of anticancer treatment has markedly increased due to improvements in patient survival, aging of the population (including cancer patients) and the introduction of new anticancer drugs with unique toxicities.
Following cancer treatment in many patients the risk of cardiovascular death may be higher than the actual risk of tumor recurrence. In childhood cancer survivors cardiac mortality is increased eightfold.
Importantly, not all cardiovascular symptoms in patients treated for cancer are iatrogenic and the differential diagnosis should include co-morbid conditions or the adverse effects of other medications.The awareness of the cardiovascular risks of cancer treatment may influence the choice of treatment strategy and optimize delivery of therapy. Additionally, this knowledge may also allow for timely interventions, such as life-style changes or treatment of subclinical disease, which may decrease potential harmful effects.
Chemotherapeutic agents and molecular targeted therapies can injure the cardiovascular system at central level by deteriorating the heart function or in the periphery by enhancing hemodynamic flow alterations and thrombotic events often latently present in oncology patients.
Non-reversible or reversible: a cardinal distinction
Historically, non-reversible cardiovascular side effects that eventually led to progressive cardiac disease were the consequence of some oncologic therapies; a prime example being anthracycline-induced cardiotoxicity leading to progressive systolic heart failure. With the introduction of new cancer drugs, such as signalling inhibitors, a new phenomenon has been observed: cardiac dysfunction that resolves for most patients over time. In an effort to classify cardiotoxicity of cancer drugs, Ewer proposed a system to identify drugs that have the potential to cause irreversible damage (Type I) vs. drugs that predominantly induce reversible dysfunction (Type II). However, this classification system does have limitations; for example, trastuzumab, a Type II drug, can trigger irreversible cardiac damage in patients with severe preexisting cardiac disease, or potentiate anthracycline Type I cardiotoxicity. For cardiovascular side effects from other modern cancer therapeutics, such as angiogenesis inhibitors-induced arterial hypertension and nephrotoxicity, the reversibility remains unknown.
Cardiac dysfunction and heart failure
Cardiac dysfunction and heart failure are among the most serious cardiovascular side effects of systemic cancer treatment. Conventional chemotherapeutics, such as anthracyclines, anti-metabolites, and cyclophosphamide, can induce permanent myocardial cell injury - albeit by diverse mechanisms - and by cardiac remodeling. Signaling inhibitors currently in use, like human epidermal growth factor receptor 2 (HER2/erbB2) and angiogenesis inhibitors, predominantly affect cardiac metabolism and contractile proteins, leading to transient contractile dysfunction. Understanding the mechanistic pathophysiology of cancer drug-associated cardiac dysfunction is important to predict, treat, and prevent these side effects, although it can be challenging to identify the proper mechanism in individual patients.
Anthracyclines and agents with cumulative dose-related cardiotoxicity (Type I agents)
Anthracyclines and the non-anthracycline analogue mitoxantrone are among the most effective antitumor agents; however, their use is compromised by cardiotoxicity, which has been the subject of considerable attention over the past 35 years. Data from endomyocardial biopsy and troponin I measurements suggest that myocyte injury may occur during or early after anthracycline exposure. However, due to substantial cardiac reserves and the activation of compensatory mechanisms, clinical manifestation may not become apparent until months to years after the initial chemotherapy exposure.
Clinically, early cardiac side effects are typically reversible and self-limiting and include dysrhythmia, repolarization changes in the electrocardiogram, pericarditis, and less frequently myocarditis. It remains uncertain whether patients who experience these early cardiac side effects are also more likely to develop late anthracycline cardiotoxicity, a condition that leads to cardiomyopathy and systolic heart failure. Patients treated with anthracyclines are five times more likely to develop chronic heart failure or reduced left ventricular ejection fraction (LVEF) compared with those treated with a non-anthracycline-containing chemotherapy. The incidence of anthracycline-induced cardiotoxicity is dose-dependent. Patients with no other risk factors usually tolerate cumulative doses of doxorubicin of up to 300 mg/m2 (equivalent to 550 mg/m2 of epirubicin) quite well, with a rate of heart failure of less than 2%. Above this dosage, the rates of cardiotoxicity rise exponentially. However, there is significant inter-individual heterogeneity; patients over 65 years of age and children may develop toxicity at lower cumulative dosages. Other factors that seem to influence sensitivity to anthracycline-induced cardiotoxicity include genetic predisposition, arterial hypertension, previous or concurrent mediastinal radiation therapy, and combination with alkylating or antimicrotubulechemotherapeutics; many other risk factors have been studied, and from a practical standpoint we may assume that any insult that has previously damaged (i.e. depleted reserves) or any factor that makes the heart more susceptible to ongoing or future damage should be considered a potential risk factor for anthracycline cardiotoxicity. It should be noted, however, that those risk factors that have been studied have had a relatively short follow-up period and long-term investigations are needed to better assess the true impact of risk factors for anthracycline cardiotoxicity.
Several methods were investigated to reduce anthracycline cardiotoxicity, including pharmacokinetic modification by liposomal encapsulation, alteration of chemical structure leading to drugs such as epirubicin, altering drug-infusion regimens to decrease peak plasma levels, and attenuation of iron chelation through pre-treatment with dexrazoxane. Most of these methods have been associated with a reduction in cardiovascular events in anthracycline-treated patients; however, except for the use of epirubicin, most of these strategies are not in common practice in the clinical setting. Other approaches to mitigate the cardiotoxic impact of anthracyclines employ potentially cardioprotective medications, such as angiotensin-converting enzyme (ACE) inhibitors. Although promising data have been published recently, convincing evidence from large randomized and prospective trials is still needed.
Other agents with myocyte destruction
Any cancer drug that may lead to myocyte injury or destruction can induce irreversible cardiotoxicity. For example mitoxantrone, an anthracyclineanalogue, can result in cardiotoxicity that is not clinically different from the cardiac damage caused by true anthracyclines. Cyclophosphamide can cause haemorrhagic cell necrosis that is more common with larger single doses, and may lead to severe heart failure or death. However, with the lower cycle doses presently used, these toxicities are seen infrequently. Cisplatin has also been associated with late-onset cardiac dysfunction, although the cardiovascular side effects appear less severe than those of anthracyclines. Finally, myocardial ischaemia induced by pyrimidine analogues infrequently leads to myocardial infarction with all long-term cardiovascular sequelae.
Type II agents - myocardial dysfunction from agents not associated
with cumulative dose-relate cardiotoxicity
A number of recently introduced cancer drugs cause cardiac dysfunction. Among them are the ‘targeted drugs’ against HER2/erbB2 - and vascular endothelial growth factor (VEGF) signaling pathways.
Anti-HER2/erbB2 cancer drugs
Trastuzumab, a monoclonal antibody against the HER2/erbB2 receptor, in combination with chemotherapy substantially improves overall survival of women with HER2-overexpressed breast cancer and prolongs lives of patients with advanced gastric cancer. It was the first type II agent to be studied broadly with regard to cardiotoxicity, as the pivotal trial of trastuzumab and anthracyclines found severe (NYHA III-IV) heart failure in 16% of patients. This incidence was much higher than that associated with anthracycline treatment alone. One common finding was that the concomitant use of trastuzumab with anthracycline greatly increased the risk of cardiotoxicity. Consequently, in all adjuvant breast cancer trials, trastuzumab was only used after anthracyclines or with anthracycline-free chemotherapy. This lowered the incidence of severe heart failure to 0-3.9% and the rate of (asymptomatic) cardiac dysfunction to 7-34%. Importantly, patients in these trials were carefully selected and were required to have a normal cardiac function (i.e. LVEF >50-55%) and no significant pre-existing cardiac disease. The stringent criteria for trastuzumab discontinuation were employed and the withdrawal rate for cardiac dysfunction was as high as 16%. Further analysis of the time interval between the administration of the anthracycline and the start of trastuzumab suggested that a strong correlation in the concomitant administration was associated with the highest reported incidence of cardiotoxicity, while an interval of 3 months had an incidence that was almost as low as was the incidence for those who had not been treated with prior anthracyclines. This observation supported the concept that trastuzumab may well act as a modulator of anthracycline toxicity when administered during a period of myocyte vulnerability following anthracycline exposure.
Based on the observations in these trials, the following risk factors for trastuzumab-associated cardiotoxicity were identified: prior treatment with anthracycline chemotherapy, a borderline lower limit of normal LVEF, prior treatment with anti-hypertensive medication (for the lack of better definition this likely means pre-existing arterial hypertension) and advanced age.
One common finding in these trials was that cardiac dysfunction and heart failure occurred predominantly during the trastuzumab treatment and was frequently reversible. However, only data from about 5 years of the patient follow-up in the most prominent trastuzumab trials are available, and longer-term surveillance is needed. The cardiotoxicity of other anti-HER2 therapies, such as the small molecule tyrosine kinase (TKI) inhibitor lapatinib, look promising, however they are still under investigation.
Angiogenesis inhibitors (anti-vascular endothelial growth factor) cancer drugs
Angiogenesis inhibitors that target VEGF with either antibodies against VEGF (bevacizumab) or small molecule TKIs (sunitinib, sorafenib) prolong the lives of patients with a variety of solid tumours. Vascular endothelial growth factor signaling also plays a role in myocardial and vascular homeostasis, so it is not surprising that these drugs can affect endothelial cells, myocyte function, and metabolism.
Bevacizumab causes cardiac dysfunction and heart failure in 3.8% of patients, particularly when used together with or after anthracyclines.Two recent meta-analysis, including almost 7000 patients treated with sunitinib and 900 patients treated with sorafenib showed a rate of 4.1% for sunitinib-induced heart failure and 1% for sorafenib-associated cardiac dysfunction.
The pathophysiology of anti-VEGF-induced cardiac dysfunction and heart failure remains poorly understood.Sunitinib can induce myocyte apoptosis in preclinical models: although, similar to trastuzumab, cardiac biopsies from patients treated with this agent show no major myocardial injury. Furthermore, all of these agents can induce arterial hypertension, which may lead to secondary heart failure in vulnerable patients.
Imatinib and dasatinib are small molecule TKIs used for the treatment of chronic myelogenousleucemia (CML) and gastrointestinal stromal tumours. Initial reports described severe heart failure in 10 CML patients treated with imatinib, but these findings could not be confirmed in a large follow-up study. Isolated events of heart failure were also reported in CML patients treated with dasatinib. Both compounds can also induce peripheral oedema, pleural and pericardial effusion unrelated to heart failure - a condition that has to be considered in the differential diagnosis.
Cardiovascular side effects beyond cardiac dysfunction
Cancer drug-induced arterial hypertension is now recognized as an entity primarily associated with the use of angiogenesis inhibitors. On a dose-dependent basis, these drugs can worsen pre-existing hypertension, or can cause de novo hypertension to develop. The incidence of arterial hypertension associated with bevacizumab, sunitinib and sorafenib appear similar ~23%. The mechanism of angiogenesis inhibitor-induced hypertension is not completely understood, but may be directly linked to the inhibition of VEGF-2 signaling. Hypertension involves mechanisms similar to those of tumor destruction, and therefore may also be a marker for efficacy of angiogenesis inhibitors.
Vasospastic and thromboembolic ischaemia associated with anti-cancer treatment
Among agents associated with coronary artery spasm, the pyrimidine analogues 5-fluorouracil (5-FU) and its oral pre-drug capecitabine are the most common.Nitroglycerin and calcium-channel blockers are often effective for the treatment and prevention of ischaemia.In rare instances, progression to myocardial infarction has been reported.
Patients with malignancies are in a hypercoagulable state and conventional chemotherapeutics, signaling inhibitors, and endocrine cancer therapies can further increase a patient’s risk of VTE and ATE. Cisplatin Bevacizumab tamoxifen sunitinib and sorafenib showed increased incidences of thromboembolic events.
Dysrhythmia and QT prolongation
Rhythm disturbances associated with anti-cancer treatment are typically transient and not especially troubling. They occur most commonly as a consequence of metabolic changes and generally resolve after electrolyte homeostasis is re-established. Anthracyclines cause supraventricular arrhythmias and ventricular ectopy, taxanes cause sinus bradycardia and QT prolongation is associated with a number of anti-cancer drugs and may constitute a significant problem.
Virtually all anticancer drugs impact the cardiovascular system one way or another!
Cardiovascular evaluation of patients
before treatment with anticancer agents
All patients undergoing chemotherapy should have prior careful clinic evaluation and assessment of CV risk factors or comorbidities. Frequent vital signs monitoring is recommended during chemotherapeutic agent infusion, particularly with 5-FU or paclitaxel. ECG and clinic cardiovascular evaluation are useful to screen signs of cardiomyopathy, conduction disturbances, QT interval, before beginning anticancer therapy with anthracycline or paclitaxel or small molecule TKIs. Early detection of cardiotoxicity allows the treating oncologist to redirect therapy or dose modify, taking into account the cost of a reduction in therapy against the potential of further injury to the patient.
In these instances, the role of the cardiologist is to assist and advise the oncologist by providing diagnostic and prognostic information regarding developing cardiotoxicity. Evaluation and surveillance of cardiac function is recommended before, during, and after administration of chemotherapeutic agents with associated cardiotoxicity.
“Is it time for oncologists to get to know their cardiologists?”
Given the variety of effects and mechanisms described above, there is an increasing awareness of the concept: “Is it time for oncologists to get to know their cardiologists?”. A patient who has a comorbidity of cardiovascular disease and cancer could possibly have a different outcome depending on whether he or she was first seen by an oncologist or a cardiologist.
The oncologist takes a tumor-centric perspective in diagnosis, and in the past might have been missing the incumbent cardiopathy of the individual. The cardiologist treats the cardiopathy correctly, but may not pick up early signs of cancer, thus the patient risks further progression and oncologic complications. Teamwork should improve patient life expectancy, treating cancer while protecting the heart, or treating the heart and providing a thorough oncologic check up.
In a cardio-oncology team effort, the oncologist and cardiologist should work together, evaluating the patient’s cardiovascular risk level as an integral part of the choice of cancer therapy. The patient is monitored throughout therapy and follow-up so that eventual cardiovascular alterations can be detected in a timely manner and treated either by intervention on the cardiovascular side or by modulation of the cancer therapy.
Close cooperation between cardiologists and oncologists is thus crucial in order to balance the risks and benefits of cardiotoxic anticancer therapy and the oncologist should be aware of the cardiotoxic potential of cancer therapies.
Initial assessment, treatment decision in accordance to the patient’s cardiovascular status, monitoring and strategies to reduce the impact on the heart fall with the treating oncologist, but once HF appears, the patient should be referred to a cardiology specialist for further investigations and treatment of the condition!