In the past 30 years, malignant disease mortality has been reduced, among other things, owing to advances in chemotherapeutic protocols. (1) However, prolonged survival frequently is achieved at the expense of damage to other organs including cardiovascular (CV) system. (2) Currently, CV diseases are the second leading cause of long-term morbidity and mortality among patients treated for carcinoma. (3) Both conventional chemotherapy and targeted biological therapy increase the risk of heart injury, left ventricular (LV) dysfunction and symptomatic heart failure (HF). (4) In addition, hypertensive reaction, vasospastic and/or thrombotic myocardial ischemia, rhythm and conductivity disorders may also occur. Some of these adverse effects are irreversible and cause progressive CV disease, whereas others cause only transient dysfunction without long-term sequels. (5) Predisposition to development of cardiotoxicity is multifactorial and is determined by the interaction of genetic and environmental factors. (6) Cardiotoxicity may manifest during or immediately after treatment (within days or weeks), or even long after completion of anti-cancer therapy. Some of the defined risk factors are for coronary artery disease or congestive HF positive family history, age, sex, arterial hypertension and dyslipidemia. An increased risk of cardiotoxicity has also been reported in patients with reduced systolic LV function and significant arrhythmias.
The ever-growing number of patients treated with chemotherapy and biological agents has resulted in the continuously increasing incidence of cardiotoxicity. (7) The extent of the problem is even greater taking into account that some of the patients have to take a combination of several cardiotoxic agents. (8) These unfavorable facts have pointed to the need of establishing cardio-oncologic teams and defining guidelines for follow up and treatment of these patients, such as those recently issued by the European Society of Cardiology in 2016. (9)
Tumor biological therapy with monoclonal antibodies or tyrosine kinase inhibitors (TKI) targets human epidermal growth factor 2 (HER2) receptors (e.g., trastuzumab, pertuzumab, etc.), vascular endothelial growth factor (VEGF) and VEGF receptors (e.g., bevacizumab, sunitinib, sorafenib, etc.), or Abl kinase activity (e.g., imatinib, nilotinib, dasatinib, etc.) (10) (Table 1). However, these therapies also impair molecular mechanisms that are crucial for CV health, resulting in cardiotoxicity. The aim of the article is to point to the potential CV side effects associated with particular biological drugs and antibodies used in the treatment of carcinoma in adult patients.
HER2 = human epidermal growth factor receptor 2; VEGF = vascular endothelial growth factor.
Trastuzumab is a humanized monoclonal antibody that targets human epidermal HER2 receptor by inhibiting transfer of the signal induced by HER2 activation. (11, 12) In breast cancer patients with HER2 receptor overexpression, HER2 receptor blockade was found to improve survival and time of remission significantly, and has been used in the standard treatment protocol for metastatic or localized disease. (13, 14) The major side effect of trastuzumab therapy is the occurrence of cardiotoxicity independent of the drug cumulative dose, mostly manifesting as asymptomatic reduction of the left ventricular ejection fraction (LVEF), and less frequently as clinically symptomatic HF. (15) Unlike irreversible (type I) anthracycline induced damage, trastuzumab therapy results in reversible cardiac stunning in most cases, which resolves within 30 days (type II) in 65%-70% of patients. (16) However, in some patients it may progress to irreversible dilated cardiomyopathy. In large studies, the incidence of cardiotoxicity ranges from 8% to 13%, and similar data have also been reported from meta-analyses of randomized controlled studies, where the incidence of cardiotoxicity was around 10%. (17, 18) It appears that cardiotoxicity is mostly caused by direct cardiac HER2 protein blockade, however, other mechanisms cannot be excluded. (19) Risk factors for development of cardiotoxicity are pre-existent arterial hypertension, low LVEF at initiation of trastuzumab therapy, high body mass index (>25), coronary and valvular disease, and previous treatment with high anthracycline doses. (20, 21)
The incidence and type of cardiotoxicity of other anti-HER2 biological agents (pertuzumab and trastuzumab-emtansine) generally are similar to those associated with trastuzumab. (22) In recent protocols of neoadjuvant therapy for breast cancer and in the treatment of metastatic gastric cancer, trastuzumab is combined with other anti-HER2 drugs. According to data available so far, these combinations did not result in additional aggravation of CV side effects. (23) Yet, results of a large prospective randomized study (Aphinity) investigating a combination of pertuzumab and trastuzumab as adjuvant therapy are expecting to shed more light on the issue. (24) Another two studies of neoadjuvant therapy (Neosphere and Tryphaena) showed better results in women with breast cancer treated with chemotherapy and dual HER2 blockade (pertuzumab and trastuzumab) as compared with patients treated with chemotherapy and trastuzumab alone. In the Tryphaena study, the primary endpoint of CV safety with a low incidence of symptomatic and asymptomatic systolic LV dysfunction was achieved in all study groups. (25) Finally, it should be noted that the benefit of trastuzumab in terms of reducing the risk of the underlying malignant disease outweighs the increased risk of cardiotoxicity.
Bevacizumab is a humanized anti-VEGF antibody that is used in the treatment of patients with metastatic colon and breast cancer, non-small-cell lung carcinoma, renal cell and ovarian carcinoma, and glioblastoma multiforme. Bevacizumab cardiotoxicity generally manifests in the form of uncontrolled arterial hypertension. The most severe grade 3 and 4 arterial hypertension occurs in 9.2% of patients, with rare cases of hypertensive crisis including encephalopathy or intracranial hemorrhage. Hypertension may develop at any time during bevacizumab therapy, with some data suggesting an association of individual dose size and unfavorable outcomes. (26, 27) The mechanism of HF that occurs in 1.7%-3.0% of cases may be related to uncontrolled hypertension and inhibition of VEGF signaling. (28)
Fatal thromboembolic events such as myocardial infarction, ischemic stroke and pulmonary embolism may occur in 3.8% of patients on bevacizumab therapy. Thromboembolic events can occur at any time from therapy initiation. The mechanism of their occurrence remains obscure and does not appear to be related to either individual or cumulative drug dose. The risk is higher in elderly patients (age ≥65) and in those with a history of arterial thromboembolic event. (29) It is speculated that these events are induced by the antitumor therapy effect on the coagulation cascade with vascular intimal and endothelial cell continuity impairment, while anti-VEGF therapy reduces nitric oxide and prostacyclin levels, thus favoring development of thromboembolism. (30)
Tyrosine Kinase Inhibitors
Tyrosine kinase inhibitors can also be classified into HER2 pathway blockers such as lapatinib, and specific (axitinib) or nonspecific (sunitinib, sorafenib, vandetanib and pazopanib) VEGF pathway inhibitors.
Lapatinib is a TKI efficacious in the treatment of HER2p95 (aberrant form of HER2) positive breast cancer. It appears that lapatinib therapy is associated with a low prevalence of HF or other adverse CV effects. (31) In clinical studies, LVEF reduced by at least 20% was recorded in only 1.6% and symptomatic HF in 0.2% of patients. The prevalence of cardiotoxic complications was increased in patients having previously received anthracyclines or trastuzumab (32). In addition, reversible QT interval prolongation was recorded in some patients. In these patients, regular electrocardiographic (ECG) follow up along with dose adjustment or therapy discontinuation is recommended.
Sorafenib is a TKI used in the treatment of advanced renal cell and hepatocellular carcinoma, and advanced radioactive iodine-refractory thyroid carcinoma. Hypertension is the major side effect of sorafenib therapy, recorded in 17%-43% of cases. (33) Sorafenib therapy has been reported to be associated with development of acute coronary syndrome and of myocardial infarction in 2.9% of patients. Sorafenib toxicity can be explained by the inhibition of RAF1, which inhibits proapoptotic kinases. The occurrence of hypertension can be attributed to the VEGF receptor inhibition, which leads to reduced capillary permeability and increased volume load. (34)
Sunitinib is a TKI used in the treatment of renal cell carcinoma and gastrointestinal stromal tumor. Sunitinib acts on tumor cell proliferation and tumor angiogenesis. (35) Hypertension develops in a substantial proportion of sunitinib treated patients (47%), while 11% of patients experience CV events including acute myocardial infarction and HF. Asymptomatic LVEF reduction by at least 10% was recorded in nearly 28% of patients. (36) The mean time to HF development is 22-27 days; however, it appears to respond well to medical therapy. High-risk patients are those with a history of coronary disease, HF, LV dysfunction and previous anthracycline therapy. The true mechanism of cardiotoxicity remains unknown; however, it is most likely induced by inhibition of a series of growth factor receptors in cardiomyocytes. (37)
Ipilimumab, Nivolumab and Pembrolizumab
Antibodies for immune response modulation have proved efficacious in the treatment of various tumor types including melanoma (anti-CTLA-4 and PD-1), non-small-cell lung carcinoma and renal cell carcinoma. However, this therapy leads to a number of immune mediated side effects, so far including occasional cases of myocarditis and/or pericarditis. (38)
Follow up in Patients on Antitumor Biological Therapy
Thorough CV evaluation must be performed in all oncologic patients planned to be administered biological therapy with potentially cardiotoxic agents; yet CV complications will only develop in a minor proportion of patients. Therefore, it is of utmost importance to early identify and follow-up patients at high risk. All patients should undergo clinical examination and ECG before and during treatment. Detecting any ECG abnormalities such as tachycardia at rest, ST-T segment changes, conductivity impairment, QT-interval prolongation or arrhythmia may point to cardiotoxicity. Transthoracic echocardiography is the main diagnostic method for LV function assessment; it is recommended to perform it prior to therapy initiation, then at 3-month intervals, and upon completion of cardiotoxic therapy. Evaluation of LV function is crucial in anti-HER therapy since the majority of patients had received anthracyclines prior to targeted therapy introduction; it is of utmost importance to assess LV function after previous chemotherapy and before targeted therapy initiation. (39) LV function is assessed by two-dimensional (2D, Simson) method or by 3D echocardiography if available. (40) Other novel echocardiography techniques such as contrast echocardiography and stress echocardiography are indicated for assessment of borderline standard echocardiography findings. Tissue Doppler imaging and strain analysis are useful in early detection of LV dysfunction and should be used whenever possible. Assessment of the global longitudinal systolic strain is highly useful, as its reduction to less than 15% is an early sign of systolic dysfunction. (41) Therapy is suspended or temporarily discontinued in case of LVEF 15%-16% reduction from baseline or 10%-15% reduction from normal. Discontinuation of targeted therapy is recommended if LVEF fails to recover within 4 weeks. Monitoring cardiac biochemical markers (troponin and natriuretic peptides) during cardiotoxic therapy can help detect an early myocardial lesion. However, elevated levels of biochemical markers can only identify patients at high risk of cardiotoxicity because for the time being, there is no clear evidence that oncologic therapy should be suspended or discontinued in case of their pathologic finding. (42)
Treatment of anti-HER2 therapy induced cardiotoxicity does not differ from treatment of other HF patients; generally, angiotensin-converting enzyme inhibitors (ACEi) and beta-blockers are used, along with diuretics in case of symptomatic HF. (43) In patients administered VEGF signal pathway blockers, careful assessment of CV risk factors is required at therapy initiation, followed by regular blood pressure follow up and early introduction of antihypertensive therapy. In most patients, anti-VEGF therapy can be continued upon proper blood pressure regulation. (44)
Oncologic patients receiving targeted biological therapy associated with a high risk of cardiotoxicity require multidisciplinary approach and regular cardiologic follow up for timely recognition and appropriate treatment of CV side effects. Such an approach results in more favorable clinical outcomes and patient quality of life, along with optimal continuation of specific oncologic treatment if possible.