Introduction
Cardiotoxicity is one of the worrisome side effects of cancer-directed therapy. Cardiac adverse events can range from mild to severe and vary between classes of targeted agents. Some relevant cardiac adverse events include electrocardiogram (ECG) changes, QT prolongation, hypertension, arrhythmias, pericardial disease, and heart failure. Cardiac toxicities can limit the use of these drugs and warrant their discontinuation. Preexisting comorbidities and cardiac conditions can add to or worsen cardiac toxicity. The Common Terminology Criteria for Adverse Events (CTCAE) provides descriptions and grading for cardiovascular side effects. In this chapter, we will first review the various targeted therapies that are known to cause cardiotoxicities, and then discuss in detail each of the cardiotoxicities and their respective management. Table 16.1 shows the grading of each cardiac toxicity based on the National Cancer Institute (NCI) CTCAE version 5.0.
| CTCAE Term | Grade 1 | Grade 2 | Grade 3 | Grade 4 | Grade 5 |
|---|---|---|---|---|---|
| Heart failure | Asymptomatic with laboratory (e.g., BNP) or cardiac imaging abnormalities | Symptoms with moderate activity or exertion | Symptoms at rest or with minimal activity or exertion; hospitalization; new onset of symptoms | Life-threatening consequences; urgent intervention indicated (e.g., continuous IV therapy or mechanical hemodynamic support) | Death |
| Left ventricular systolic dysfunction | – | – | Symptomatic due to drop in ejection fraction responsive to intervention | Refractory or poorly controlled heart failure due to drop in ejection fraction; intervention, such as ventricular assist device, intravenous vasopressor support, or heart transplant indicated | Death |
| Corrected QT interval prolongation on the ECG | Average QTc 450–480 ms | Average QTc 481–500 ms | Average QTc ≥501 ms; >60 ms change from baseline | Torsade de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia | Death |
| Hypertension | Systolic BP 120–139 mmHg or diastolic BP 80–89 mmHg | Systolic BP 140–159 mmHg or diastolic BP 90–99 mmHg if previously WNL; change in baseline medical intervention indicated; recurrent or persistent (≥24 h); symptomatic increase by >20 mmHg (diastolic) or to >140/90 mmHg; monotherapy indicated or initiated | Systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg; medical intervention indicated; more than one drug or more intensive therapy than previously used indicated | Life-threatening consequences (malignant hypertension, transient or permanent neurologic deficit, hypertensive crisis); urgent intervention indicated | Death |
Targeted Therapies Associated With Cardiotoxicity
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HER2 targeting antibodies (trastuzumab, pertuzumab, T-DM1): Trastuzumab and pertuzumab are monoclonal antibodies directed toward the HER2 receptor. They specifically target the erbB2 receptor tyrosine kinase. Trastuzumab is used mainly in HER2-neu-positive breast cancer and in metastatic HER2-neu-positive gastric cancers. These drugs carry a black box warning for cardiomyopathy and heart failure, with an increased risk of heart failure in patients with concomitant use of anthracyclines. T-DM1 (ado-trastuzumab emtansine) is an antibody drug conjugate, which is composed of trastuzumab, a thio linker, and a microtubule inhibitor. This drug had been approved for use in first- or second-line HER2 neu-positive metastatic breast cancer.
Mechanism of action
ErbB2/neu is a member of the epidermal growth factor family. Its gene is amplified in many cancer types, and its overexpression is associated with poor prognosis in breast and ovarian cancer. It is overexpressed in 25% to 30% of breast cancer patients.
Mechanism of cardiotoxicity
Neuregulins (neu-differentiation factors) and heregulin (ligand with acetyl choline receptor–inducing activity and glial growth factor) along with erbB2 are associated with cardiac myocyte development and have been shown to inhibit the growth of cardiac stem cells and lack capacity for cardiogenic differentiation and vascular formation. Thus interruption of this pathway can lead to cardiac toxicity. Manifestations range from asymptomatic decline in heart function to symptomatic congestive heart failure. Reported symptoms include tachycardia, palpitations, lower extremity edema, dyspnea on exertion, and clinical heart failure.
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HER2–targeting tyrosine kinase inhibitors (TKIs) (lapatinib): Lapatinib is a TKI against EGFR1 and HER2 that results in the inhibition of signaling pathways downstream of HER2. Lapatinib is metabolized in the liver and thus dose adjustments are required in patients with hepatic impairment. Lapatinib has been used in combination with chemotherapy, mostly capecitabine. The most common side effects are diarrhea, rash, and anorexia. Based on a clinical trial comparing lapatinib and capecitabine with capecitabine alone, there were no significant symptomatic cardiac adverse events in the combination treatment arm. Furthermore, no treatment withdrawal or dose reductions due to decreases in left ventricular ejection fraction (LVEF) were reported. There were, however, reports of asymptomatic cardiac events in 4 out of 163 women in the combination treatment arm. One of the four women in the combination arm developed Prinzmetal angina; however, with treatment cessation, her symptoms improved. Due to the decrease in LVEF, the dose was reduced to 1000 mg daily and there was no recurrence of cardiac event noted thereafter.
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Multi-TKIs (sorafenib, sunitinib, pazopanib, axitinib, vandetanib, regorafenib, lenvatinib, cabozantinib)
Mechanism of action
An overview of the vascular endothelial growth factor (VEGF) pathway and the mechanism of action of VEGF inhibitors is discussed elsewhere in this book. The specific effects of VEGF inhibition on cardiac tissue are discussed here.
TKIs have antitumor activity in a variety of malignancies
These TKIs have anti-VEGF activity, but also have activity against growth factor receptors such as EGFR, FGFR, and RET. Their broad coverage is attributed to the similarity of structures at the ATP-binding site region. Because their effects are not limited to VEGF receptors, but also to other growth factor receptors, these drugs are referred to as multitargeted TKIs, or antiangiogenic TKIs. Examples of antiangiogenic TKIs that are in clinical use are sorafenib (inhibits VEGFR2, fms-like tyrosine kinase 3 [FLT3], PDGFR, and fibroblast growth factor receptor [FGFR]-1); sunitinib (inhibits c-kit, VEGFR1-3, PDGFR-alpha, PDGFR-beta, FLT3, CSF-1R, RET); pazopanib (inhibits VEGFR1-3, PDGFR-alpha and -beta, FGFR1 and 3, c-KIT); axitinib (selective VEGFR inhibitor that targets VEGFR1-3); vandetanib (inhibits VEGFR, RET, and EGFR); regorafenib (targets VEGFR1-3 in addition to RET, c-KIT, PDGFR-alpha and -beta, FGFR1 and 2, and other membrane-bound and intracellular kinases); and lenvatinib (targets VEGFRs, RET, and FGFR).
Mechanism of cardiotoxicity
VEGF is a protein that upregulates endothelial cell nitric oxides synthase (ecNOS), which upregulates nitric oxide (NO) production, thereby modulating vasodilation, microvascular hyperpermeability, and angiogenesis. VEGF inhibitor-induced hypertension is mediated by suppression of NO production.
Types of cardiotoxicity
In general, the cardiotoxicities associated with anti-VEGF agents are hypertension, thromboembolic disease, left ventricular dysfunction, myocardial ischemia, QT prolongation, and thrombotic angiopathy.
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BCR/ABL and c-KIT inhibitors (imatinib, dasatinib, nilotinib, bosutinib, ponatinib): The mechanism of cardiotoxicity with BCR/ABL and c-KIT targeting drugs is similar to that of multitargeted TKIs.
Imatinib
Imatinib is known to induce myocyte death by necrosis, autophagy, and apoptosis. The mechanism of imatinib-induced cardiotoxicity was evaluated in animal studies. Dose-related increases in cardiac expression were observed for several genes associated with endoplasmic reticulum stress response, protein folding, and vascular development and remodeling.
Dasatinib
Dasatinib has been approved for the frontline treatment of chronic myeloid leukemia (CML). The most common adverse events associated with dasatinib therapy are cytopenias, particularly neutropenia and thrombocytopenia. Fluid retention, pleural effusion, skin rash, headache, and gastrointestinal disturbances are some other notable side effects. The most common cardiac toxicity associated with dasatinib is fluid retention, especially pleural effusion.
Nilotinib
Nilotinib has been described to cause QT prolongation and thus must be used with particular caution when combined with other QT-prolonging drugs.
Bosutinib
Bosutinib is used in the treatment of CML. It is primarily metabolized in the liver by CYP3A4; thus concurrent use of bosutinib with CYP3A inhibitors and inducers should be avoided whenever possible. P-glycoprotein inhibitors should be avoided, as these can increase the drug concentrations. Most of the cardiotoxicities associated with this drug are reported in the BELA study, a phase III study comparing bosutinib to imatinib in the first-line treatment of CML. Reported cardiac reasons for discontinuation were arrhythmia, pericardial effusion, right bundle branch block, congestive heart failure (CHF), and QT prolongation. Dose reductions due to cardiac toxicities have been reported with bosutinib.
Ponatinib
Ponatinib is also used in the treatment of CML, particularly as a second-line treatment for chronic, accelerated, or blast phase CML, especially in patients who are T315I-positive. Ponatinib is also indicated for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Ponatinib is associated with multiple cardiotoxicities including hypertension, peripheral vascular disease, arterial ischemia, cerebral ischemia, coronary artery disease, arterial occlusive disease, and mesenteric occlusive disease.
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VEGF inhibitors (aflibercept, ziv-aflibercept): Aflibercept is a soluble decoy receptor that binds to all isoforms of VEGF (VEGF-A and -B) and placental growth factor (PIGF). The binding of VEGF with its receptors promotes endothelial proliferation and causes angiogenesis.
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ALK inhibitors (alectinib, crizotinib, ceritinib, brigatinib): Anaplastic lymphoma kinase (ALK) is a fusion oncogene that is commonly rearranged in non–small-cell lung cancer (NSCLC). ALK inhibitors, such as alectinib, brigatinib, crizotinib, and ceritinib, are indicated in metastatic NSCLC harboring ALK gene rearrangements.
Crizotinib and Alectinib
Crizotinib was initially developed as a c-MET inhibitor but was later found to have activity in cancers with ALK gene rearrangements and was the first drug to be US Food and Drug Administration (FDA)–approved for use in this setting. , Crizotinib also inhibits the ROS1 receptor tyrosine kinase. Crizotinib is given at a dose of 250 mg twice daily. However, based on randomized studies, alectinib, which is given 600 mg twice daily, has become a more popular first-line agent when compared with crizotinib. Crizotinib and alectinib have both reported cardiac side effects of bradycardia and QT prolongation.
Ceritinib
The approved dose of ceritinib is 450 mg once daily. The ASCEND-4 trial, an open label phase III study, which led to the approval of first-line ceritinib in ALK-positive metastatic NSCLC, reported no significant cardiac side effects in treated patients except for one patient treated with ceritinib who developed grade 5 myocardial infarction.
Brigatinib
Brigatinib is a next generation ALK inhibitor which has also been show to have better efficacy over crizotinib and is approved for in the first line setting. Brigatinib is given as 90 mg daily for 7 days, and if tolerated, the dose is increased to 180 mg daily. The most commonly reported cardiac side effect of brigatinib is hypertension.
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PARP inhibitors (niraparib, olaparib): Niraparib is a poly ADP-ribose polymerase (PARP) inhibitor approved for the treatment of ovarian, fallopian, or primary peritoneal cancer. Niraparib blocks both PARP1 and PARP2 enzymes. Niraparib was found to inhibit tumor growth in models with loss of BRCA activity and loss of function mutation of tumor suppressor PTEN proteins. Niraparib is either given at 200 mg daily or 300 mg daily depending on weight and platelet count. Olaparib is used in the treatment of HER2-negative, germline BRCA-mutated (gBRCAm) metastatic breast cancer, advanced ovarian, pancreatic, and prostate cancers. In general, patients should be demonstrated to have homologous recombination deficiency, most commonly in the form of BRCA mutations. The notable exception is in the maintenance treatment of recurrent ovarian cancer. Olaparib is either given at 300 mg tablets twice daily or 400 mg capsules twice daily. Some of the most common side effects of niraparib and olaparib are cytopenias including thrombocytopenia, anemia, and neutropenia. Some cardiac side effects were reported with niraparib and olaparib, the most common of which are hypertension, tachycardia, and palpitations.
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CDK4/6 inhibitors (ribociclib, palbociclib, abemaciclib): CDK4/6 inhibitors in combination with endocrine therapy are used in the first-line treatment of many patients with ER/PR-positive, HER2-negative, metastatic breast cancer. The three drugs that are currently approved in this category are ribociclib, palbociclib, and abemaciclib. In the PALOMA-2 trial, which used palbociclib and letrozole, cardiac side effects were not described in detail. However, there were subsequent reports of QT prolongation with this class of drug, and in the mentioned study, patients with baseline QT prolongation were not included.
BRAF inhibitors (vemurafenib, dabrafenib) Vemurafenib
Vemurafenib is an orally available BRAF inhibitor and is approved for the treatment of metastatic melanoma with a BRAF V600E mutation. Vemurafenib is metabolized by CYP3A4, and thus CYP3A4 inducers and inhibitors need to be avoided during treatment, as these can alter drug concentrations.
Dabrafenib/Trametinib
Dabrafenib is a BRAF inhibitor that is approved for unresectable stage III and stage IV melanoma patients. Dabrafenib was approved after a phase III trial which compared single agent dabrafenib to dacarbazine. Trametinib is a MEK inhibitor given in combination with dabrafenib to improve efficacy. Dabrafenib, when given in combination with trametinib has been associated with cardiotoxicity. Decreased ejection fraction (EF) was noted in a patient who had combination chemotherapy, which improved after cessation of treatment. There are also reports of cases of cardiomyopathy in patients treated with a combination therapy of dabrafenib and trametinib. As there are reports of cardiotoxicity with trametinib, a baseline echocardiogram needs to be obtained, and then periodically while on treatment. If there is a decline in EF of 10% or greater, treatment should be withheld, and cardiac function should be reassessed. If cardiac function improves, the drug can be resumed at a lower dose. Treatment should be discontinued in patients who develop symptomatic heart failure. If the initial decline in the EF is greater than 20%, treatment should be discontinued permanently.
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EGFR inhibitors (erlotinib, gefitinib, osimertinib)
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Erlotinib: Rash and diarrhea are the main side effects with this drug. Dyspnea and pneumonitis have been reported, but cardiac side effects are relatively low. Cardiomyopathy causing a decline in EF, which improved with erlotinib cessation, has been reported.
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Gefitinib: Gefitinib-induced cardiotoxicity and cardiac hypertrophy in vivo and in vitro rat models has been described. The mechanism behind these is through cardiac apoptotic cell death and altered oxidative stress pathways. Except for occasional reports of fluid retention, no significant clinical cardiac adverse effects have been reported.
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Osimertinib: Osimertinib is approved as first-line treatment for patients with metastatic NSCLC with sensitizing EGFR mutations. Osimertinib is known to cause QT prolongation. ECGs and electrolytes should be monitored in patients who have a history or predisposition for QT prolongation and in those who are taking medications that are known to cause QT prolongation. Grade 1 or 2 toxicity may require temporary treatment interruption. If clinically significant severe QT prolongation is found, osimertinib should be permanently discontinued (according to the FDA recommendations). Cardiomyopathy has been reported in 1.4% of patients and thus baseline echocardiogram and periodic assessment of LVEF is recommended. In the FLAURA study, which led to the approval of osimertinib in the first-line setting for EGFR-positive metastatic NSCLC, changes in QT interval were reported in a higher percentage of patients in the osimertinib group (10%) compared with the first-generation EGFR-TKI group (5%).
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Common Cardiotoxicities Caused by Targeted Therapie
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Hypertension
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Sunitinib: Sunitinib is a multitargeted TKI used in the treatment of renal cell carcinoma (RCC) , and gastrointestinal stromal tumor (GIST) in the second-line after imatinib use. The dose of sunitinib varies from 37.5 mg daily to 50 mg daily depending on the indication. The reported incidence of hypertension with sunitinib in various clinical trials ranges from 15.3% to 29.6%. , Patients receiving sunitinib should be monitored for hypertension and changes in LVEF, especially those with prior cardiac disease.
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Pazopanib: Pazopanib is another multitargeted TKI, with a similar side effect profile to sunitinib. In a meta-analysis of phase II and phase III prospective clinical trials using pazopanib, the overall incidence of hypertension was 39.5% for all grades and 6.5% for grades 3 and 4 hypertension. A higher incidence of all-grade hypertension was reported in patients taking axitinib (42%) and pazopanib (36%) compared to sorafenib (29%) and sunitinib (22%).
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Lenvatinib: Lenvatinib, a multikinase inhibitor with particular activity against VEGFR kinases, is also reported to have a high incidence of hypertension. Associated risk factors included a prior history of hypertension, obesity, and age greater than 60 years. Periodic assessments of hypertension are warranted, especially in the initial months of starting treatment, and if required, antihypertensive medications can be prescribed to improve VEGF-TKI medication tolerance. Poorly controlled, prolonged hypertension can lead to cardiomyopathy, decreased LVEF, and CHF.
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Ramucirumab: Ramucirumab is a monoclonal antibody targeting against VEGFR2. It is associated with an increased risk of hypertension and arterial thrombotic events.
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Ziv-aflibercept: Ziv-aflibercept has been approved for the treatment of metastatic colon cancer in combination with FOLFIRI (5FU, leucovorin, and irinotecan) in patients who have progressed on oxaliplatin-based chemotherapy. It is administered at a dose of 4 mg/kg. Results from the pivotal trial VELOUR, a phase III study of aflibercept and FOLFIRI versus placebo and FOLFIRI for metastatic colorectal cancer as second line-therapy, led to the approval of this drug. Grade 3 hypertension was seen in 19.1% of patients in the aflibercept group compared with only 1.5% of patients in the control group; however, only one patient in the study arm developed grade 4 hypertension. Given this risk, baseline ECG and blood pressure assessment are required. There are no specific guidelines for blood pressure monitoring, and clinical judgement must be exercised. Treatment consists of antihypertensives for grades 1 and 2 hypertension. If a patient develops severe hypertension, temporary discontinuation of the drug is recommended. On some occasions, permanent discontinuation may be necessary.
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ALK inhibitors: Patients receiving selective ALK inhibitors have been reported to develop hypertension. Hypertension developed in 21% of patients on brigatinib, 5.9% of whom had grade 3 hypertension. Baseline hypertension screening and periodic blood pressure assessments are recommended, and if elevated, antihypertensive treatment is recommended. It should be noted that ALK inhibitors can cause bradycardia, thus antihypertensives which may cause bradycardia such as beta-blockers should be used carefully.
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PARP inhibitors: Some PARP inhibitors, such as niraparib and olaparib, cause hypertension, tachycardia, and palpitations, and thus patients receiving these drugs should be monitored reguarly. The actual proportions of patients who suffer cardiovascular toxicities, however, have not been described in detail. Dose reductions and use of antihypertensive medications may help in uncontrolled hypertension associated with PARP inhibitors.
Congestive Heart Failure
Heart failure is a clinical syndrome in which heart function decreases such that demand is not adequately met. CHF is characterized by symptoms, such as shortness of breath and lower extremity edema, resulting from fluid retention due to inadequate cardiac output. The functional staging of heart failure has been described by the New York Heart Association (NYHA).
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CHF associated with HER2–targeted therapies (trastuzumab, pertuzumab, ado-trastuzumab emtansine): The development of CHF in patients who were enrolled in phase II and phase III trials has been retrospectively studied to note the incidence of trastuzumab-related toxicities. In patients who had received concomitant trastuzumab and anthracycline-based chemotherapy, there was an increased risk of cardiac toxicity (27%) compared to patients who had received paclitaxel and trastuzumab (13%). Cardiac toxicity with trastuzumab alone has been reported to be between 3% and 7%. Of the patients who developed cardiomyopathy, 75% were symptomatic.
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Baseline cardiac function should be determined with ECG or multigated acquisition (MUGA) scan (a radionuclide scan used to assess cardiac function) prior to the initiation of HER2–directed therapy. These tests should be repeated every 3 months, or when patients become symptomatic. Periodical assessments of troponin I and pro-BNP levels may aide in the early detection of heart failure. Most patients have improvement in cardiac function after the cessation of therapy. Treatment can generally be restarted after the return of heart function to baseline. Dose adjustments for cardiotoxicity are determined based on data from clinical trials of adjuvant trastuzumab, such as the NSABP B-31 trial and the NCCTG N9831 trial. Cardiotoxicity is generally neither dose- nor duration-dependent, thus posing a particular problem for clinicians. The risk of cardiotoxicity is thought to be temporary and occurs only when patients are on active treatment. There is no reported evidence of late cardiac adverse effects in patients after completion of treatment.
Cardiac toxicities of T-DM1, the antibody drug conjugate ado-trastuzumab emtansine, were reported in the MARIANNE study. A decrease in EF of less than 50% with more than a 15% decrease in heart function was observed in 0.8% of patients treated with single agent T-DM1 compared to 4.5% of patients treated with trastuzumab plus taxane and 2.5% of patients treated with T-DM1 plus pertuzumab.
CHF Associated with VEGF Inhibitors
Sunitinib An increased incidence of CHF in patients receiving multitargeted TKIs has been reported across various clinical trials for different indications. The studies that led to the approval of sunitinib in RCC observed a concerning incidence of decreased LVEF. In the phase I/II trial, 8 of the 75 patients (11%) who were given continued cycles of sunitinib had a cardiovascular event, with CHF recorded in 6 patients (8%). LVEF reductions of at least 10% occurred in 10 of the 36 patients (28%) treated at the approved sunitinib dose, and 7 patients (19%) had LVEF reductions of 15% or more. In another study, the overall incidence for all-grade and high-grade CHF in patients treated with sunitinib was 4.1% and 1.5%, respectively. The relative risk of all- and high-grade CHF in these patients was reported to be 1.81% and 3.30%, respectively. Although the incidence of CHF was alarming in this setting, CHF and left ventricular dysfunction generally responded well to sunitinib cessation and institution of medical management. Another retrospective study of sunitinib in metastatic RCC and GIST reported that 2.7% of patients who received sunitinib developed heart failure. The mean time of onset was 22 days after the initiation of therapy, and notably, some patients with GIST who received sunitinib did not have a reversal of cardiac dysfunction even after treatment discontinuation.
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A multicenter analysis of 175 patients who received sunitinib therapy for metastatic RCC showed that 17 patients (9.7%) developed grade 3 hypertension 33 of the 175 (18.9%) patients developed some degree of cardiac abnormality and 12 of the 175 patients developed grade 3 CHF. Based on this analysis, hypertension and coronary artery disease have been considered as independent predictors of cardiac dysfunction.
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Bevacizumab Heart failure associated with bevacizumab has been sporadically reported in several trials.
Pazopanib Pazopanib has been associated with a decrease in heart function, as noted in the PALETTE trial of pazopanib in sarcoma patients. A decline in heart function was noted in 6.7% of patients compared with 2.4% of placebo-treated patients.
Lenvatinib and regorafenib Cardiac dysfunction has been reported in patients receiving lenvatinib. In patients receiving regorafenib, biventricular CHF and myocardial ischemia has been reported.
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In a systematic review and meta-analysis conducted to determine the rates of CHF in patients treated with multitargeted TKIs, a total of 10,647 patients from 16 phase III trials and 5 phase II trials were studied. All-grade CHF occurred in 2.39% of patients treated with VEGFR TKI compared with 0.75% in patients in the non-TKI groups. High-grade CHF occurred in 1.19% of patients receiving VEGFR TKIs compared with 0.65% in patients in the non-TKI groups. The relative risk (RR) of all-grade and high-grade CHF for TKI versus no TKI was 2.69 ( P < .001; 95% confidence interval [CI]: 1.86–3.87) and 1.65 ( P = .227, 95% CI: 0.73–3.70), respectively. The RR of relatively specific TKIs (axitinib) was similar to relatively non-specific TKIs (sunitinib, sorafenib, vandetanib, pazopanib). Potentially fatal cardiac failure has been observed in patients treated with axitinib.
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Baseline echocardiogram or MUGA scans should be performed and periodic monitoring of cardiac function should be done thereafter. The FDA recommends permanent cessation of sunitinib in patients who develop severe heart failure. For patients who experience a decrease in EF of between 20% and 50% below baseline values, dose reduction or interruption is recommended.
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CHF associated with BCR/ABL targeting therapy In a study of 103 patients with CML treated with imatinib, there were no significant cardiac side effects. However, there have been subsequent case reports of cardiac toxicity, including a decrease in LVEF, reported with imatinib. Another study of imatinib use in GIST reported a low incidence of cardiac toxicity (0.2%–0.4%). Slight increases in NT-pro BNP levels were noted in some patients, however, these increases were not statistically significant. A study of 90 patients on long-term imatinib for CML (median treatment time of 3.3 years) evaluated EF. In this study, the mean EF was 68 ± 7%; based on this study, imatinib-related cardiotoxicity is considered to be relatively uncommon even when administered long term. Routine cardiac monitoring is not indicated in all patients who are receiving imatinib. There were no differences in cardiac and vascular adverse events between the bosutinib and imatinib groups in the BELA study. The overall incidence of heart failure was 2.9% and grade 3 and 4 toxicity was 0.8%. The discontinuation rates of bosutinib due to cardiac toxicities were higher than in other studies.
CHF associated with BRAF inhibitors Cardiomyopathy has been reported with trametinib alone and also with the combination of trametinib and dabrafenib. Baseline echocardiogram should be obtained, and then periodically while patients are on treatment. If there is a decline in EF of 10% or greater, treatment should be withheld, and the patient should be monitored for improvement. If heart function recovers, the drug can be resumed at a lower dose. For patients who develop symptomatic heart failure, treatment should be discontinued permanently. If the initial decline in EF is greater than 20%, treatment should be discontinued, promptly and permanently.
CHF associated with EGFR inhibitors Cardiomyopathy has been reported to occur with an incidence of 1.4% of patients treated with osimertinib. These data are based on the FLAURA study, which led to its first-line approval in NSCLC. Baseline echocardiogram and periodic assessment of LVEF is recommended. The treatment of heart failure should be provided per recommendations of the American College of Cardiology/American Heart Association (ACC/AHA).
Thromboembolic Events
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Arterial thromboembolic events associated with VEGF–targeting agents: Arterial thromboembolic events (ATE) have been reported in VEGF-TKI drugs, specifically with sorafenib and sunitinib. Based on meta-analyses, the reported incidence is estimated to be around 1.4%. An increased incidence of ATE has also been reported with the use of pazopanib (3%) and lenvatinib (5%). Upon development of ATE, VEGF-TKI should be discontinued promptly and patients should undergo standard treatment for ATE. According to American College of Clinical Pharmacy (ACCP) guidelines, patients at high risk for ATE should receive aspirin for prophylaxis. VEGF-TKIs are not recommended for 6 to 12 months after a serious event such as this.
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An increased incidence of thromboembolic events is associated with bevacizumab, as reported with the use of bevacizumab-containing chemotherapy regimens for advanced colorectal cancer. In a study which reviewed cardiovascular risk factors in 471 patients with bevacizumab in metastatic colorectal cancer, bevacizumab was found to be associated with a slightly increased risk of ATE. Age, previous history of ATE, and vascular risk factors did not seem to increase the risk of ATE in these patients. The effect of aspirinuse in the prevention of ATE in patients on bevacizumab was indeterminate in this particular study. A meta-analyses of over 13,000 patients in 20 randomized trials, which evaluated the relative risk of ATEs had interesting findings. The highest incidence of ATE was seen in patients treated for metastatic colorectal cancer (3.2%, 95% CI: 1.9–5.4), and the lowest was in patients treated for breast cancer (0.7%, 95% CI: 0.1–3.6), a diagnosis that bevacizumab is no longer approved for. Incidence rates of ATE in patients with NSCLC and RCC were 2.5% (95% CI: 1.8–3.7) and 2.3% (95% CI: 1.4–3.7), respectively.
Aflibercept In the VELOUR study, an increased risk of arterial thromboembolic events (1.8% vs. 0.5%) and venous thromboembolic events (7.9% vs. 6.3%), was observed in the combination treatment arm of aflibercept and FOLFIRI, compared with placebo and FOLFIRI.
Arterial thromboembolic events associated with ponatinib Ponatinib has been evaluated for the treatment of CML in the EPIC study, a phase III randomized trial. The EPIC study was terminated due to the observation of increased ATEs in concurrent trials utilizing ponatinib. Preliminary data from this study suggested an increased risk of ATE with ponatinib as compared with imatinib, although the direct mechanism of these vascular occlusive events is not well understood.
Venous Thromboembolic Events (VTEs)
Meta-analyses of randomized phases II and III trials of sunitinib, sorafenib, pazopanib, vandetanib, and axitinib have studied the incidence of VTE. Based on these meta-analyses, an increased risk of VTEs with these drugs was not detected. Thus these agents are not considered to pose an increased risk of VTEs and can be used safely in patients with a prior history of VTE. , In general, once a patient develops VTE while taking targeted therapy, the drug can be discontinued temporarily and resumed once adequate anticoagulation is established. The National Comprehensive Cancer Network (NCCN) guidelines do not recommend routine anticoagulation with the use of these drugs. Similar to the TKIs discussed, ramucirumab has not been associated with increased risk of VTE and ATE.
Arrhythmias
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QT prolongation: QT prolongation has been described with a variety of targeted therapies. Patients receiving such drugs should undergo baseline ECG monitoring, as well as electrolyte monitoring at regular intervals. Electrolytes, particularly potassium and magnesium levels, should be replenished accordingly. Drug–drug interactions should also be considered to minimize the chance of patients receiving multiple QT prolonging drugs. Although QT prolongation typically does not cause symptoms, it is clinically significant, as it can result in tachyarrhythmias including sustained torsades de pointes.
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VEGF-TKI: Sunitinib is known for its dose-dependent QT prolonging effect. When compared with sunitinib, sorafenib has a lesser effect on QT prolongation. Baseline ECG should be obtained in all patients before starting these drugs, and then periodically, although no guidelines specify time intervals. It is also recommended to avoid other concomitant drugs that may prolong the QT interval. Pazopanib and axitinib are not associated with statistically significant risks of QT prolongation. Higher doses of vandetanib are associated with a greater risk of QT prolongation.
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BCR/ABL targeting TKIs
Nilotinib Nilotinib is known to be associated with QT prolongation at the recommended dose of 800 mg/day. Treatment should be withheld for QTc interval greater than 480 ms. Current recommendations are to resume treatment if QTc interval returns to less than 450 ms. Oftentimes, the dose prior can be resumed. If QT prolongation recurs again, then a dose reduction can be considered. If the QTc remains prolonged even after dose reduction, then permanent discontinuation of treatment is advised.
Bosutinib Bosutinib is also associated with QT prolongation and cardiac arrhythmias. QT prolongation and arrhythmias have been reported (overall 5.7% and grades 3 and 4, 1.5%) in two major studies, which led to the approval of bosutinib. Reported cardiac reasons for discontinuation of bosutinib include cardiac arrhythmias, pericardial effusion, right bundle branch block, CHF, and QT prolongation.
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ALK inhibitors: Alectinib is commonly used as a first-line agent for ALK-positive metastatic NSCLC. In the ALEX trial, a phase III trial comparing alectinib versus crizotinib, cardiac disorders like bradycardia were reported in 1% of patients on alectinib compared with 6% of patients on crizotinib. Furthermore, in the J-ALEX study, where crizotinib was compared with alectinib, crizotinib was associated with sinus bradycardia in 6% of patients. Subsequent case reports have also corroborated reports of bradycardia. QT prolongation is also observed with ceritinib. In patients being treated with crizotinib and ceritinib, treatment should be temporarily discontinued if patients develop severe QT prolongation, and the drug should be restarted when the QTc returns to baseline. Recurrent QT prolongation warrants treatment discontinuation.
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CDK 4/6 inhibitors: QT prolongation has also been reported in patients treated with CDK 4/6 inhibitors such as ribociclib and abemaciclib. A QTc interval of greater than 480 ms was noted in 3.3% of patients treated with ribociclib at a dose of 600 mg. This side effect is thought to be dose dependent, and thus patients with baseline QT prolongation were excluded from the study. Dose-reduction, interruption, and discontinuation of the drug was required in the study if patients developed QT prolongation. The use of abemaciclib was approved based on the MONARCH-3 trial. This particular drug has the same cardiac side effect profile as the other drugs in this group.
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BRAF inhibitors: Vemurafenib is also known to be associated with QT prolongation. Similar to other drugs which cause QT prolongation, this agent should be avoided in patients with baseline prolonged QT interval.
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EGFR inhibitors: Osimertinib is also known to cause QT prolongation. Cardiotoxicity, such as changes in QT interval, were reported in a higher percentage of patients in the osimertinib group (29 patients [10%]) than in the first-generation EGFR-TKI group (13 patients [5%]).
Pleural Effusions
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Bosutinib: Bosutinib, a BCR/ABL TKI for CML, is known to be associated with pleural effusions. Pleural effusions have been reported in 18.5% of patients on bosutinib, with the majority occurring within 3 months of treatment initiation. Large pleural effusions may require thoracentesis, oxygen supplementation, and diuretics. If severe, dose reduction and treatment interruption should be considered. For grade 3 pleural effusions, treatment should be withheld until the effusion resolves. Another important cardiotoxicity associated with bosutinib is fluid retention, which manifests as peripheral edema.
References
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