Cardiac toxicity associated with antineoplastic agents

Ranges from 3-9%^r

Commonly occurs in cycle one, but can occur at any stage of treatment

Most frequent clinical manifestation is angina (4.6%)^r

Other symptoms include MI, arrhythmias and death

Previous cardiac toxicity during chemotherapy with fluorouracil

Concurrent chemotherapy with cardiotoxic drugs

Presence of coronary artery disease

Prior radiation therapy

Cease capecitabine, referral to a cardiologist for symptomatic treatment may be necessary

Re-challenge is controversial and generally not recommended

Cardiac symptoms recur in up to 62% of patients and are not influenced by dose reduction or medical prophylaxis with vasodilators^r

Ranges from 1-19%^r

The mean onset of cardiac symptoms is 3 days (range 2 to 5 days), with the majority of patients experiencing angina within hours of administration^r

Most common symptom is chest pain (non specific or angina) normally associated with ECG changes

Other symptoms include angina (45%), MI (22%), arrhythmias (23%), acute pulmonary oedema (5%), cardiac arrest (1.4%) and pericarditis (2%)^r

Method of administration (infusional over bolus)

Presence of coronary artery disease

Prior radiation therapy

Prior chemotherapy with anthracyclines and other cardiotoxic regimens

Cardiac symptoms usually resolve with cessation of fluorouracil

Referral to a cardiologist for symptomatic treatment may be necessary

Re-challenge is controversial and generally not recommended

Cardiac symptoms recur in up to 47% of patients and may occur with lower doses or different schedules^r

Transient asymptomatic bradycardia occurred in 29% of patients in a small phase II trial^r

MI has been reported in ~5% of patients in a retrospective study^r

Bradycardia and heart block are the most frequent cardiac effects although usually asymptomatic

Other symptoms include arrhythmias and myocardial ischaemia

Direct oxidative cardiac injury

Impaired protein synthesis

Dose related (>150 mg/kg and 1.5 g/m²/day)^r

Correlated to prior anthracycline or mitozantrone therapy and mediastinal radiation therapy

Note: not cumulative dose related

Ifosfamide can induce the onset of HF, with a dose-response trend (doses >12.5 g/m²)^r

9.2% hypertension 3.8% thromboembolic events^r

Can occur at any time throughout treatment

Elderly patients

Prior arterial thromboembolic event

Sinus bradycardia

QTc prolongation

Heart failure, bradyarrhythmias, electrolyte abnormalities, or patients who are taking other medications known to prolong the QTc interval or that cause bradycardia

Use with caution in patients who are receiving other drugs that inhibit CYP3A4

Dose adjustment for symptomatic bradycardia and QTc prolongation^r

Monitor heart rate and blood pressure regularly during treatment

Consider baseline ECG for patients with risk factors or that develop bradycardia

Inhibition of the hERG K+ channel and action potential prolongation has the potential to prolong cardiac ventricular repolarisation

7% cardiac conduction disturbance

4% ischaemic heart disease (IHD)

<4% cardiac disease

<4% pericardial effusion^r

CHF/cardiac dysfunction

Pericardial effusion

IHD

Arrhythmias

QT prolongation

HT

The development of arrhythmic symptoms or new onset dyspnoea should be clinically evaluated and, if indicated, an ECG performed^r

For persistent AF, consider risks/benefits of treatment and follow dose modification guidelines^r

~1-2% HF

0.7% cardiac failure and LVD^r

QTc prolongation

1.6% reduced LVEF by at least 20%^r

0.2% symptomatic HF^r

Asymptomatic decline in LVEF or rarely symptoms of a decline in cardiac function

QTc prolongation

Dose adjustment or discontinuation of therapy may be necessary if QTc prolongation occurs or decrease in LVEF^r

72.8% HT

3.8% venous thromboembolic events^r

2.7% arterial thromboembolic events^r

8.8% QTc prolongation

1.5% pulmonary embolism^r

<1% MI/AMI, right bundle branch block, cerebral ischaemia, cerebrovascular accident, ischaemic stroke, transient ischaemic attack

HT

Venous thromboembolism (VTE) or arterial thromboembolism (ATE)

QTc prolongation

Blood pressure should be monitored after 1 week of treatment, then every 2 weeks for the first 2 months, and monthly thereafter

Do not administer in patients with QTc interval >450 milliseconds (ms). Dose interruption in patients who develop QTc interval >500 ms until QTc returns to <450 ms

Periodic monitoring of ECG and electrolytes, correction of electrolyte imbalances prior to commencement

10-11% HT

5-9% IHD

1-3% cerebral ischaemia^r

HT

IHD

Cerebral ischaemia

Arrhythmias

QTc prolongation

Pre-existing cardiac disease, bradycardia, hypokalaemia or taking medications which prolong the QTc interval

Concomitant treatment with potent CYP3A4 inhibitors

ECG at baseline, after 7 days of treatment, then as clinically indicated^r

Monitor for hypokalaemia or hypomagnesaemia and correct deficiencies^r

Use with caution in uncontrolled or significant cardiac disease

Withhold if QTc exceeds 480 msec^r

53-71% HT

>23% vascular occlusion

12% MI

8% HF (including fatal)^r

HT

Left ventricular dysfunction

Vascular occlusion

QTc prolongation

Arrhythmias

Increasing age

Increasing dose

Prior history of ischaemia, hypertension, diabetes or hyperlipidaemia^r

Assess all patients' cardiovascular status before commencing treatment and manage cardiovascular risk factors^r

Blood pressure should be monitored at each clinic visit^r

Monitor for signs and symptoms of HF and treat as clinically indicated^r

Interrupt or stop ponatinib for new or worsening HF^r

Myocardial ischaemia and infarction

Arterial hypertension

17-43% hypertension

2.9% acute coronary syndrome including MI^r

Hypertension normally occurs early in treatment

Hypertension is the most common cardiac sign

QTc prolongation

28% asymptomatic LVEF reduction of at least 10%^r

11% cardiovascular events including MI

47% hypertension^r

Most commonly HT

Arrhythmias, LVEF dysfunction, HF, acute coronary syndrome have been reported

QTc prolongation

Pre-existing cardiac disease, bradycardia, electrolyte imbalance or taking medications which prolong the QTc interval

Concomitant treatment with potent CYP3A4 inhibitors

Blood pressure should be monitored and treated (if required)

Monitor for clinical signs and symptoms of CHF

Consider LVEF monitoring

Monitor LVEF prior to commencement, after one month and three monthly thereafter

Withhold treatment if LVEF decreases by 10% from pre-treatment level to less than lower limit of normal

Permanently discontinue for symptomatic HF or decrease in LVEF >20%^rr

32% HT

14% QTc prolongation

<1% ischaemic cerebrovascular events, arrhythmias, heart failure

Torsades de Pointes^r

HT

QTc prolongation

Pre-existing cardiac disease

Congenital long QT syndrome, electrolyte imbalance or taking medications which prolong the QTc interval

Blood pressure should be monitored regularly in the first few months of treatment and control as appropriate

Do not administer in pts with QTc interval > 450 milliseconds (ms)

Dose interruption in pts who develop QTc interval > 500 ms until QTc returns to <450 ms

ECG and electrolytes (potassium, calcium and magnesium) should be performed at baseline, 1, 3, 6, and 12 weeks after starting treatment and every 3 months for at least a year thereafter

Immune response activation:

• PD-1 is known to protect against tissue inflammation and myocyte damage
• PD-L1 may regulate potentially autoreactive lymphocytes at effector sites, thus playing a role in limiting activities of T cells in the heart, where PD-L1 is highly expressed

Overall incidence of cardiac AEs is <1%

Variable onset: Early myocarditis (0.09%) can occur at median onset 17 days after first treatment

Combination therapy with dual-immunotherapy associated with more severe and frequent myocarditis than single-agent immunotherapy

Withhold therapy

Start high dose steroids (methylprednisolone intravenously)

Echocardiogram

Cardiac MRI if stable enough

Consider endomyocardial biopsy (EMB) if needed and feasible

ATG or IVIg and plasma exchange for unstable patients​

Consider alternative immunosuppressive therapy if high grade myocarditis on EMB or failure to respond to steroids e.g. infliximab (if no HF), mycophenolate mofetil

Appropriate treatment of HF/cardiomyopathy

If unstable consider heart failure consult to discuss mechanical support

ECG monitoring QTc at baseline, mid-cycle 1 and beginning of cycle 2

If QTcf 480-500 ms: Interrupt dose until recovery to <481 ms. If first occurrence: resume at same dose

If recurs: resume at next lower dose

If QTcf >500 ms: Interrupt dose until recovery <481 ms then resume at next lower dose

Permanently discontinue if QTcf interval prolongation is either >500 ms or >60 ms change from baseline AND associated with Torsades de Pointes, polymorphic ventricular tachycardia, unexplained syncope or signs/symptoms of serious arrhythmias

Monitor electrolytes prior to each of the first 6 cycles

QTc interval prolongation

Torsade de pointes

Maintain potassium concentrations above 4.0 mmol/L, magnesium concentrations above 0.8 mmol/L and QTc less than 500 msec.

Monitor twice weekly (more frequently in unstable patients) during treatment^r