Treating Cardiovascular disease in patients with cancer presents a unique challenge for the clinician

The mechanisms might differ from the usual pathogenesis, and thus extrapolating treatment guidelines might not always be appropriate.

Presence of cancer often limits the treatment options

It is as yet an imperfect science with no standardised protocols or guidelines

Research opportunities are immense

LV DYSFUNCTION AND CARDIOMYOPATHY

Anthracycline cardiotoxicity

Anthracycline-associated cardiotoxicity can be divided into three forms

The first is an immediate pericarditis–myocarditis syndrome

early onset chronic progressive cardiomyopathy

late-onset cardiotoxicity :asymptomatic /symptomatic cardiomyopathy and arrhythmias

The most important consideration in managing a patient with any evidence of cardiotoxicity is prevention and the avoidance of further anthracycline exposure.

Managing CHF due to cardiotoxicity

Pharmacological treatment of CHF takes cues from that of other CHF pts

The initial step is to exclude other causes of cardiac dysfunction, particularly coronary artery disease (CAD)

The presence of exertional chest pain, regional wall motion abnormalities, or multiple risk factors for CAD should prompt an evaluation that should consist of stress testing, or preferably, coronary angiography

If CAD, valvular heart disease, or other reversible causes of cardiac dysfunction are not present, the management of cardiomyopathy due to cardiotoxic agents is identical to that of other nonischemic cardiomyopathies, and should proceed in accordance with the guidelines established by the ACC and the AHA

The management must start in stage A!!

Stage A includes cancer patients treated with potentially cardiotoxic agents

Patients in stage A should receive aggressive medical care, including modification of risk factors for CAD such as diabetes and hyperlipidemia

ACE inhibitors or angiotensin receptor blockers (ARBs) should be strongly considered for the treatment of hypertension in stage A patients

Smoking cessation and regular aerobic exercise should be encouraged in all patients treated with potentially cardiotoxic cancer therapies.

EVIDENCES FROM EXCLUSIVE ONCOLOGIC PTS

In a RCT comparing enalapril with placebo in 135 patients 8 years or older treated with anthracycline chemotherapy enalapril reduced LV systolic wall stress but could not influence exercise performance

Recently, it has been reported that the angiotensin II receptor blocker, valsartan, significantly prevented acute cardiotoxicity (assessed with ECG, echocardiography and neurohumoral markers) in lymphoma patients treated with doxorubicin-based chemotherapy

SILBER JH et al.: J. Clin. Oncol. (2004) 22:820-828.

NAKAMAE H, et al.: Cancer (2005) 104:2492-2498.

EVIDENCES FROM EXCLUSIVE ONCOLOGIC PTS Angiotensin-converting enzyme inhibitors (ACEIs)

and β-adrenergic blocking drugs have been shown to improve symptoms and prolong survival

In a series of 92 breast cancer patients treated with epirubicin, 9 developed life-threatening CHF Within 3 months of commencing an ACEI, in 8 out of 9 of these patients an increase in LVEF to normal or near normal was observed1

A few case series have been published reporting

the beneficial effects of carvedilol in anthracycline-induced CHF

1JENSEN BV et al: Lancet (1996) 347:297-299.

Asymptomatic patients who have demonstrated LV dysfunction are now treated, and the results of major trials in adult patients with decreased LVEF not specifically due to anthracycline therapy, suggest that there is a clear benefit of early intervention.

Drugs of choice are ACE/ARB and beta blockers.

Other therapies

Once symptoms of CHF have occurred, diuretics are cost-effective

Furosemide is the most commonly used initial agent

Metolazone is sometimes useful in refractory CHF

Potassium- sparing diuretics, such as amiloride or triamterene, are sometimes helpful

Other therapies

Spironolactone and eplerenone has been shown to increase survival in non cancer DCM patients

Occasionally, the judicious use of digitalis preparations offers symptomatic relief, but probably does not prolong life.

Other therapies

For patients with advanced CHF, inotropic agents given by intravenous infusion (dopamine or milrinone) may be helpful as a bridge therapy during the time that it may take for other strategies to become effective

LV assist devices, biventricular

pacemakers and implantable defibrillators may also be considered

Other therapies For patients with significant heart failure,

aspirin should be considered for its antiplatelet properties

Dysrhythmia may be treated with β-adrenergic blockers or, in severe cases, amiodarone

For the rare patient with end stage CHF in whom cancer is either cured or expected to remain in remission for a prolonged period of time, heart transplantation may be considered

The indications for heart transplantation in the cancer patient are gradually becoming broader

Prevention A number of interventions have been proposed

as potential cardioprotectants

Nutritional approaches to prevent anthracycline- induced cardiotoxicity have concentrated on free radical scavengers including vitamins, endogenous antioxidants and plant-derived flavonoids

A number of small clinical studies of cardioprotecive interventions, including studies of coenzyme Q10, phenetylamines, N-acetylcysteine and combination of vitamins E and C with N-acetylcysteine have been conducted

Prevention

Laboratory studies have suggested a protective role for probucol, carnitine, selenium , erythropoietin, glutamine and garlic against anthracycline-induced cardiotoxicity.

Further large prospective studies are required to clearly define the role of these agents

MYOCARDIAL ISCHEMIA AND INFARCTION

Coronary vasospasm is an important effect of cancer therapy that leads to myocardial ischemia and/or infarction.

Myocardial ischemia, and occasionally MI is caused by 5-fluorouracil (5-FU), vincristine vinblastine and vinorelbine

The estimated incidence of cardiac events is reported to be 7.6% in patients receiving high-dose 5-FU by continuous infusion :transient symptoms in most but 2.2% experienced cardiac death due to arrhythmias or circulatory collapse

Patients with established CAD might be at increased risk of developing myocardial ischemia during infusion of 5-FU.

The vast majority of patients who experience myocardial ischemia during 5-FU treatment respond to temporary termination of therapy either alone or with anti-anginals (calcium channel blockers or oral nitrates)

In patients who experience myocardial ischemia in response to 5-FU, the risk of recurrence increases after subsequent drug exposure

Prophylactic treatment with coronary vasodilators does not seem to prevent such recurrences although this prophylactic treatment is often used in clinical practice.

Jensen Sa et al Cancer Chemother. Pharmacol. 58, 487–493 (2006)

Most challenging clinical scenario is treatment of cancer patients with acute MI, regardless of the causal link to cancer therapy

Application of AHA and ACC guidelines for the management of patients with acute STEMI are often difficult to apply due to occurrence of bleeding diathesis, thrombocytopenia or presence of relative or absolute contraindications(like intracranial malignancy )

Substantial dosages of heparin together with glycoprotein IIB/IIIA inhibitors, aspirin, and clopidogrel, which collectively might expose a cancer patient with bleeding diathesis to an unacceptable risk of major bleeding

MYOCARDIAL INFARCTION

Deployment of stents increases the level of dilemma with associated compulsions to use antiplatelets.

Prefer to use bare rather than drug coated stents.

The risk:benefit ratio of aggressive, guideline-based therapy for cancer patients with ACS is unclear, and management must be tailored to the individual patient

Anecdotal studies have suggested substantial survival benefit in cancer patients with aspirin therapy in ACS even in the presence of profound thrombocytopenia

Sarkiss MG et al. Cancer (2007) 109: 621–627

MYOCARDIAL INFARCTION

RHYTHM DISTURBANCES

Taxanes

The most common cardiac effect of the taxanes is bradycardia and other rhythm disturbances including ventricular arrhythmias, varying degrees of atrioventricular (A-V) conduction block, bundle branch block, ventricular tachycardia

The incidence of all grade 4 and 5 cardiac events reported to the Cancer Therapy Evaluation Program (CTEP) was 0.5%

Arbuck SG, J. Natl. Cancer Inst. Monogr. 15, 117–130 (1993).

Taxanes

In the presence of asymptomatic sinus bradycardia, paclitaxel may be continued without dose modification.

Those who develop symptomatic bradycardia or heart block should be monitored closely

Discontinuation of drug resolves most instances

In certain instances, the need for temporary or permanent pacemaker insertion will need to be considered.

The list of drugs with cardiac toxicities is long but most present with similar syndromes

The broad lines of treatment are similar: discontinuation or decreasing the dosage Judicious use of standard treatment

regimes with an eye on risk- benefit ratio due to different milieu of cancer patients

Now What we need

Standarized screening protocol

New Guidelines /Protocols clearly defining the diagnosis and management of cardiotoxicity

It is time for cardio oncology clinic in MAX Healthcare.

TTThank You