Cardiotoxicity of Chemotherapy

Cardiotoxicity of Chemotherapy:

Case StudyKrystal PerezCardiac Stress Lab Intern

Beth Israel Deaconess Medical CenterNovember 8, 2016

No relevant disclosures

Anthracyclines• Treat hematologic malignancies and solid tumors via selective transport to nuclei of proliferating cells and binding to DNA to stop further proliferation.

• Doxorubicin used most often due to efficacy in solid tumor treatment

• Used in combination with other drugs• Types of cancer used for: breast cancer, small lung cancer, ovarian cancer

Cardiac Effects: CHF/LV Dysfunction

• Dose-Related Response • High dosage correlates with LV dysfunction due to

increased myocardial cell death • Schedule of delivery: rapid vs continuous infusion of drug

• Drug combination: when taken with other drugs can increase toxicity

• Doxorubicin combined with Paclitaxel can cause CHF in 20% of patient

• Time between administration of both drugs influence incidence rates

Monoclonal Antibodies• Treat hematologic malignancies and solid tumors

• Antibodies that bind to specific receptors with that limit tumor growth.

• Trastuzumab: antibody that selectively binds to HER2 which is overexpressed in 25-33% of breast cancer cases

Cardiac Effects: CHF/LV Dysfunction

• Drug combination: increased incidence of CHF when used with other chemotherapeutic drugs that are administered in close proximity.

• Rose from 7% to 27% incidence • Lead to cardiac dysfunction but have high reversibility potential.

• Mechanism for dysfunction is unknown• Shows lower morbidity and mortality than

anthracycline-induced dysfunction.• Cardiac events range from HTN, Arrhythmias, and CHF depending on the monoclonal antibody used.

Antimetabolites• Treat solid tumors by mimicking purines/pyrimadines/folic acid and inducing cell death by interfering with DNA synthesis and inhibiting enzymes used in nucleic acid production.

• 5-Fluourouracil (5-FU) widely used in sold tumor treatment in many cancers (breast, ovarian, colon-rectal, adrenal, liver, etc).

• Among the first effective chemotherapy agents.

Cardiac Effects: Ischemia• Most commonly causes cardiac ischemia but is usually reversible with cessation.

• Dose-response relationship – high doses proportional to greater incidence.

• Schedule of administering drug – rapid vs continuous infusion

Radiation• High-energy radiation administered internally or externally to kill cancer cells and shrink tumors.

• Used in at some point in time during most cancer treatments.

• Cancer cells are killed by damaging their DNA or creating free radicals within cell that lead to DNA damage.

• Normal cell DNA is damaged in the process so proper placement of radiation is crucial.

Cardiac Effects: Wide Range of CVD

• Location: the closer to the heart, the more potential damage to the hear.

• Thorax :• Pericardium – pericarditis (short-term) or pericardial effusion• Myocardium – fibrosis causing perfusion defects• Valves: thickening• Coronary Artery – endothelium damage

• Most common cardiac effect is cardiomyopathy.• Dose-related response: major cardiac events rate increase with increased dose by 7.4%.

• Type of cancer: excess risk of ischemic heart disease for women with left-sided breast cancer

Treatments• Anthracycline-induced CHF/LV Dysfunction:

• Dexrazoxane: iron chelator – reduces free iron in myocytes caused by anthracyclines

• Questionable efficacy of cancer treatment• Beta blockers and ACE inhibitors

• Monoclonal Antibody-incuded CHF/LV Dysfunction: • Cessation• Beta blockers and ACE inhibitors

• Antimetabolite-induced Ischemia: • Cessation• Calcium channel blockers and oral nitrates to resolve symptoms• Capecitabine alternative

• Radiation-induced CAD:• Better radiation field direction• Subcarinal block• CABG/Angioplasty• NSAIDS, Diuretics, ACE Inhibitors, Beta Blockers

Difference in Treatment

• Revascularization for treatment-induced MI’s are not ideal due to possibility of bleeding diathesis.

• Stent placement can stop treatment regimens and prolong the process cause medications required can cause bleeding.

• Especially the cause with DES

Monitoring Cardiotoxicity of Chemotherapy

• Echocardiogram to measure LV dysfunction periodically

• Limit:• Decreased LVEF generally occurs late in history of treatment-

related injury• LV dysfunction is only measureable after enough cardiac

damage has occurred to cause functional impairment. • Positive ECHO can mean irreversible damage especially in the

case of anthracycline-induced cardiomyopathy• Not ideal for asymptomatic patients

• Research show 33% of Patients with preserved LVEF had underlying systolic and and diastolic cardiac dysfunction

• 47% of CHF is diastolic in nature, occurring with a preserved LVEF

Monitoring Cardiotoxicity of Chemotherapy

• Cardiac biomarkers like Troponin I and BNP as an indication for a cardiac event due to high correlation with subsequent cardiac systolic and diastolic dysfunction before reduction in LVEF is seen.

• Used to determine high risk patients before drug administration to start preventive measures beforehand.

• Limits:• BNP elevation can be due to non-cardiac events

Monitoring Cardiotoxicity of Chemotherapy

• Global longitudinal strain (GLS) recently used to detect subtle changes in LV systolic function by assessing the longitudinal contraction of the myocardium to predict overall mortality and cardiac events.

• More sensitive predictor of cardiac events than LVEF.• Use as a comparative measure before, during and after treatments.

• Early reduction in GLS predicts subsequent chemotherapy-related cardiac dysfunction.

• Limits• Has not been tested on a larger population. • Price

Stress Testing Cancer Survivors/Patients

• Hx of cancer should be mentioned in patient history and taken into account when determining relative risk levels despite years of remission.

• Pay attention to the treatment regimen because the type of drug and dosage can have an affect on patients despite symptoms.

• If a patient has CAD risk factors (HTN, HLD, Smoking, etc) along with the history of cancer, they have a higher chance of a positive stress test at a younger age than those without history of cancer.

• Cancer treatment cannot be identified as a direct reason for a positive stress test or cardiac events (MI/CHF), only a contributing factor.

• Determining stress test protocol using this additional information.

Patient Information•53 yr old Male•Chief Complaint: CP and SOB•CAD Risk Factors:

• HLD, +Family Hx, Obesity (BMI: 31.7)•02.2016 – Colon Cancer•Labs: RBC 4.44, HgB 13.3•Walks occasionally and plays golf

Medications •FOLFOX

• 955mg Leucovorin Calcium• 950mg Fluorouracil bolus• 2850mg Fluorouracil continuous infusion• 155mg Oxaliplatin

•40mg Prednisone•16mg Ondansetron•0.5mg Lorazepam tablets•Vitamins

Pretest: HR 67, BP 128/86

Bruce 5:01 min: HR 142, BP 158/78

Bruce 5:36 min (Peak): HR 148

Recovery 0:14 min: HR 133

Recovery 1:43min: HR 81

Recovery 15 min: HR 93, BP 128/82

Diagnosis & Follow Up• + Ischemia via Stress Test• ECHO: EF = 55%, regional left systolic dysfunction,

dyskinesis of apex, hypokinesis of distal septal and anterior walls

• Cath (3 days later): • 80% Stenosis LAD DES • 50-60% stenosis Left Cx

• Labs (before Cath): Trop<0.01 x 4• Follow up:

• cardiac rehab for CAD • placed on Atorvastatin, Clopidogrel, Lisinopril, Metoprolol,

ASA

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