Chemotherapy Cardiotoxicity

Evaluation and Management of Patients With Heart Disease and Cancer: Cardio-Oncology

Herrmann, Joerg, MD; Lerman, Amir, MD; Sandhu, Nicole P, MD, PhD; Villarraga, Hector R, MD; Mulvagh, Sharon L, MD; et al. Mayo Clinic Proceedings89.9 (Sep 2014): 1287-306.

Introduction

• Divided into:
  • Cardiotoxicity
    • Type 1: Myocardial Injury/Damage - Unlikely to improve
    • Type 2: High likelihood of near complete recovery
  • Vascular Toxicity

• Effect	Type 1	Type 2
  Prototype	Doxorubicin (Anthracyclines)	Trastuzumab (Herceptin)
  Non-Invasive Testing	Global decrease in wall motion and ejection fraction	Global decrease in wall motion vand ejection fraction
  Clinical Course	Stabilization possible but likely irreversible damage with poor tolerance to subsequent stressors	High likelihood of (near) complete recovery within months and good long-term prognosis
  Ultrastructure	- Vacuolization - Necrosis - Microfibrillar disarray	- NONE
  Mechanism	- Oxidative injury - Mitochondrial dysfunction - Altered calcium homeostasis - Altered cardiac gene expression - Cardiomyocyte death - topoisomerase 1-β inhibition	- HER-2/ErbB2 signaling pathway inhibition
  Effects	Dose Related	Not Dose Related
  Preditors	- Cumulative dose - Administration type and rate - (Prior) mediastinal radiation - Concurrent cyclophosphamide - Pre-existing cardiovascular disease including coronary artery disease, cardiomyopathy, aortic stenosis and hypertension - Diabetes mellitus - Very high or very low body weight - Age (<15 and >65 years) - Female gender - African-American	- Age ≥70 (60-80) years - Hypertension - Diabetes mellitus - Coronary artery disease - Cardiomyopathy - Arrhythmia (esp. afib) - Alcohol intake (≥10 drinks per week) - Female gender - Prior chest radiation - Concurrent Paclitaxel and prior anthracycline therapy - Concurrent anthracycline and cyclophosphamide therapy
  Progresive Rechallenge	Progressive Dysfunction	Likely Safe
  Late sequential stress	Likely not tolerated	Likely tolerated
  Increased CV Mortality?	YES	NO

 

Assessment of Risk

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Follow-Up

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• Cyclophosphamde and Trastuzumab do not require follow-up in otherwise healthy ppl (late complications not reported)

• Patients with breast cancer and lymphoma who have undergone anthracycline-based therapy and patients who have had mediastinal radiation therapy are prime candidates for long-term cardiac surveillance programs

 

Management

• Follow AAHA guidelines for heart failure
• ACE inhibitors
  • Trial of patients with breast Ca treated with epirubicin. (enalapril/ramipril better than diuretics and digoxin)
  • ARB data very limited (use only if ACEi contraindicated)
• Beta-Blockers
  • Carvedilol after low-dose enalparil + titrate both drugs up in pts LVEF ≤ 45% after chemo completed.
    • After 3y restored EF > 50% in 42% of pts. 
    • Timing of completion of anthracycline to development of HF is prognostic     
  • Only carvedilol and nebivolol beneficial (metoprolol = neutral, propranolol = worse outcomes!)   
• ARR (Spironolactone)
  • Consider if NYHA class II-IV, EF < 35%
• LVAD & other mechanical support if needed.
• Dexrazoxane
  • Meta-analysis: dexrazoxane reduced the incidence of clinical heart failure by more than 80%
  • Progression-free and overall survival rates were similar, there was a trend toward lower response rate
  • Worry it may reduce anti-tumor activity
  • Only approved for metastatic breast cancer who may benefit from further anthracycline therapy after having already received 300 mg/m2.38
•  
• NOTE:
  • Role of ACEi and BB less defined for: Type II cardiotoxicity .  Discontinuing the drug improves it.
• OVERCOME Trial (Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive Chemotherapy for the treatment of Malignant hEmopathies (OVERCOME)
  • Universal consideration of enalapril and carvedilol for all patients referred for intensive chemotherapy or stem cell transplant
  • POSITIVE for preventing LVEF reduction at 6 months (primary endpoint) and even outlined a benefit in terms of the combined secondary end point of death or heart failure.

 

Effects of Radiation

• Involves all layers of cardiac structure
  • Pericardium:
    • Acute/Chronic Pericarditis
    • Fibrinous exudates, fibrous adhesions, and collagenous thickening of pericardium
  • Endocardium
    • Fibrosis
  • Valves
    • Fibrosis: Retraction and regurgitation and over time (>20 years) also stenosis, especially of the left-sided valves.
  • Vasculature
    • Diffuse interstitial fibrosis as well as thickening and narrowing of arterioles and capillaries
    • Microvascular ischemia
  • Electrical Conduction
    • Calcification of aorto-mitral ridge can cause AV block
• Management post-rads
  • CV surgery CABG is challenging (LIMA damaged by rads), aorta may be calcified, subclavian steal from LIMA?
  • Generally prefer PCI in these ppl.
  • ASA & clopidogrel are not effective in preventing atherosclerosis.
  • Pericardiectomy for constrictive pericarditis
    • However, make sure restrictive physiology is absent (otherwise stripping pericardium = no benefit)

 

List of Chemo Agents

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Notes

• Cardiac Review and Evaluation Committee of trastuzumab-associated cardiotoxicity
  • Defines chemotherapy-induced cardiotoxicity:

    • A decrease in left ventricular ejection fraction (LVEF) by 5% or more to less than 55% in the presence of symptoms of heart failure (diagnosed by a cardiologist) or an asymptomatic decrease in LVEF by 10% or more to less than 55%

• Anthracycline induced cardiotoxicity
  • Acute (Acute toxicity)
  • Chronic
    • Early onset (<1yr)
    • Late onset (>1yr)