ECHO 2013 / Cancer Treatment Related Cardiotoxicity
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Cumulative Incidence of A-CHF in
Childhood Cancer Survivors
•Risk of CHF reached 19% 25 years later for those received >250 mg/m2
•No safe threshold for adriamycin induced cardiotoxicity.
Risk of CHF 0.30
>250 mg m-2
0.20
0.10
<250 mg m-2
0 |
5 |
10 |
15 |
20 |
30 |
Time since anthracycline (years)
Pein et al., Br J Cancer. 2004 Jul 5;91(1):37-44.
Chronic Progressive Cardiac Dysfunction Years After Doxorubicin Therapy for Childhood Acute Lymphoblastic Leukemia
Median age at diagnosis = 4.8 yrs
Median f/up 12 yrs
Median cumulative dose = 352 mg/m2
Lipshultz S, et al. J Clin Oncol 2005; 23:2629-2636
↓LV Shortening
Fraction
↑LV Afterload 
(LVESWS)
↓Thickness- 
Dimension ratio
Late Cardiac Abnormalities in Adult
Survivors of Childhood Cancers
Raikhelker, J, Liu JE, JACC. 2011; 57
Cardiotoxicity: Anti-HER 2 Therapy
Trastuzumab (Herceptin)
•Overexpression of human epidermal growth factor receptor type 2 (HER2) occurs in approximately 20-30% of invasive breast cancer. Patients with HER2 positive tumors have decreased overall survival
•The development of trastuzumab, a humanized monoclonal antibody against HER2, has led to a major breakthrough in the treatment of HER2+ breast cancer.
–50% reduction in the 3-year recurrence of breast cancer
–33% reduction in the risk of death from breast cancer
•Trastuzumab therapy in combination with other chemotherapy regimens is currently the standard of care for the treatment of early stage HER2+ breast cancer
Cardiotoxicity: Anti-HER 2 Therapy
Trastuzumab (Herceptin)
•Metastastic breast cancer trials - 16% incidence of CHF (Class III/VI) when trastuzumab given concurrently with anthracycline based therapy.
•Adjuvant trials (>14,000 pts) - 4.7% incidence of CHF and 14.2% asymptomatic decline in LVEF when anthracycline and trastuzumab were given sequentially.
•Improvement of LV systolic function on withholding treatment and initiating cardioprotective agents in the majority - 70% of patients had a decrease in LVEF relative to baseline on 6 month follow-up.
•High cardiac event rate (CM/CHF) 4-5 years post treatment (Cochrane Collaboration meta-analysis w/ N= 10,281 RR 5.11; observational study w/N= 12,500 RR 7.19)
Anti-HER2 Cardiotoxicity: Mechanism
ErbB signaling in ErbB2-overexpressing tumor cells and in cardiomyocytes
•HER2 signaling promotes cell proliferation and survival and is required for cardiac developement.
•Trastuzumab prevents HER2 mediated signaling and interferes with the heart’s ability to respond to stress.
•HER2 deficient hearts are more susceptible to the cardiotoxic effects of the stressors.
De Keulenaer, Circ Res 2010
Cancer Treatment-Related Cardiotoxicity
Overview
•The Burden of Disease
•Chemotherapeutic related cardiotoxicity
• Monitoring and detection of cardiotoxicity
• Gaps in Knowledge
Cardiac Monitoring
Chemotherapy Induced Cardiotoxicity
•Monitoring methods
–Echo vs. MUGA
•Measured parameter for LV systolic function to monitor cardiotoxicity
–Ejection fraction or fractional shortening
EF by 2D Echo: Advantages
•Advantages: feasible, safe and low cost
–Most commonly used method in the assessment of LV function in the general population.
–LV EF is a robust predictor of cardiovascular outcomes and the parameter used historically to assess LV systolic function at baseline and during chemotherapy.
EF by 2D Echo: Disdvantages Temporal Variability of EF
2D EF: inter-measurement variability 10%
3D EF: inter-measurement variability 6%