Curr Cardiol Rep (2015) 17:16 DOI 10.1007/s11886-015-0570-3
CARDIO-ONCOLOGY (SA FRANCIS, SECTION EDITOR)
Advanced Heart Failure Due to Cancer Therapy Sachin Shah & Anju Nohria
# Springer Science+Business Media New York 2015
Abstract Certain chemotherapeutic agents and mediastinal irradiation can be cardiotoxic and place cancer survivors at risk for developing advanced heart failure (HF). Anthracyclines are the prototypical agents associated with left ventricular (LV) dysfunction. Newer agents including trastuzumab and certain tyrosine kinase inhibitors such as sunitinib can also cause cardiomyopathy. Cancer survivors with advanced HF refractory to standard medical management should be considered for advanced therapies, including mechanical circulatory support (MCS) and transplantation. While overall outcomes after MCS and transplantation are similar in cancer survivors compared to other etiologies of HF, patients with radiation-induced restrictive cardiomyopathy have a significantly worse prognosis after transplantation. The increased need for right ventricular (RV) support after MCS in cancer survivors necessitates a careful evaluation for pre-operative RV dysfunction. Special consideration must also be given to the risk for recurrent malignancy, neurocognitive dysfunction, and increased psychological needs in this patient population. Keywords Anthracyclines . Cardiotoxicity . Chemotherapy . Heart failure . Mediastinal radiation . Trastuzumab
Introduction Certain chemotherapeutic agents and radiation therapy can be cardiotoxic placing cancer survivors at risk for the developThis article is part of the Topical Collection on Cardio-Oncology S. Shah : A. Nohria (*) Section of Advanced Heart Disease, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA e-mail: [email protected] S. Shah e-mail: [email protected]
ment of advanced heart failure (HF) [1, 2]. HF due to cancer therapy relates to the agent and dose, patient characteristics, and the synergistic effects of various therapies including other cancer chemotherapeutics and radiation [3]. In general, patients with chemotherapy-induced HF fare more poorly than those with HF due to idiopathic or ischemic etiologies [4]. Despite this overall worse prognosis, patients who undergo cardiac transplantation or durable mechanical circulatory support (MCS) for advanced HF due to chemotherapy have similar outcomes to those with HF from other causes [5•, 6•]. The unknown long-term risk related to novel chemotherapeutic agents, improved cancer survivorship, and technological advances in the mechanical support options for patients with advanced HF make this a constantly evolving field.
Heart Failure with a Reduced Ejection Fraction Related to Cancer Therapy The definition of HF with a reduced ejection fraction related to cancer therapy has not been standardized. The National Cancer Institute has attempted to overcome this by establishing a five-point HF grading system for adverse event reporting during oncologic clinical trials (Table 1) [7]. However, some studies report only clinical HF whereas others report asymptomatic left ventricular (LV) dysfunction of varying degrees. Most define LV dysfunction as a ≥20 % absolute reduction in LV ejection fraction (LVEF) from baseline or a ≥10 % reduction in LVEF from baseline to below the upper limit of normal. As a result of these inconsistencies in reporting, the true incidence of chemotherapy-induced cardiotoxicity is unknown. The prototypical chemotherapeutic agents responsible for HF are anthracyclines. Anthracyclines appear to have the highest attributable risk, are the best studied, and thus will be reviewed in detail. Other agents will also be discussed, but overall there is less data regarding the cardiotoxicity of non-anthracycline chemotherapy.
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Curr Cardiol Rep (2015) 17:16
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Table 1 Common terminology criteria for adverse events related to cancer therapy as described by the National Cancer Institute [7] and the relationship to AHA/ACC heart failure stage and NYHA functional class [37] CTCAE heart failure
AHA/ACC heart failure stage
NYHA functional class
Grade 1
B
I
C
II
Grade 2 Grade 3 Grade 4 Grade 5
Asymptomatic (biomarker or imaging evidence of cardiac dysfunction) Symptoms with mild to moderate level of exertion Severe symptoms at rest or minimal activity Life threatening Death
III-IV D
IV
CTCAE Common Terminology Criteria for Adverse Events, AHA American Heart Association, ACC American College of Cardiology, NYHA New York Heart Association
Anthracyclines Anthracyclines have been the model for chemotherapyinduced HF given their widespread efficacy in the treatment of various malignancies and the heightened risk of HF associated with their use. Anthracyclines cause a dose-dependent cardiotoxicity that is felt to be irreversible and is associated with ultrastructural changes including increased vacuolization, myofibrillar dropout, and cellular necrosis [8]. The exact mechanism of anthracycline-induced cardiotoxicity remains unclear. Increased myocardial oxidative stress via redox-cycling of the quinone moiety of anthracyclines and through the formation of anthracycline-iron complexes has been the predominant proposed mechanism. Other mechanisms include disruption of cellular and mitochondrial calcium homeostasis, disruption of mitochondrial energetics, degradation of ultrastructural proteins including titin and dystrophin, direct DNA damage via inhibition of topoisomerase 2β, inhibition of pro-survival pathways such as neuregulin 1 and ErbB, and direct cytotoxic effects on cardiac progenitor cells diminishing repair potential after myocardial injury [9–11]. Anthracycline cardiotoxicity may manifest as asymptomatic LV dysfunction or symptomatic HF and may be acute (within the first week of therapy, often after the first dose), early (within the first year of therapy), or late (1 to 20 years following therapy) in onset. Acute anthracycline cardiotoxicity clinically presents as acute HF, arrhythmia, heart block, or myopericarditis and appears to be largely reversible if the offending agent is withdrawn, whereas early and late cardiotoxicity can lead to progressive HF with an adverse prognosis [12]. Early and late cardiotoxicity most often takes the form of a dilated cardiomyopathy, although survivors of childhood cancers may have a restrictive form of the disease.
Among 5-year childhood cancer survivors, subclinical LV dysfunction (defined as LV fractional shortening
CARDIO-ONCOLOGY (SA FRANCIS, SECTION EDITOR)
Advanced Heart Failure Due to Cancer Therapy Sachin Shah & Anju Nohria
# Springer Science+Business Media New York 2015
Abstract Certain chemotherapeutic agents and mediastinal irradiation can be cardiotoxic and place cancer survivors at risk for developing advanced heart failure (HF). Anthracyclines are the prototypical agents associated with left ventricular (LV) dysfunction. Newer agents including trastuzumab and certain tyrosine kinase inhibitors such as sunitinib can also cause cardiomyopathy. Cancer survivors with advanced HF refractory to standard medical management should be considered for advanced therapies, including mechanical circulatory support (MCS) and transplantation. While overall outcomes after MCS and transplantation are similar in cancer survivors compared to other etiologies of HF, patients with radiation-induced restrictive cardiomyopathy have a significantly worse prognosis after transplantation. The increased need for right ventricular (RV) support after MCS in cancer survivors necessitates a careful evaluation for pre-operative RV dysfunction. Special consideration must also be given to the risk for recurrent malignancy, neurocognitive dysfunction, and increased psychological needs in this patient population. Keywords Anthracyclines . Cardiotoxicity . Chemotherapy . Heart failure . Mediastinal radiation . Trastuzumab
Introduction Certain chemotherapeutic agents and radiation therapy can be cardiotoxic placing cancer survivors at risk for the developThis article is part of the Topical Collection on Cardio-Oncology S. Shah : A. Nohria (*) Section of Advanced Heart Disease, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA e-mail: [email protected] S. Shah e-mail: [email protected]
ment of advanced heart failure (HF) [1, 2]. HF due to cancer therapy relates to the agent and dose, patient characteristics, and the synergistic effects of various therapies including other cancer chemotherapeutics and radiation [3]. In general, patients with chemotherapy-induced HF fare more poorly than those with HF due to idiopathic or ischemic etiologies [4]. Despite this overall worse prognosis, patients who undergo cardiac transplantation or durable mechanical circulatory support (MCS) for advanced HF due to chemotherapy have similar outcomes to those with HF from other causes [5•, 6•]. The unknown long-term risk related to novel chemotherapeutic agents, improved cancer survivorship, and technological advances in the mechanical support options for patients with advanced HF make this a constantly evolving field.
Heart Failure with a Reduced Ejection Fraction Related to Cancer Therapy The definition of HF with a reduced ejection fraction related to cancer therapy has not been standardized. The National Cancer Institute has attempted to overcome this by establishing a five-point HF grading system for adverse event reporting during oncologic clinical trials (Table 1) [7]. However, some studies report only clinical HF whereas others report asymptomatic left ventricular (LV) dysfunction of varying degrees. Most define LV dysfunction as a ≥20 % absolute reduction in LV ejection fraction (LVEF) from baseline or a ≥10 % reduction in LVEF from baseline to below the upper limit of normal. As a result of these inconsistencies in reporting, the true incidence of chemotherapy-induced cardiotoxicity is unknown. The prototypical chemotherapeutic agents responsible for HF are anthracyclines. Anthracyclines appear to have the highest attributable risk, are the best studied, and thus will be reviewed in detail. Other agents will also be discussed, but overall there is less data regarding the cardiotoxicity of non-anthracycline chemotherapy.
16
Curr Cardiol Rep (2015) 17:16
Page 2 of 9
Table 1 Common terminology criteria for adverse events related to cancer therapy as described by the National Cancer Institute [7] and the relationship to AHA/ACC heart failure stage and NYHA functional class [37] CTCAE heart failure
AHA/ACC heart failure stage
NYHA functional class
Grade 1
B
I
C
II
Grade 2 Grade 3 Grade 4 Grade 5
Asymptomatic (biomarker or imaging evidence of cardiac dysfunction) Symptoms with mild to moderate level of exertion Severe symptoms at rest or minimal activity Life threatening Death
III-IV D
IV
CTCAE Common Terminology Criteria for Adverse Events, AHA American Heart Association, ACC American College of Cardiology, NYHA New York Heart Association
Anthracyclines Anthracyclines have been the model for chemotherapyinduced HF given their widespread efficacy in the treatment of various malignancies and the heightened risk of HF associated with their use. Anthracyclines cause a dose-dependent cardiotoxicity that is felt to be irreversible and is associated with ultrastructural changes including increased vacuolization, myofibrillar dropout, and cellular necrosis [8]. The exact mechanism of anthracycline-induced cardiotoxicity remains unclear. Increased myocardial oxidative stress via redox-cycling of the quinone moiety of anthracyclines and through the formation of anthracycline-iron complexes has been the predominant proposed mechanism. Other mechanisms include disruption of cellular and mitochondrial calcium homeostasis, disruption of mitochondrial energetics, degradation of ultrastructural proteins including titin and dystrophin, direct DNA damage via inhibition of topoisomerase 2β, inhibition of pro-survival pathways such as neuregulin 1 and ErbB, and direct cytotoxic effects on cardiac progenitor cells diminishing repair potential after myocardial injury [9–11]. Anthracycline cardiotoxicity may manifest as asymptomatic LV dysfunction or symptomatic HF and may be acute (within the first week of therapy, often after the first dose), early (within the first year of therapy), or late (1 to 20 years following therapy) in onset. Acute anthracycline cardiotoxicity clinically presents as acute HF, arrhythmia, heart block, or myopericarditis and appears to be largely reversible if the offending agent is withdrawn, whereas early and late cardiotoxicity can lead to progressive HF with an adverse prognosis [12]. Early and late cardiotoxicity most often takes the form of a dilated cardiomyopathy, although survivors of childhood cancers may have a restrictive form of the disease.
Among 5-year childhood cancer survivors, subclinical LV dysfunction (defined as LV fractional shortening
