1. Chapter 3: Screening and Monitoring for Cardiotoxicity during Cancer Treatment
Michel G. Khouri
Igor Klem
Chetan Shenoy
Jeffrey Sulpher
Susan F. Dent
Cardio-Oncology
Eds: Kimmick, Lenihan, Sawyer, Mayer, Hershman

2. Surveillance strategies for cancer patients receiving potentially cardiotoxic cancer therapy.
Baseline*
During cancer therapy
Following completion of cancer therapy
Heart Failure Association - European Society of Cardiology (2011) (43)
careful cardiovascular work-up with attention to co-morbidities esp. CAD and hypertension
regular cardiovascular evaluation
follow-up cardiac surveillance should be considered especially in those patients receiving high doses of anthracyclines
European Society of Medical Oncology (ESMO, 2012)(38)
baseline cardiovascular evaluation (risk factors and co-morbidities)
baseline 12 lead ECG and Echocardiogram or MUGA
baseline biomarkers (troponin, BNP) treatent of pre-exisitng cardiopathies
patients receiving anthracyclines +/- trastuzumab should have serial monitoring of cardiac function at 3, 6 and 9 months during treatment then 12 and 18 months after initiation of treatment
biomarkers with each cycle
monitoring following treatment as clinically indicated
increased vigilence for patients > 60 years old
assessment of cardiac function recommended 4 and 10 years after anthracyclines in patients treated < 15 years old and those > 15 years old with a cumulative dose of doxorubucin > 240 mg/m2 or epirubucin > 360 mg/m2
European Association of Cardiovascular Imaging and Amercian Society of Echocardiography (2014) (41)
baseline cardiac assessment especially those > 65 years old; high risk of CTRCD; LV dysfunction or high doses of anthracyclines (>350 mg/m2)
history, physical examination, ECG,echocardiogram and baseline global longitudinal strain (GLS)and Troponin I desireable
anthracyclines: troponin each cycle if positive cardiology consult; negative echcardiogram 6 months after treatment completed.
trastuzumab: LVEF ,GLS and troponin every 3 months during therapy and 6 months after treatment completed.
yearly cardiovascular assessment by a health care provider particularly in patients not followed closely during cancer treatment
imaging at the discretion of the health care provider

3. Cardiotoxicities of Cancer Therapies (1)
Anti-Cancer Therapy
Signs & Symptoms of Toxicity
Anthracyclines
(Doxorubicin, Daunorubicin, Idarubicin, Epirubicin, Mitoxantrone)
(1) Acute Toxicity:
<1%, reversible, shortly after infusion,
toxicities include arrhythmias, QT prolongation +/-HF
(2) Early-onset chronic progressive:
%, during treatment and up to 1 year post, not reversible, clinically resembles myocarditis, accompanying diastolic dysfunction
(3) Late–onset chronic progressive:
1.6-5%, >1 year from treatment, not reversible, clinical decompensation is usually preceded by occult LVD
Symptoms of Mitoxantrone induced HF are often less severe and more responsive to medical management
Cyclophosphamide
Arrhythmias
Non-specific ST-T abnormalities
Pericardial effusion
Hemorrhagic myopericarditis
Symptomatic HF (7-28%)
Occurs within 1-14 days of dose administration and often last for a few days. Toxicity may resolve completely or have long lasting consequences
Ifosfamide
(1) Arrhythmias
(2) Non-specific ST-T changes on ECG
(3) HF 17%
Acute HF typically presents within 6-23 days of first ifosfamide dose
Cisplatin
Chest pain
ST-T changes on ECG
ACS
(5) Thromboembolism 8.5%

4. Signs & Symptoms of Toxicity Microtubule targeting agents
Cardiotoxicities of Cancer Therapies (2)
Anti-Cancer Therapy
Signs & Symptoms of Toxicity
Antimetabolites
Fluorouracil (5-FU)
(1) Chest pain or ACS in 3-7.6%
(2) Atrial fibrillation
(3) HF
(4) Sudden cardiac death (rare)
Occurs during or shortly after starting treatment. Symptoms last up to 48 hours, but generally resolve. ECG changes present in up to 68% of patients treated with continuous infusion. Elevated cardiac biomarkers in up to 43%
Capecitabine
(1) Chest pain or ACS (3-9%) with transient ST elevations on ECG
Symptoms occurs 3 hours – 4 days after initiating therapy
Cardiac biomarkers generally remain normal
Microtubule targeting agents
Paclitaxel
(1) Myocardial ischemia (1-5%)
(2) MI (0.5%)
(3) Arrhythmias and heart block
Cardiac complications occur in up to 29% with most being asymptomatic bradyarrythmias. Occur during and up to 14 days after paclitaxel administration. Symptoms generally resolve with stopping therapy
Docetaxel
(1) HF 2.3-8%
(2) Myocardial Ischemia 1.7%
Radiation therapy
(1) CAD
(2) Valvular disease
(3) Pericardial disease
(4) Restrictive cardiomyopathy
(5) Conduction system disease

5. Cardiotoxicities of Cancer Therapies (3)
Anti-Cancer Therapy
Signs & Symptoms of Toxicity
Tyrosine Kinase Inhibitors
Sunitinib
(1) Hypertension (47%)
(2) Asymptomatic decline in LVEF (10-21%)
(3) Symptomatic HF in up to 15%
Variable time to presentation (days-months)
Sorafenib
(1) MI 2.7-3%
(2) Hypertension 17-43%
(3) HF/LV dysfunction
Less cardiac dysfunction than Sunitinib
Axitinib
(1) Hypertension
Regorafenib
Vandetanib
(1) Torsades de Pointes
Imatinib
(1) LVEF reduction %
Dasatinib
(1) HF/LV dysfunction
Lapatinib
(1) LV dysfunction %
(2) Symptomatic HF %
(3) QTc prolongation
Relatively low incidence of adverse cardiac events
Monoclonal Antibodies
Trastuzumab
(1) HF / LV dysfunction with variable rates based on definitions from clinical trials 2-7% as monotherapy, 2-13% with paclitaxel
Up to 27% with anthracyclines
Bevacizumab
(1) HTN
(2) HF %
(3) MI/Angina 1.5%
(4) ATE during treatment (median 3 months)

6. Troponin for Early Detection and Prediction of Cardiotoxicity
Reference
Patient
Population
Treatment N
Detection
Cut-off
%BM+
LVEF
Modality
Mean ↓LVEF
Incidence of
↓LVEF >10% or LVEF < 50%
Incidence of HF
symptoms BM
Predicted
(P sig)
BM+
BM-
↓LVEF HF
Sawaya
Breast
ANT, H 43
hsTnI
µg/L
28%
Echo -
50%
10%
Yes 81
usTnI
30 pg/mL
14%
42%
27% 8% 5%
Fallah- Rad
FEC, H
AC, H 42
cTnT
ng/mL 0%
~4%
24%
24 % No
Cardinale
Multiple
Diagnoses
HDC
204
cTnI
0.4 ng/ml
32%
>10%
~0%
29%
Yes *
703
ng/ml
30%
71% 2%
22%
0.2 %
Yes †
211
0.5 ng/ml
33%
>15%
Sandri
179
µg/ml
18% 3% H
251
72% 7%
19%
Morris
ddAC→THL 95
ng/ml
67%
RNA
*All patients (n = 3) developing HF during study were cTnI+.
†Elevated cTnI predicted composite cardiac events, including heart failure.
AC = doxorubicin and cyclophosphamide; ANT = anthracyclines; BM = biomarker; cTnI = cardiac troponin I; cTnT = cardiac troponin T; dd = dose-dense; FEC = fluorouracil, epirubicin, cyclophosphamide; H = trastuzumab; HDC = high-dose chemotherapy; HF = heart failure; hsTnI = high-sensitivity troponin I; L = lapatinib; LVEF = left ventricular ejection fraction; RNA = radionuclide angiography; T = paclitaxel; usTnI = ultra-sensitive troponin I.
↓ = decline or impairment; Δ = change.
 Table adapted from Khouri, et al. Future Cardiol : 11(4):

7. Figure 1. Example MUGA Images from Cancer Patients.
(A) and (B) are end-diastolic and end-systolic MUGA images respectively from a 61-year-old male whose LVEF was analyzed to be abnormal at 47.0%, (C) and (D) are end-diastolic and end-systolic MUGA images respectively from a 61-year-old female whose LVEF was analyzed to be normal at 69.2%.

8. Pre-Trastuzumab LVEF 54% GLS –17% Trastuzumab x 3 mo Pre-Pertuzumab
Figure 2. Echocardiographic Strain Imaging for Early Detection of Cardiotoxicity
In many disease states, measurements of global longitudinal strain (GLS) by two-dimensional echocardiographic speckle tracking are more sensitive for detecting impaired myocardial systolic performance than left ventricular ejection fraction (LVEF) and less susceptible to alterations in loading conditions. In toxin-induced myocardial damage, both in the preclinical and clinical setting, reduced strain and strain rate have revealed impaired myocardial function prior to LVEF decline and heart failure symptoms.
Pre-Trastuzumab
LVEF 54%
GLS –17%
Trastuzumab x 3 mo
Pre-Pertuzumab
LVEF 53%
GLS –11%
Trastuzumab x 5 mo
Pertuzumab x 2 mo
LVEF 29%
GLS –7%

9. A B Figure 3. Example CMR Images demonstrating Cardiomyopathy.
A 47-year-old patient with breast cancer treated with anthracyclines, demonstrating cardiomyopathy. Panel A shows a diastolic frame and Panel B shows a systolic frame. The LVEF was quantified at 42%. A B

10. Figure 4.
Example CMR Images demonstrating Valvular Disease. A B