Supplementary Material. Signs & Symptoms of. References Anti-Cancer Therapy. Risk Factors (Doxorubicin, Classified into: (1) Acute Toxicity:

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1 Supplementary Material Supplementary Table S1: Cardiotoxicity & Cancer Therapies Anthracyclines and Anthrachinolones Mechanism & Type Signs & Symptoms of Patient Associated Therapy Associated References Anti-Cancer Therapy of Toxicity Toxicity Risk Factors Risk Factors Anthracyclines Proposed Classified into: (1) Advanced age (1) Doxorubicin > 1 10 (Doxorubicin, mechanisms: (1) Acute Toxicity: (2) Very young age idarubicin or epirubicin Daunorubicin, (1) Reactive <1%, reversible, shortly (3) Female sex (2) IV bolus Idarubicin, oxygen/free radical after infusion, (4) Pre-existing administration Epirubicin, generation by iron- toxicities include heart disease (3) High peak Mitoxantrone) anthracycline arrhythmias, QT (5) Hypertension concentrations in some complexes causes prolongation +/-HF (6) Diabetes studies lipid peroxidation (2) Early-onset chronic (7) Smoking (4) History of and membrane progressive: (8) Very high or low irradiation disruption %, during body weight (5) Concurrent (2) Transcriptional treatment and up to 1 (9) Black race administration of change in myocyte year post, not (10) Increased cyclophosphamide, ATP pathway reversible, clinically biomarkers after trastuzumab and/or (3) Decreased resembles myocarditis, administration paclitaxel mrna expression, accompanying diastolic (11) Trisomy 21 (6) Time from therapy

2 reduced dysfunction (12) Genetic completion contractility (3) Late onset chronic polymorphisms (7) Most important RF (4) Topoisomerase progressive: is cumulative dose IIβ interference 1.6-5%, >1 year from treatment, not Rates of HF: Generally reversible, clinical Doxorubicin 400mg/m2 irreversible toxicity decompensation is = 3-5% (Type I) usually preceded by 550mg/m2= 7-26% occult LVD 700mg/m2 =18-48% Symptoms of Maximal cumulative Mitoxantrone induced doses (mg/m2): HF are often less Doxorubicin: severe and more Daunorubicin: responsive to medical 600mg/m2 management Idarubicin : 100mg/m2 Epirubicin: mg/m2 Mitoxantrone: 160 mg/m2

3 Supplementary Table S2: Cardiotoxicity & Cancer Therapies Alkylating Agents Mechanism & Type of Signs & Symptoms Patient Therapy References Anti-Cancer Therapy Toxicity of Toxicity Associated Associated Risk Risk Factors Factors Cyclophosphamide Proposed Include: (1) Increasing (1) High dose mechanisms: (1) Arrhythmias age Cyclophosphamid (1) Direct endothelial (2) Non-specific ST- e: mg/kg injury & T abnormalities or >1.5 g/m2/day extravasation of toxic (3) Pericardial (2) History of metabolite resulting effusion anthracyclines or in cardiomyocyte (4) Hemorrhagic Mitoxantrone damage, edema & myopericarditis therapy interstitial (5) Symptomatic HF (3) Mediastinal hemorrhage (7-28%) radiation (2) Ischemia from intracapillary micro- Occurs within 1-14 Toxicity related to emboli days of dose single rather than (3) Coronary administration and cumulative drug vasospasm often last for a few dose

4 days Toxicity may resolve completely or have long lasting consequences Ifosfamide Proposed mechanism (1) Arrhythmias (1) Potentially 1 10 similar to that of cyclophosphamide due to structural and mechanistic similarities Fluid, acid-base & electrolyte imbalance secondary to nephrotoxicity may influence cardiac function (2) Non-specific ST- T changes on ECG (3) HF 17% Acute HF typically presents within 6-23 days of first ifosfamide dose dose related: doses > 150mg/kg or > 12.5 g/m2 Toxicity related to single rather than cumulative drug dose Cisplatin Specific mechanisms (1) Chest pain (1) Increasing Combined 8 10

5 of toxicity unclear (2) Arrhythmias age therapy with Nephrotoxicity may (3) ST-T changes on cyclophosphamid cause ECG e and mediastinal hypomagnesemia & (4) ACS radiation may hypokalemia (5) increase risk of predisposing to Thromboembolism HF arrhythmias 8.5% May lead to thrombosis due to effects on platelet aggregation

6 Supplementary Table S3: Cardiotoxicity & Cancer Therapies - Antimetabolites Mechanism & Type of Signs & Symptoms Patient Therapy References Anti-Cancer Therapy Toxicity of Toxicity Associated Risk Associated Risk Factors Factors Antimetabolites Metabolic 11 Syndrome Fluorouracil (5-FU) Proposed mechanisms: (1) Chest pain or (1) Pre-existing (1) Potentially 1 10 (1) Coronary artery ACS in 3-7.6% cardiovascular dose related: thrombosis, arteritis, (2) Atrial disease doses>800mg/m vasospasm or fibrillation 2 vasoconstriction (3) HF (2) Concurrent (2) Direct myocardial (4) Sudden cardiac chemotherapy toxicity leading to death (rare) (especially apoptosis cisplatin) (3) Autoimmune Occurs during or (3) Prior response shortly after mediastinal (4) Krebs cycle starting treatment radiation interference by Symptoms last up fluoroacetate metabolite to 48 hours, but Toxicity is not

7 generally resolve related to cumulative dose ECG changes present in up to Cardiotoxicity 68% of patients occurs with treated with higher frequency continuous in continuous infusion (7.6%) vs. bolus Elevated cardiac (2%) biomarkers in up administration to 43% Symptoms may recur if rechallenged Capecitabine Mechanisms not well (1) Chest pain or (1) Pre-existing (1) History of established ACS (3-9%) with CAD FU related transient ST cardiotoxicity An oral pro-drug of elevations on ECG fluorouracil with similar

8 but less pronounced toxicity Symptoms occurs 3 hours 4 days after initiating therapy Cardiac biomarkers generally remain normal

9 Supplementary Table S4: Cardiotoxicity & Cancer Therapies Microtubule Targeting Agents Mechanism & Type Signs & Symptoms of Patient Associated Therapy Associated References Anti-Cancer Therapy of Toxicity Toxicity Risk Factors Risk Factors Paclitaxel Multiple (1) Myocardial (1) Hypertension (1) Cardiotoxicity 8, 10 mechanisms: ischemia (1-5%) (2) Pre-existing CAD increased if paclitaxel is (1) Effect of (2) MI (0.5%) administered before Cremophor EL (3) Arrhythmias and anthracycline since vehicle heart block Cremophor EL diluent (2) Significant reduces the clearance histamine release Cardiac complications of anthracycline promoting occur in up to 29% with thereby enhancing hypotension and most being exposure resulting myocardial asymptomatic (2) Potential taxane damage bradyarrythmias induced formation of toxic doxorubicin Occur during and up to metabolite 14 days after paclitaxel administration Above pharmacokinetic interaction not

10 Symptoms generally resolve with stopping therapy Docetaxel Myocyte damage (1) HF 2.3-8% (2) Myocardial Ischemia 1.7% observed with epirubicin 8, 10, 14

11 Supplementary Table S5: Cardiotoxicity & Cancer Therapies Tyrosine Kinase Inhibitors Mechanism & Type of Signs & Symptoms Patient Therapy Associated References Anti-Cancer Therapy Toxicity of Toxicity Associated Risk Risk Factors Factors Sunitinib Multiple possible (1) Hypertension (1) CAD (1) Concurrent 4, 8, 9, 13 mechanisms: (47%) (2) Pre-existing anthracycline 15 (1) Induces myocyte (2) Asymptomatic hypertension therapy mitochondrial damage decline in LVEF (10- (3) Renal cell (2) Impairs myocyte 21%) carcinoma (vs. function in setting of (3) Symptomatic HF other tumours) hypertensive stress in up to 15% (3) Reduction in nitric oxide production Variable time to through VEGF presentation (days- inhibition months) (4) AMPK inhibition Toxicity likely reversible with

12 stopping therapy and implementing medical management Sorafenib Similar mechanism to (1) MI 2.7-3% (1) CAD 4, 8, 13, 16, Sunitinib (2) Hypertension 17- (2) Pre-existing 17 43% hypertension Inhibition of RAF1 (3) HF/LV (3) Renal cell dysfunction carcinoma (vs. Toxicity is generally other tumours) reversible and Less cardiac responsive to medical dysfunction than treatment Sunitinib

13 Axitinib (1) Hypertension (1) Renal cell carcinoma (vs. other tumors) 18 Regorafenib (1) Hypertension (1) Gastrointestinal stromal tumor (vs. other tumors) Vandetanib (1) Torsades de (1) Congenital Pointes Long QT Syndromes (2) History of Torsades de 19 20

14 Pointes (3) QTc >450ms Imatinib Proposed (1) LVEF reduction 13, 14 mechanisms: % (1) Mitochondrial damage (2) Protective mitochondrial pathway inhibition Dasatinib Proposed (1) HF/LV 13, 14 mechanisms: dysfunction (1) Mitochondrial damage (2) Protective mitochondrial pathway inhibition Lapatinib Potential mechanism: (1) LV dysfunction (1) Female (1) Prior 9, 14 (1) Targeting of % (2) Elderly anthryacyline or HER1/EGFR & HER2 (2) Symptomatic HF (3) Prior trastuzumab

15 receptors % (3) QTc prolongation Relatively low incidence of adverse cardiac events ischemia/ Infarction (4) Electrolyte imbalances (5) Concomitant QTc prolonging meds therapy

16 Supplementary Table S6: Cardiotoxicity & Cancer Therapies Monoclonal Antibodies Mechanism & Type Signs & Symptoms of Patient Therapy Associated References Anti-Cancer Therapy of Toxicity Toxicity Associated Risk Factors Risk Factors Trastuzumab Proposed (1) HF / LV (1) Age > 50 (1) Concurrent 8, 9 mechanisms: (1) Inhibition of HER2 (Erbβ2) signaling may interfere with growth and signaling of cardiomyocytes and may induce mitochondrial damage Generally reversible toxicity (Type II) dysfunction with variable rates based on definitions from clinical trials 2-7% as monotherapy 2-13% with paclitaxel Up to 27% with anthracyclines (2) Lower range or borderline LVEF prior to initiating therapy (3) Pre-existing CVD (4) Increased BMI paclitaxel or anthracycline based therapy (2) Cumulative anthracycline dose >300mg/m2) (3) Concomitant use of antihypertensive drugs Generally toxicity is not dose related Bevacizumab Proposed (1) HTN (1) Concurrent or (1) Concurrent 8, 9, 21

17 mechanisms: (2) HF % previous HTN anthracycline 24 (1) Inhibition of (3) MI/Angina 1.5% (2) Age 75 years therapy VEGF signaling with (4) ATE during (3) Black race subsequent effects treatment (median 3 (4) Renal cell No increase in CV on regulation of months) carcinoma risk when combined vascular tone with oxaliplatin and resulting in 5-FU based therapy uncontrolled HTN ATE (2) Risk of HF (1) Prior ATE ATE events not through impaired event believed to be adaptive response (2) Age 65 associated with dose to pressure overload (3) Colorectal or or cumulative (3) Decreased NO renal cell exposure and prostacyclin carcinoma production and expose vascular collagen to tissue factor increasing risk of thrombosis

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