March 16, 2013 Beth Faiman, PhDc, MSN, APRN, BC, AOCN®

1. Managing the adverse events due to molecularly targeted therapies: Cardiovascular and Pulmonary Side Effects March 16, 2013 Beth Faiman, PhDc, MSN, APRN, BC, AOCN® Nurse Practitioner, Cleveland Clinic Taussig Cancer Institute PhD Candidate, Case Western Reserve University Cleveland, Ohio

2. Molecularly Targeted Therapies (MTTs) • Small-molecule drugs • act on targets inside the cell • Monoclonal antibodies • cannot penetrate the cell’s plasma membrane and are directed against targets that are outside cells or on the cell surface Molecularly Targeted Therapies March 16, 2013 l 2

3. Molecularly Targeted Therapies (Randomly Selected From MANY….) Information from: http://www.cancer.gov/cancertopics/factsheet/Therapy/targeted ; MoAb= Monoclonal Antibody; Her2=human epidermal growth factor receptor 2; GIST= gastrointestinal stromal tumor ; pancreatic neuroendocrine tumor; NSCLCA = non small cell lung cancer; PNET; VEGF=Vascular Endothelial Growth Factor Molecularly Targeted Therapies March 16, 2013 l 3

4. Molecular Targeted Therapies (MTT) and Cardiotoxicity • Cardiotoxicity • a general term to describe a broad range of adverse effects on heart function induced by therapeutic molecules. • MTT-induced cardiovascular side effects include • left ventricular systolic dysfunction • heart failure • conduction abnormalities • acute coronary syndrome, and • hypertension • Angiogenic inhibitors can cause QT prolongation with the risk of torsades de pointe and sudden death • If a cancer is incurable, the risk of cardiotoxicity will often outweigh the safety risk Molecularly Targeted Therapies March 16, 2013 l 4 Ederhy S, Izzedine H, Massard C, et al, 2011;80(3):369-379.

5. Molecular targeted therapies (MTT) and cardiotoxicity • Kinase-targeting agents can affect cardiac function • sunitinib, imatinib, dasatinib, trastuzumab, and sorafenib • There is an overlap of signaling pathways targeted in tumor growth and important in maintaining cardiac homeostasis Mellor et al 2011; Motzer et al., 2007; Seidman et al.,2002; Brave et al., 2008; Escudier et al., 2009; Llovet et al., 2008 Molecularly Targeted Therapies March 16, 2013 l 5

6. Is Hypertension a Good Thing and Should We Treat It? • Treatment with angiogenesis inhibitors (either antibodies or TKIs that target VEGF) can cause life-threatening HTN • Poorly controlled hypertension can: • lead to cardiovascular events • renal disease • stroke • necessitate discontinuation of anti-cancer therapy Ederhy et al; Copur MS, Obermiller A. An Algorithm for the Management of Hypertension in the Setting of Vascular Endothelial Growth Factor Signaling Inhibition. Clinical Colorectal Cancer. 2011;10(3):151-156. Molecularly Targeted Therapies March 16, 2013 l 6

7. Is Hypertension a Good Thing and Should We Treat It? • BP is regulated by cardiac output and blood volume regulation through baroreceptors in the kidneys and the vasculature • No specific recommendations for drug treatment of HTN • Maintain BP < 140/90 mmHg. • Discontinuation of anti-angiogenic treatment may be applicable if systolic BP is >200mmHg or diastolic BP > 100mmHg or in case of a hypertensive crisis. Ederhy et al, 2011; Syrigos K, Karapanagiotou E, Boura P, Manegold C, Harrington K. Bevacizumab-Induced Hypertension. BioDrugs. 2011/06/01 2011;25(3):159-169. Molecularly Targeted Therapies March 16, 2013 l 7

8. Yes We Should Treat Hypertension! • Recommendations: American Heart Association and American College of Cardiology guidelines for the treatment of heart failure or of patients at high risk of heart failure • Beta Blockers (metoprolol, carvedilol, atenolol) • Angiotensin Converting Enzyme (ACE) Inhibitors (e.g. lisinopril, enalapril, ramipril) • Medications that interfere with cytochrome P450 and inhibitors of CYP3A4 (e.g. diltiazem, verapamil) should be avoided • Many oral anti-angiogenic agents are also cytochrome substrates Molecularly Targeted Therapies March 16, 2013 l 8 Jessup M, et al. (2009) Circulation. 119(14):1977-2016; Ederhy et al, 2011

9. How serious is Q-T interval prolongation? • Q-T interval prolongation increases the risk of fatal arrhythmia • can be induced by several novel anti-cancer therapies. • Torsades de pointes and Ventricular fibrillation • Torsades is a characteristic illusion of a twisting of the QRS complex around the isoelectric baseline • Predispose the patient to an “R-on-T” which can initiate torsades • Long Q-T is associated with several MTT classes including: • Histone deacetylase inhibitors, multi-targeted TKIs, vascular-disrupting agents, farnesyl protein transferase (FTPase) inhibitors, Src/Abl kinase inhibitors, and protein kinase C inhibitors Mellor HR, et. al (2011). Toxicological Sciences. March 1, 2011;120(1):14-32. Molecularly Targeted Therapies March 16, 2013 l 9

10. Long Q-T QTc prolongation (559 msec) torsade de pointes (TdP) followed by sustained TdP into ventricular fibrillation Molecularly Targeted Therapies March 16, 2013 l 10 Ayad et al, Proc (Bayl Univ Med Cent). 2010 July; 23(3): 250–255

11. Management of Q-T Prolongation Ayad et al., 2010Proc (Bayl Univ Med Cent). 2010 July; 23(3): 250–255; ; Mellor et al, 2011; ECG= Electrocardiogram Molecularly Targeted Therapies March 16, 2013 l 11

12. Caution When Prescribing • Select Antiarrhythmic drugs • Serotonin agonists/antagonists • Antipsychotics: phenothiazine, droperidol, haloperidol • Antidepressants: amitryptyline, clomipramine, desipramine, imipramine • Antimicrobial agents: clarithromycin, erythromycin, halofantrine, pentamidine, ketoconazole, miconazole, itraconazole • Anti-emetic agents: chlorpromazine, droperidol • Anthracyclines (doxorubicin) • Arsenic • Methadone Ayad et al., 2010Proc (Bayl Univ Med Cent). 2010 July; 23(3): 250–255; ; Mellor et al, 2011; ECG= Electrocardiogram Molecularly Targeted Therapies March 16, 2013 l 12

13. Monitoring Left ventricular systolic dysfunction and heart failure • The diagnosis of heart failure is difficult to correlate clinically in cancer patients • Dyspnea may be due to different etiologies such as pulmonary embolism, cardiac tamponade, heart failure, or disease progression • Biomarkers such as BNP are not always accurate • Cardiomyopathy with a decrease in left ventricular (LV) ejection fraction (LVEF) can progress to heart failure (HF) and in some cases death Thomas JT, Kelly RF, Thomas SJ, et al. Am J Med 2002;112:437–45.; Burjonroppa SC, Tong AT, Xiao LC, et al.. Am J Clin Oncol 2007;30:287–93. Molecularly Targeted Therapies March 16, 2013 l 13

14. Monitoring Left ventricular systolic dysfunction and heart failure • According to ACC/AHA guidelines for the diagnosis and management of heart failure, echocardiography is considered the single most useful diagnostic test in the evaluation of patients with heart failure • Asymptomatic decreased LV (>20%): • Modification of risk factors for coronary heart disease, lifestyle changes, and treatment of hypertension • Asymptomatic >50% decrease in LV: • ACE inhibitor, cardiology referral Jessup et al 2009 Molecularly Targeted Therapies March 16, 2013 l 14

15. Monitoring Left ventricular systolic dysfunction and heart failure • Any Symptomatic evidence of LVEF dysfunction • Refer to cardiologist; BBlockers, ACE –I • Dobutamine stress echo to exclude CAD which could lead to CABG, angioplasty; • Consider surgical intervention for significant valvuar dysfunction if found on echocardiology • Balance co morbidities, life expectancy Jessup et al 2009 Molecularly Targeted Therapies March 16, 2013 l 15

16. Who is at risk for pulmonary complications? • mTOR inhibitors • temsirolimus, everolimus, and ridaforolimus • Erlotinibinduced pneumonitis, and that occurs in about 1% of patients treated in the US • Bevacizumab binds to lung receptors, can cause hemoptysis • Incidence varies according to study, indication • Breast cancer, PNET, metastatic RCCa • Many MTTs are associated with pulmonary events, novel mechanism of action Molecularly Targeted Therapies March 16, 2013 l 16 Lind JSW, et al. 2012, Journal of Clinical Oncology.30(8):e104-e108; Gartrell et al, 2013; Vahid & Esmaili, 2007 Can Respir J. 2007 April; 14(3): 167–170;

17. Patterns of Pulmonary Toxicity Other MTTs can cause pulmonary events of unclear etiology Molecularly Targeted Therapies March 16, 2013 l 17 Dimopoulou I et al. Annals of Oncology. March 2006 2006;17(3):372-379.

18. Interventions: Pulmonary complications • Balance risk/benefit ratio with MTTs • In many cases, benefit of MTT therapy outweighs the risk of complications • Monitor lung sounds, respiratory status at every visit • Inhalers (albuterol, corticosteroid based therapy) • Smoking cessation • Prompt treatment of suspected respiratory infection • Consider drug holiday or dose reduction if cancer status warrants Molecularly Targeted Therapies March 16, 2013 l 18 Iacovelli et al.,September 2012, Vol. 51, No. 7 , Pages 873-879

19. Conclusion • MTTs continue to be in drug development and are integral to the hope for quality of life, progression free survival • Cardiac and pulmonary adverse events are commonly seen with these classes of drugs • Knowledge as to risk of these events, prompt recognition of symptoms and intervention will benefit patients Molecularly Targeted Therapies March 16, 2013 l 19