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

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Managing the adverse events due to molecularly targeted therapies:

Cardiovascular and Pulmonary Side Effects

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

Nurse Practitioner, Cleveland Clinic Taussig Cancer Institute PhD Candidate, Case Western Reserve UniversityCleveland, Ohio

Molecularly Targeted Therapies April 22, 2023 l 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 (Randomly Selected From MANY….) Name Type Target

Trastuzumab MoAb HER-2, a receptor with tyrosine kinase activity

Lapatinib Small molecule inhibits several tyrosine kinases, including HER-2

Gefitinib NSCLCA; small-molecule inhibits the tyrosine kinase activity of EGFR

Vorinostat Small molecule; CTCL HDAC inhibitor

Bevacizumab monoclonal antibody; many indications

Binds to VEGF and prevents endothelial cell interaction, angiogenesis

Sunitinib small-molecule tyrosine kinase inhibitor; metastatic renal cell carcinoma,PNET, GIST

blocks kinases involved in VEGF signaling

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

http://www.cancer.gov/cancertopics/factsheet/Therapy/targeted


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

Ederhy S, Izzedine H, Massard C, et al, 2011;80(3):369-379.


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


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.


• 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.

Is Hypertension a Good Thing and Should We Treat It?


• 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

Yes We Should Treat Hypertension!

Jessup M, et al. (2009) Circulation. 119(14):1977-2016; Ederhy et al, 2011


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.


Long Q-T

torsade de pointes (TdP) followed by sustained TdP into ventricular fibrillation

QTc prolongation (559 msec)

Ayad et al, Proc (Bayl Univ Med Cent). 2010 July; 23(3): 250–255


Management of Q-T ProlongationSelect Risk Factors Intervention

Baseline Q-T prolongation

Subclinical long Q-T syndrome

Female gender,

diabetes,

cirrhosis

Myocardial ischemia,

Congestive heart failure, bradycardia, Hypokalemia, hypomagnesemia, hypocalcemia Hypothyroidism, hyperparathyroidism, hyperaldosteronism Digitalis therapy Rapid rate of intravenous infusion with a Q-T prolonging drug

Baseline ECG, 7 days after the initiation of treatment, and periodically following any dose adjustments.

- Then ECG periodically during therapy in order to detect asymptomatic prolongation of the Q-T interval

A baseline QTc > 470 ms in men and 480 ms in women should be considered abnormal

Stop if QTc is >500 ms or with Q-T prolongation exceeding 60 ms

-Administer Magnesium infusion

-Shorten the QTc by increasing heart rate

Ayad et al., 2010Proc (Bayl Univ Med Cent). 2010 July; 23(3): 250–255; ; Mellor et al, 2011; ECG= Electrocardiogram


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


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.



• 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



• 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


Who is at risk for pulmonary complications?• mTOR inhibitors

–temsirolimus, everolimus, and ridaforolimus

• Erlotinib induced 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

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;


Patterns of Pulmonary Toxicity

Dimopoulou I et al. Annals of Oncology. March 2006 2006;17(3):372-379.

Pattern of Injury Agent(s)

Non-Specific pneumonitis Gemcitabine

Fludarabine

Gefitinib

Imatinib

Rituximab

Erlotinib

Bevacizumab

Temsirolimus

Everolimus

Carfilzomib, Bortezomib

Hypersensitivity pneumonitis Bevacizumab

Imatinib

Other MTTs can cause pulmonary events of unclear etiology


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

Iacovelli et al.,September 2012, Vol. 51, No. 7 , Pages 873-879


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

Documents

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