Cancer Treatment and Heart Failure Mandar Aras, MD, PhD Assistant - - PDF document

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Cancer Treatment and Heart Failure Mandar Aras, MD, PhD Assistant Professor of Medicine UCSF Advanced Heart Failure and Heart Transplant 1 Disclosures None 2 2 1 | [footer text here] Increasing cancer survivors over time 3 De Moor et.

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Cancer Treatment and Heart Failure

Mandar Aras, MD, PhD Assistant Professor of Medicine UCSF Advanced Heart Failure and Heart Transplant

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Disclosures

§ None

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Increasing cancer survivors over time

De Moor et. al. Cancer Epidemiol Biomarkers Prev. 2013; 22(4): 561. 3

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Cancer patients are dying of CV disease

Zaorsky, et al., Causes of death among cancer patients. Annals of Oncology 2017; 28:2. 4

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Clinical Questions in Cardio-oncology

Armenian SH, et al. Journal of Clinical Oncology 2017 35: 893-911. 6

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CV complications from cancer therapy

Babiker et al., Critical Reviews in Oncology/Hematology; 126 (2018): 186-200. 7

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What does heart failure mean to an

  • ncologist?

§ Cardiomyopathy with decreased EF globally or due to

regional changes in interventricular septum contraction

§ Symptoms associated with HF § Signs of HF such as S3 gallop, tachycardia or both § Decline in initial LVEF of at least 5% to < 55% with clinical HF

OR asymptomatic decrease in LVEF of at least 10% to < 55%

Seidman A et al., J Clin Oncol 2002; 20:1215-1221. 8

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  • Anthracyclines
  • Targeted therapies against HER-2 pathway
  • Proteasome inhibitors
  • Checkpoint inhibitors

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Who is at risk of cardiomyopathy following chemotherapy?

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Anthracycline Mechanism

Chang H-M, et al., JACC 2017, 70 (20) 2536-2551. Shakir, D.K., Rasul, K.I., 2009. Chemotherapy induced cardiomyopathy: pathogenesis, monitoring and

  • management. J. Clin. Med. Res. 1 (1), 8–12

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§

Widely used chemotherapy

§

First reported in 1967 in children receiving doxorubicin

§

Mechanisms:

  • Disabling function of

topoisomerase II beta (TOP2B)

  • Mitochondrial dysfunction
  • Oxidative stress and

generation of ROS 10

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Anthracycline toxicity is dose-dependent

§ Risk factors include:

  • Cumulative dose
  • Age (> 65yo)
  • Other sequential

cardiotoxic treatments (anti-HER2, RT)

  • Pre-existing cardiac

disease

Swain SM, et al., Cancer 2003; 97:2869-2879. 11

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What is the frequency of Anthracycline toxicity

§

Asymptomatic LV dysfunction event rates:

  • 150 mg/m2 = 7%; 350 mg/m2 = 18%; 550 mg/m2 = 65%

§

Clinical HF event rates:

  • 400 mg/m2 = 5%; 700mg/m2 = 48%

Henriksen PA et al., Heart 2018; 104:971-977. Cardinale D et al., Circulation 2015; 131:1981-1988. 12

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What is the timeline for Anthracycline toxicity

§

In 2,625 cancer patients who received anthracycline (74% women; 51% breast cancer):

  • Cardiotoxicity incidence was 9% with 98% of cases developing in the first year

(median time 3.5 months).

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Pediatric populations receiving anthracycline chemotherapy remain at elevated risk of developing HF decades after receiving a cancer cure.

Henriksen PA et al., Heart 2018; 104:971-977. Cardinale D et al., Circulation 2015; 131:1981-1988. 13

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Preventing Anthracycline Cardiotoxicity

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Avoid or minimize use of cardiotoxic therapies if alternative exist

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Manage CV risk factors (smoking, DM, dyslipidemia, obesity)

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Drug delivery

  • Liposomal doxorubicin
  • Continuous rather than bolus administration

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Cardioprotective medications

  • Dexrazoxane (mechanism via TOPII)
  • Neurohoromonal antagonists (ACE-I, BB)
  • Statins

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Neurohormonal antagonists

§ OVERCOME trial 2013 § PRADA trial 2016 § CECCY trial 2018

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In patients receiving chemotherapy, does the addition of neurohormonal antagonists PRIOR to cancer treatment reduce the risk of cardiac toxicity?

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OVERCOME trial

Bosch X et al. JACC 2013; 61:2355 16

  • N=90
  • RCT
  • Heme malignancy/high dose chemo
  • Enalapril (~8.2mg) and Carvedilol (~24mg) vs placebo
  • Endpoint: Absolute change in LVEF in 6 months

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OVERCOME trial

Bosch X et al. JACC 2013; 61:2355 17

Combined treatment with Enalapril and Carvedilol may prevent LV dysfunction in patients with hematological malignancies

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PRADA trial

Gulati G et al., Eur Heart J 2016; 37:1671-80 18

  • N=130
  • RCT, 2x2 factorial design
  • Early breast cancer

§ 20-25% + trastuzumab § 60-70% + radiation

  • Candesartan vs placebo; Metoprolol XL vs placebo
  • Endpoint: Change in LVEF on CMR in 6 months

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PRADA trial

Gulati G et al., Eur Heart J 2016; 37:1671-80 19

Candesartan prevents decline in LV function in patients with early breast cancer (LVEF decline by 2.6% in placebo vs 0.8% in Candesartan group)

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CECCY trial

Avila et al., J Am Coll Cardiol. 2018 May 22;71(20):2281-2290. 20

  • N = 200
  • RCT
  • HER2-negative breast cancer receiving anthracycline

§ 100% Anthracyclines

  • Carvedilol (25mg BID) vs placebo
  • Outcome: Reduction in LVEF in 6 months

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CECCY trial

Avila et al., J Am Coll Cardiol. 2018 May 22;71(20):2281-2290. 21

65.2 64.8 63.9 63.9

No difference in LVEF decline with carvedilol vs placebo

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Statins

Acar et al. JACC 2011; 58:988. 22

  • N=40
  • Heme malignancy
  • RCT
  • Atorvastatin 40mg

vs control (not placebo)

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Summary

§ Primary prevention with neurohormonal antagonists and

statin have a small effect on preventing LV dysfunction following anthracycline chemotherapy

§ Larger multi-center studies are needed

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How to monitor for cardiac toxicity following anthracyclines?

ASCO Guidelines

§ Baseline echo should be obtained § Echo should be performed 6-12 months after completion

  • f therapy, in asymptomatic high risk patients

§ No specific guidance on routine surveillance in

asymptomatic pts with normal echo @ 6-12 months

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  • Anthracyclines
  • Targeted therapies against HER-2 pathway
  • Proteasome inhibitors
  • Checkpoint inhibitors

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Who is at risk of cardiomyopathy?

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Anti-HER2 therapy Mechanism

Cote et al., NEJM 367; 22:2150-2153. 26

§ Treatment of ERBB2

(HER2) positive breast cancer

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Anti-HER2 therapy toxicity

Cote et al., NEJM 367; 22:2150-2153. 27

§ Risk factors

  • Sequential anthracycline administration
  • Age
  • Concurrent cardiovascular disease
  • Lower baseline LVEF
  • Obesity

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Slamon et al, NEJM 2011 Romond et al, JCO 2012 28

Anthracyclines Anthracyclines + Trastuzumab BCIRG 006 ≥10% LVEF decline 11.2 % 18.6% Cardiac Death or CHF 0.7% 2% NSABP B-31 ≥10% LVEF decline Not reported 12% Cardiac Death or CHF 1.3% 4% The addition of trastuzumab to an anthracycline based regimen is associated with a ~3x fold increased risk of HF

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Dang, et al., JAMA Onc 2016; 2: 29-36 Jones, et al., Lancet Onc 2013; 14: 1121-8 Slamon, et al.., NEJM 2011; 365: 1273-83 29

Treatment LVEF decline Severe HF Dang et al., 2016 Paclitaxel + Trastuzumab 3.2% 0.5% Jones et al., 2013 Docetaxel + Cyclophosphamide + Trastuzumab 5.6% 0.4% Slamon et al., 2011 Docetaxel + Carboplatin + Trastuzumab 9.4% 0.4%

Trastuzumab based therapy without anthracyclines is associated with low risk of cardiac toxicity

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LV dysfunction improves with Trastuzumab interruption

Yu AF, et al. Breast Cancer Res Treat 2015. 149:489. 30

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Guidelines for managing Trastuzumab cardiotoxicity

§ Screen for and manage CV risk factors § Echo at baseline and at regular intervals during treatment

Armenian et al. JCO 2017; 35:893 31

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Cardiac Monitoring

Presentation Title 32

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Managing Trastuzumab cardiotoxicity

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Manage CV risk factors

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Echo at baseline and at regular intervals during treatment

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Withhold trastuzumab for at least 4 weeks if:

  • > 15% decrease in LVEF from baseline
  • ≥ 10% decrease in LVEF from baseline to < 50%

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Resume trastuzumab within 4-8 weeks if LVEF normalizes to normal and the absolute decrease from baseline is ≥ 15%

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Consider permanent termination of trastuzumab for:

  • > 8 weeks LVEF decline
  • More than 3 occasions for LV dysfunction

Armenian et al. JCO 2017; 35:893 33

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Prevention of trastuzumab cardiotoxicity

Pituskin et al. JCO; 35, 8: 870-877. 34

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MANTICORE

Pituskin et al. JCO; 35, 8: 870-877. 35

  • N = 94
  • Her2-positive Breast

Cancer

  • Perindopril vs bisoprolol vs

placebo

  • Endpoint: Indexed LVED

volumes using CMR

  • LVEDD increased in pts treated with

perindopril (+7 ml/m2)

  • LVEDD increased in pts treated with

bisoprolol (+8 ml/m2)

  • LVEDD increased in placebo (+4

ml/m2)

  • Secondary analysis – change in EF
  • Bisoprolol attenuated decline in

LVEF

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USF Study

Lisinopril vs Carvedilol vs Placebo

Guglin M…Munster PN, JACC 2019; 73:2859-2868. 36

  • N = 468
  • RCT
  • Breast cancer undergoing

treatment with trastuzumab + Anthracycline 189

  • Anthracycline 279

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Non-trastuzumab HER-2 antagonists

Perez et al. JCO 2017; 35; 2. 37

  • Pertuzumab, Lapatinib, T-

DM1

  • Lower rates of LV

dysfunction and symptomatic HF

  • Dual HER-2 antagonist

therapy with no increase risk compared to monotherapy

Cardiac toxicity (EF<50% and decrease 15% from BL) 0.8% TDM-1 2.5% TDM-1 + pertuzumab 4.5% Traztuzumab 37

Summary

§ Trastuzumab cardiac toxicity is more common in patients who

have previously received anthracyclines

§ Trastuzumab cardiac toxicity is reversible with HF

medications

§ Primary prevention with neurohormonal antagonists can

prevent LV dysfunction especially in patients receiving combination anthracycline + trastuzumab therapy

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  • Anthracyclines
  • Targeted therapies against HER-2 pathway
  • Proteasome inhibitors
  • Checkpoint inhibitors

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Who is at risk of cardiomyopathy?

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Anderson K. Clin Cancer Res 2016; 22(22); 5419–27. 40

Proteasome inhibitors

Multiple Myeloma

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  • Bortezomib, reversible proteasome inhibitor is not known to cause HF
  • Carfilzomib, a novel irreversible proteasome inhibitor
  • In a phase 2 trial of 266 patients treated with carfilzomib monotherapy for

relapsed myeloma, 10 experienced HF (3.8%), 4 (1.5%) had a cardiac arrest, and 2 (0.8%) had a myocardial infarction (MI) during the study

  • Cardiotoxicity appears to be largely reversible with cessation of therapy and

the initiation of HF treatment

Siegel DS. Blood 2012; 120:2817-2825 Grandin EW. J Card Fail 2015; 21:138-144. 41

Proteasome inhibitors

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  • Anthracyclines
  • Targeted therapies against HER-2 pathway
  • Proteasome inhibitors
  • Checkpoint inhibitors

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Who is at risk of cardiomyopathy?

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Checkpoint inhibitors

  • Anti-CTLA-4 and anti-PD1

agents

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Immunotherapy

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Cardio-oncology at UCSF

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Thank you! Mandar.Aras@ucsf.edu

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