Cardio oncology Double Jeopardy

Cardio oncology Double Jeopardy Edie Pituskin RN MN (NP Adult) PhD NP Forum for Nursing and Allied Health, April 10, 2015

Aims Describe the double jeopardy faced by cancer patients Discuss issues in detection Describe first 2 years of ENCORE Implications & future directions

Question 1 A 45 year old Alberta woman with early stage breast cancer should be most concerned about: A. Death from breast cancer B. Death from ovarian cancer C. Death from cardiovascular disease D. Death from old age

Competing causes of death

What is going on? Shortand long term treatmenteffects effects Poor understanding of competing risks, particularly in relation to cardiovascular morbidity and mortality Increasingly important given growing numbers of survivors

Traditional paradigm in cancer treatment

Traditional paradigm in cancer treatment Surgery to remove malignancy SLASH

Consequences of surgery Pain Lymphedema Altered vasculature Disability, disfigurement

Traditional paradigm in cancer treatment Surgery to remove malignancy Radiation therapy BURN

for each Gy of radiation, there is a 7.4% increase in the occurrence of a subsequent major coronary event. Cardiac deaths 27% higher in breast cancer patients treated with RT vs none.

Traditional paradigm in cancer treatment Surgery to remove malignancy Radiation therapy Chemotherapyh POISON

Consequences of chemotherapy Multiple short and long term toxicities Negative cardiovascular sequelae

Anthracyclines Risk factors associated with cardiovascular sequelae Cumulative dose? Age extremes Dose scheduling Mediastinal radiotherapy Previous cardiac events Hypertension females

Yancik JAMA 2001 N = 1800

Figure 1: Multiple-hit hit hypothesis. (Jones, L.W. JACC, 50(15)1435-1441). 1441)

New paradigm in cancer treatment Surgery to remove malignancy Radiation Therapy Chemotherapyh Targeted Therapy

Hallmarks of Cancer: The Next Generation Hanahan & Weinberg, Cell 144, March 4, 2011 Elsevier Inc.

Standard treatment for early stage breast cancer Surgery to remove malignancy Chemotherapy Radiation i Therapy Targeted Therapy

Trastuzumab in breast cancer Approximately 20 25% 25% of breast cancer patients overexpress human epidermal growth factor for receptor 2 (HER2), a high risk marker for future metastatic disease and a poor prognosis. trastuzumab reduces the 3 year breast cancer recurrence and risk of death rate by half. standard of care since 2006

Trastuzumab major side effect Few adverse effects BUT cardiac toxicity, has emerged as a significant complication of trastuzumab treatment. Clinical heart failure (HF) was found in up to 4% of treated patients and asymptomatic declinesin ventricular function have been reported in up to 20% of patients in randomized trials. BC and MB clinical experiences: up to 25% experienced a cardiac event, requiring temporary or permanent discontinuation of trastuzumab

Developing strategies to link basic cardiovascular sciences with clinical drug development: another opportunity for translational sciences. Feldman AM, Koch WJ, Force TL. Clin Pharmacol Ther. 2007 Jun;81(6):887 92. Epub 2007 Mar 28.

Q3monthly cardiac assessment while on one year of trastuzumab CCO 2014

What is left ventricular ejection fraction (LVEF)?

What is Ejection Fraction (EF)? The FRACTION of blood ejected with each heartbeat LVEDV = LVESV = LV end diastolic LV end systolic volume volume LVEDV LVESV / LVEDV The left ventricle as FULL as it can get before contracting The left ventricle as EMPTY as it can get after contracting

EF can be deceiving LVEDV LVESV Stroke Volume (LVEDV EF LVESV) 120 ml 50 ml 70mL 60% 135mL 55mL 80mL 60% 150mL 60mL 90mL 60% Cardiac remodeling

Patient case trastuzumab Baseline 32 year old female Ex smoker Asymptomatic JVP flat, no edema Fatigue (chemo) Elliptical twice weekly

3 month echo

Issues in detecting cardiotoxicity Clinical symptoms Fatigue Exercise intolerance Pedal edema

Why is early detection important? Percentage of Responders According to the Time Elapsed From AC Administration and Start of HF Therapy AC = anthracyclines; HF = heart failure. (Cardinale JACC 2010)

Issues in detecting cardiotoxicity Clinical symptoms Fatigue Exercise intolerance Pedal edema Diagnostic imaging i

Definitions of trastuzumab related cardiotoxicity trastuzumab mediatedcardiac toxicity as: 1) a cardiomyopathy with a decrease in left ventricular ejection fraction (LVEF), (2) symptoms or signs of heart failure, (3) an absolute decline in LVEF by 5% and < 55% with symptoms of HF or (4) an asymptomatic ti absolute decline in LVEF by 10% and LVEF < 50%. Seidman A,, et al. Cardiac dysfunction in the trastzumab clinical trials experience. J Clin Oncol 2002;20:1215-1221. Mackey JR et al. Cardiac management during adjuvant trastuzumab therapy: recommendations of the Canadian Trastuzumab Working Group. Curr Oncol. 2008;15(1):24-35.

Issues in detecting cardiotoxicity MUGA (multi gated acquisition scan) provides LVEF, reproducible Widely available, commonly used in oncology

MUGA Radionuclide scan - RBCs are tagged, flow measured by camera

Issues in detecting cardiotoxicity MUGA (multi gated acquisition scan) provides EF, reproducible Widely available, commonly used in oncology Echocardiography Provides LVEF AND measures volumes of each heart chamber Technique, expertise dependent d

Issues in detecting cardiotoxicity MUGA (multi gated acquisition scan) provides EF, reproducible Widely available, commonly used in oncology Echocardiography Provides EF AND measures volumes of each heart chamber Technique dependent d

Issues in detecting cardiotoxicity BASELINE LVEDV 120ml, LV mass 91 g, LVEF 55%

Issues in detecting cardiotoxicity BASELINE LVEDV 120ml, LV mass 91 g, LVEF 55% FOLLOW UP LVEDV 187ml, LV mass 91 g, LVEF 53%

What can we do?

Vision to prevent and treat cardio toxic effects of cancer therapy To develop a rapid access clinic for cancer patients to p p p obtain cardio oncology team assessment

2011 2013 70 60 50 40 30 20 10 0 Breast Heme CRC Other

Adjuvant breast n = 59 12 13 baseline 34 (29 trastuzumab, 5 other) during post tx

n = 20 completed adjuvant therapy (TCH) average age 55 (32 67) 7 on CVD meds (ACEI, BB, CCB, statin, diuretic) i 5 current, 4 ex smokers (~20PY) 2 + family history CVD BMI Mean 28 11overweight/obese overweight/obese, 9 normal

Reason for referral ARRHYTHMIA N = 2 LVEF < 50%, DROP OF > 10% N = 4 LVEF > 50%, DROP OF > 10% N = 14

Interventions 100% recommended to continue therapy Additional or other diagnostic imaging 9 (45%) Eh Echo (5), MRI (4) Initiate/change pharmacotherapy 9 (45%) ACEI (4) BB (3) both (1) stop offending med (1)

End of treatment cumulative dose 8000 7000 6000 5000 N = 20 consult cumulative 100% of planned dose 4000 3000 2000 1000 0 epirubicin docetaxel carboplatin trastuzumab

LV function 64 62 60 N = 20 58 Pre consult 56 54 52 50 48 Post 46 MJGA ECHO MRI

Mrs K.

2008-2011 retrospective review, n = 48, 85% anthra

Anthracycline/trastuzumab? 100% received sequential Fallah-Rad et al JACC anthracycline / trastuzumab Vol 57, No 22, 2011 regimen

Why is this important?

Best supportive care

Vision to prevent and treat cardio toxic effects of cancer therapy To develop a rapid access clinic for cancer patients to obtain cardio oncology team assessment To develop a research program involving multidisciplinary and multimodality approaches

MANTICORE Overview assessment* MRI biomarkers assessment* MRI biomarkers assessment* MRI biomarkers assessment* MRI biomarkers Randomization medication titration Bisoprolol** 2.5mg 5 10 Perindopril** il** placebo 2mg 4 8 telephone follow up telephone follow up telephone follow up 0 7d 14d 21d 1 3 6 9 12 18 24mos trastuzumab *assessment = history, physical, labs ** or placebo

What can YOU do?

A 40 year old breast cancer patient has the cardiopulmonary function of a: A. 40 year old sedentary female B. 50 year old sedentary female C. 60 year old sedentary female D. 70 year old sedentary female

Courtesy M Haykowsky PHD

Modifiable risk factors cardiovascular disease The major modifiable risk factors for cardiovascular disease are well established, and include tobacco use, high blood pressure, high cholesterol, alcohol use, obesity and physical inactivity. Public Health Agency of Canada http://www.phac-aspc.gc.ca/cd-mc/cvd-mcv/risk-risques-eng.php

Vital role of comprehensive clinical assessment Health promotion Maintain function, prevention Awareness of short and long term potential effects of cancer treatment Documentation of changes over time Detection of developing problems

Cardio oncology oncology Increasingly important Traditional therapies New therapies, targeting vital pathways Heart health promotion major role during therapy full dose of treatment, potentially reduce toxicity long term survivorship, health lthhbit habits, empowerment, family health

Team Cross Cancer Institute

Thank you!