Cardio-Oncology at MHI. Kasia Hryniewicz, M.D.

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1 Minneapolis Heart Institute at Abbott Northwestern Hospital Cardio-Oncology at MHI Cardiovascular Nursing Conference Kasia Hryniewicz, M.D. October 7 th, 2015 No disclosure 1

2 Why cardio-oncology? Background The advent of modern cancer therapy has considerably improved the outcome of patients with cancer and, for the first time, has introduced "survivorship" as a theme in the management of cancer patients. These therapies may have cardiovascular consequences that may affect continued therapy of the cancer and cause shortand long-term morbidity or mortality. 2

3 What is chemotherapy induced cardiomyopathy? Reduction of LVEF of > 5% to < 55% with symptoms of HF OR Asymptomatic reduction of LVEF by > 10% to < 55% OR Reduction in LVEF that is <55% at baseline by 10% Adriamycin Potential offenders Trastuzumab (herecptin) Imatinib (Gleevec) Avastin (bevacizumab) Cyclophosphamide Melphalan Busulfan Carfilzomib 3

4 Mechanism of chemotherapy induced cardiomyopathy? Decrease in Ca2+ uptake and attenuated activity of Ca2+-stimulated ATPase in left ventricular sarcoplasmic reticulum. Decreased Ca2+ transport in sarcoplasmic reticulum due to modulation of SERCA2 and phospholamban expressions (overexpression) Cardiotoxicity Cardiomyopathy HTN Acute coronary syndrome/myocardial infarction Thrombosis, Electrocardiographic changes Arrhythmias, Myocarditis, pericarditis 4

5 Cardiotoxicity risk Adriamycin 2-3% in 1 year, 9% in 5 years Trastuzumab (herceptin) 2-7% A + T 5.5% in 1 year, 15.5% in 5 years Carfilzomib (KYPROLIS ) 7% cardiac events, 2% PH 5-FU coronary vasospasm, coronary thrombosis, cardiomyopathy and sudden cardiac death % Du et al. Med Onc, 2011,Dec 28; Suppl 1: S80. Risk factors - age (> 50, > 65) - female gender - history of or pre-existing cardiovascular disorders - mediastinal/chest radiation - cumulative dose - total dose administered during a day or a course - rate of administration - concurrent administration of cardiotoxic agents - prior anthracycline chemotherapy - electrolyte imbalances 5

6 Chemo-induced CM - prognosis Symptoms Often none! Often blamed on chemotherapy SOB Edema Chest Pain Early decrease in EF 3 months after last dose, usually within a year 6

7 Non-invasive monitoring Pre- therapy (Echo, MUGA) During/post therapy? - no clear guidelines from any expert group Diagnosis Echo EF, diastolic function, global longitudinal strain MUGA Troponin BNP Cardiac MRI Standard cardiac evaluation 7

8 2D echocardiography Most widely available and used Advantages: - portability - ability to evaluate other pathology than just decreased LVEF Disadvantages -reproducibility - dependence on acoustic windows. 3D echo even better recommended by most recent ASE guidelines! Why is accuracy so it important? Decisions regarding cessation of lifesaving therapies are based on changes in EF values. 8

9 Utility of biomarkers 2 groups of animals were used: - control group (n=8) received i.v. saline, - experimental group (n=11) received daunorubicin (3 mg/kg, i.v.) once weekly for 10 weeks, days after the last administration, LV contractility was invasively measured ctnt concentration determination - Cardiac contractility was significantly lower in seven surviving daunorubicin-treated animals than in control animals - ctnt plasma concentrations were significantly increased Simunek T et al, Cancer Chemother Pharmacol Nov;52(5): Utility of biomarkers 52 female breast cancer patients receiving doxorubicin and cyclophosphamide every 3 weeks for four cycles. EF by ECHO done at baseline and at the end of 4th cycle Patients' blood samples were serially measured for cardiac biomarkers. RESULTS: No symptomatic HF was detected during the study period. However, there were significant asymptomatic reductions of left ventricular ejection fraction (LVEF) from mean ± SD 70.7 ± 6% at baseline to 67.0 ± 5% (P < 0.001). After one dose of chemotherapy, a significant rise of serum NT-proBNP occurred in patients who subsequently developed an LVEF reduction compared with patients with normal LVEF (P = 0.04). Kittiwarawut A et al. Asia Pac J Clin Oncol Jun;9(2):

10 Utility of biomarkers Aim - Detect pre clinical LV dysfunction - 42 patients, 10% developed CM - CRP, troponin, BNP no change at 3 months - Lateral s and GLS decreased at 3 months in 10 patients. -Allof these patients developed decrease in LVEF at 6 months Fallah-Rad et a. JACC 2011; 57:2263 Therapies Prevention - carvedilol -spironolactone - allopurinol - statin Treatment - standard HF therapy - dextrazoxane 10

11 Treatment Fosinopril trial Fosinopril attenuated changes induced by DOX in rat model less increased heart and LV weights diminished lung congestion and ascites, attenuated LVEDP and LVSP diminished the levels of markers of cardiac toxicity (i.e., plasma levels LDH, CPK, ctni, and BNP). Cardioprotection 11

12 Cardioprotection Treatment 12

13 The Overcome Trial study design 90 pts with recent acute hematologic malignancies and without LVSD were randomly assigned to a group receiving enalapril and carvedilol (n = 45) or to a control group (n = 45). Echo and CMR imaging studies were performed before and at 6 months after randomization. The primary efficacy endpoint was the absolute change from baseline in LV ejection fraction (LVEF). The Overcome Trial -results The mean age of patients was 50 ± 13 years old, and 43% were women. At 6 months, LVEF did not change in the intervention group but significantly decreased in controls. Compared to controls, patients in the intervention group had a lower incidence of the combined event of death or heart failure (6.7% vs. 22%, p = 0.036) and of death, heart failure, or a final LVEF <45% (6.7% vs. 24.4%, p = 0.02). 13

14 Rechallenge with chemo? What if things not go well 14

15 Advanced therapies? Heart transplantation? Mechanical support? Challenging Doable but Increased Need for Right Ventricular Support in Patients with Chemotherapy-Induced Cardiomyopathy Undergoing Mechanical Circulatory Support: Outcomes from the INTERMACS Registry. Our experience 3 patients implanted with an LVAD, 2 did well, 1 died Evolution of Cardio-Onc Clinic at MHI 1 MD,1 RN Risk factor list Reach out to Minnesota Oncology Prevention/ therapy and f/u protocols Imaging protocols (strain) 15

16 Cardio-Oncology Clinic at MHI Kasia Michael Samara, Hryniewicz, M.D. M.D. Elizabeth Grey, M.D. Mosi Bennett, M.D. Michelle Vanhove, NP Rebecca Giraldo, RN Our philosophy Physicians and NPs available to see new referrals within 24 hours. Education provided by nurse coordinator at initial visit. Close follow up including visits and phone calls. Efficient uptitration of medications to allow the shortest time off chemotherapy We like to be bothered and we like to bother 16

17 Standardized 2D echocardiogram - Designated machine - All techs trained - All patients have longitudinal strain measurements - All patients have 3D LV systolic function assessment - Report generator updated to include strain and 3D measurements Our Stats 117 patients 90 (77%) women Mean age 68 years (31-88) Most common diagnosis breast cancer (39%) lymphoma (12%) 8/117 (7%) presented with low EF, able to restart chemotherapy after 4-6 weeks of HF treatment 17

18 When to refer? Early! Ideally before chemotherapy started if any of the risk factors present If any decrement in LVEF during therapy Symptoms of heart failure and side effects of chemotherapy are very similar refer when in doubt! Future directions Clinical trials - stem cells in chemo induced CM (SENECA trial), starting this fall - Prevention and screening - Provider manual - Patient information booklet - Expanding to outreach clinics - NP involvement 18

19 Our cases 42 years old female, diagnosed with breast CA when 23 weeks pregnant Presented 3 months after delivery with LVEF of 25% years old male with recurrent gastric cancer, who exceeded life time dose of Adriamycin 3 times 48 years old female with rare small intestinal cancer, with classic angina on 5-FU 65 years old female with metastatic renal cell cancer with know hx of Adriamycin induced cardiomyopathy for breast cancer 10 years ago Thank you! 19