Cardio-Oncology June 12, 2014 Daniel J Lenihan, MD Professor, Division of Cardiovascular Medicine Director, Clinical Research Cardio-Oncology Program Vanderbilt University Presenter Disclosure Information Dr Enrique Lopez Innovation and Humanitarian Award Presentation Tampa, FL 6.12.14 •I will not discuss off label use or investigational use in my presentation. •I have financial relationships to disclose: –Research support from: Acorda, Inc; Millenium, Inc –Consultant (modest): AstraZeneca, Roche, Onyx, Oncomed Why discuss cardiac disease and cancer? Let’s consider… • These are by far the two most common disease conditions in the developed world • Cardiac disease may pre-exist cancer therapy or may be caused/exacerbated by it • Cancer therapy is more effective than ever before at treating cancer, but has a price.. • Therapeutic choices for both cardiology and oncology have significant overlap In any patient, heart disease and cancer are likely to overlap Driver BMJ 2008:337:p. 2467 Why discuss cardiac disease and cancer? Let’s consider… • These are by far the two most common disease conditions in the developing world • Cardiac disease may pre-exist cancer therapy or may be caused or exacerbated by it • Cancer therapy is more effective than ever before at treating cancer, but has a price.. • Therapeutic choices for both cardiology and oncology have significant overlap In breast cancer patients, heart disease has a great impact…. JAMA. 2001;285:885-892 Even in early stage breast cancer, cardiac disease does matter… • Patients with early stage breast cancer are 4x more likely to die of noncancer conditions (up to 45 % are cardiac in nature) Hanrahan, et al. JCO 25: 4952-4960, 2007 Why discuss cardiac disease and cancer? Let’s consider… • These are by far the two most common disease conditions in the world • Cardiac disease may pre-exist cancer therapy or may be caused/exacerbated by it • Cancer therapy is more effective than ever before at treating cancer, but has a price.. • Therapeutic choices for both cardiology and oncology have significant overlap Increased Risk Of Fatal Side Effects From 3 'Targeted' Cancer Drugs Medical News Today Treatment with three relatively new "targeted" cancer drugs has been linked to a slightly elevated chance of fatal side effects, according to a new analysis led by scientists at Dana-Farber Cancer Institute. http://www.medicalnewstoday.com/releases/241256.php Number of PUBMED articles on Cardio-Oncology 400 350 300 250 200 150 100 50 0 1971 2014 Why discuss cardiac disease and cancer? Let’s consider… • These are by far the two most common disease conditions in the world • Cardiac disease may pre-exist cancer therapy or may be caused/exacerbated by it • Cancer therapy is more effective than ever before at treating cancer, but has a price.. • Therapeutic choices for both cardiology and oncology have significant overlap Anti-VEGF Therapy can decrease blood flow resulting in cancer control Willitt, JCO 2006 Therapy for both Oncology and Cardiology are intimately intertwined at the vascular level Kirchmair R. Circulation. 2005 May 24;111(20):2662-70. Systemic Effects of Anti-VEGF Therapy Tumor Tissues Normal Tissues (VEGF upregulated) (VEGF constitutively expressed) Hypertensive remodeling Microvascular rarefaction Cardiomyopathy (sunitinib and sorafenib) Lung cancer (bevacizumab) Inhibition of tumor growth, tumor cavitation Hepatocellular carcinoma (sorafenib) Tumor necrosis 1 2 3 Microcirculation: 1. normal arteriole, 2. functional rarefaction (endothelial dysfunction,vasoconstriction), 3. anatomic rarefaction Renal cell carcinoma (sunitinib) Tumor shrinkage, tumor cell necrosis Thrombotic microangiopathy Glomerulopathy / glomerulonephritis Proteinuria Hypertensive nephropathy Colorectal cancer (bevacizumab) Deceleration of tumor growth efficient chemotherapy delivery Vaklavos, et al Oncologist 2010, p 130. Sunitinib, a novel oral chemotherapeutic agent with anti-VEGF properties, is associated with hypertension and heart failure Khakoo, et al, 2008; 112:2500-8 Definition of a “Kinase Inhibitor”: • A drug that interferes with cell communication and growth and is sometimes used to treat cancer From: The Frequency and Severity of Cardiovascular Toxicity From Targeted Therapy in Advanced Renal Cell Carcinoma Patients JCHF. 2013;1(1):72-78. doi:10.1016/j.jchf.2012.09.001 Figure Legend: Incidence of Cardiovascular Toxicity by Type The incidence of cardiovascular toxicity varied by type of toxicity and by chemotherapy agent received. Many patients received multiple therapies in succession and are included only once in “All Patients.” CV = cardiovascular; LVEF = left ventricular ejection fraction; NT-proBNP = N-terminal B-type natriuretic peptide. Date of download: 5/31/2014 Copyright © The American College of Cardiology. All rights reserved. From: The Frequency and Severity of Cardiovascular Toxicity From Targeted Therapy in Advanced Renal Cell Carcinoma Patients JCHF. 2013;1(1):72-78. doi:10.1016/j.jchf.2012.09.001 Figure Legend: The Stanford Monitoring Algorithm for Targeted Therapies Cardiovascular monitoring algorithm for patients with renal cell carcinoma receiving targeted chemotherapy. BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure; other abbreviations as in Figure 1. Date of download: 5/31/2014 Copyright © The American College of Cardiology. All rights reserved. Newer Chemotherapy with Anti-VEGF properties What about the detection of cardiac damage during cancer treatment? Anthracycline Cardiotoxicity : Effects of Different Drugs, Scheduling, and Cardiac Protection with Dexrazoxane 15 Epirubicin 1000 mg/m2 4 Epirubicin < 900 mg/m2 12 Dauno 1000 mg/m2 1.5 Dauno 500 mg/m2 Doxo (400-499 mg/m2) + Dexrazoxane 1 Doxo low dose weekly > 600 mg/m2 5.4 Doxo bolus > 550 mg/m2 10 Doxo 1000 mg/m2 20 Doxo 500 mg/m2 7 0 5 10 15 CHF (%) Hensley ML et al J Clin Oncol 1999; 17(10):3333-3355 20 25 How often is cardiac toxicity detected by Echo and MUGA After Four Cycles of AC Chemotherapy? (NCI-CTC Version 2) Abbreviations: LVEF, left ventricular ejection fraction; NCI-CTC, National Cancer Institute Common Toxicity Criteria; AC, doxorubicin and cyclophosphamide; MUGA, multiple-gated aquisition; ECHO, echocardiogram. Perez EA et al. J Clin Onco. 2004:22, 3700-3704 Heart Failure definitely occurs over time Bowles, Erin et al JNCI 2012 p1293 The real world incidence of HF with chemotherapy is higher than expected Chen J, et al JACC 2012 23% increased rate of developing HF compared to age matched controls In the case of HER2+ breast cancer, treatment clearly benefitted the disease but came at a cost Slamon D et al; NEJM 2011:365:1273-83 Principles for the Management of Cardiac Disease that provides benefit for Cancer Patients • Biomarkers used in Cardiology are also used in Oncology • Cardiac specific therapy allows for more effective cancer treatment Troponin I is valuable in detecting Cardiotoxicity Cardinale et al. Circ. 2004;109:2749-2754 BNP guided therapy for cardiac disease (eg. HF) is very useful and appears to change the outcome…. Kaplan-Meier curves examining time to first event of the primary clinical endpoint showed a clear divergence between the groups by 6 months (p=0·034) and remained significant when reanalysed to include only heart-failure events or death (p=0·049). Troughton et al. Lancet. 2000: 355, 1126-30 In a pilot study of 109 patients undergoing anthracycline based therapy… Comparison of LV Ejection Fraction at Baseline and Completion* Shaded box: Patients with Cardiac Events * Only 3/10 had LVEF criteria for toxicity The test characteristics of BNP in detecting cardiotoxicity Test n Sensitivity Specificity Positive Predictive Value Negative Predictive Value 1 BNP >100 109 100 (72,100) 59 (49, 69) 22 (11, 35) 100 (94, 100) 1 BNP > 150 109 100 (72,100) 81 (71, 88) 37 (20, 56) 100 (95, 100) 1 BNP > 200 109 91 (59, 100) 90 (82, 95) 50 (27, 73) 99 (94, 100) 102 30 (7,65) 84 (75, 91) 17 (4, 41) 92 (84, 97) LVEF<50% or change >15% All data is % with 95 % CI 6 of 9 patients with elevated BNP greater than 200 who did not develop an event were on cardioprotective medications throughout chemotherapy Elevated pre-chemo BNP predicted toxicity in patients receiving anthracyclines Lenihan, et al: JCO 08, abstract 18S Factors associated with having a cardiac event during the study period Normal BNP < 100 pg/ml PREDICT Study: A multicenter study in Patients undergoing anthRacycline-based chemotherapy to assess the Effectiveness of using biomarkers to Detect and Identify Cardiotoxicity and describe Treatment Daniel J Lenihan, MD Professor, Division of Cardiovascular Medicine Vanderbilt University CCOP Annual Meeting 2010 PREDICT Study Total Accrual: 597 patients PREDICT: Demographics and risk of cardiotoxicity Abstract 9624 Univariate Analysis of Cardiac Biomarkers (Table 2) PREDICT study: Utility of Biomarkers Abstract 9644 Reduced Multivariate Analysis (Table 3) Diagnostic Performance of Biomarkers (Table 4) Out of 51 patients at Vandy, 7 have confirmed cardiac events. Cardiac Biomarker Elevation from Baseline and Cardiac Events The effect of time for initiation of HF therapy and the percent of patients who improve Responders (%) 100 80 64% 60 28% 40 7% 20 0% 0% 0% 0% 0 1-2 2-4 4-6 6-8 8-10 10-12 (n=75) (n=35) (n=20) (n=12) (n=8) (n=7) >12 months (n=44) D Cardinale, et al. JACC 2010, jan 26. In regards to Ischemic insults, we have a paradigm Kloner et al, Circ 2001; p2981 Classic Triad of Heart Failure • Dyspnea • Lower extremity edema • Fatigue How Accurate is Clinician Reporting of Chemotherapy Adverse Effects? Journal of Clinical Oncology, Vol 22, No 17 (September 1), 2004: pp. 3485-3490 How Accurate is Clinician Reporting of Chemotherapy Adverse Effects? • Comparative study of patient reporting of eight symptoms with physician reporting of same symptoms • Physician Sensitivity=47% • Physician Specificity=68% JCO 2004 22:3485-3490 Principles for the Management of Cardiac Disease provide Benefit to Cancer Patients • Biomarkers used in Cardiology are also used in Oncology • Cardiac specific therapy allows for more effective cancer treatment There is significant reversibility of LV dysfunction with trastuzumab-related cardiac toxicity Ewer, et al Journ of Clinical Oncology 2005,23;p 7820-6. • What about Prevention? Ben Franklin thought it was a good idea… ACE Inhibition appears quite important in preventing heart failure Cardinale D et al. Circulation. 2006;114:2474-2481 Carvedilol appears protective during adriamycin based chemotherapy Data expressed as mean values. Kalay et al. JACC. Dec 2006. 48:2258-62 Statin therapy prior to and during chemotherapy was protective JACC 2012, p 2384 Prevention of Cardiotoxicity is possible Bosch, X et al, JACC 2013, p 2355 Are there things on the cancer therapy horizon that could be concerning for cardiomyopathy? There is a balance between protein synthesis and degradation Monte S. Willis, M.D., Ph.D., and Cam Patterson, M.D., M.B.A. NEJM 2013;368:455-64. Dick,LR and Flemming,PE Drug Discovery Today ;15 (5/6) March 2010 A report of 6 cases describing carfilzomib related cardiac dysfunction and the patterns of cardiotoxicity Carfilzomib Exposure Baseline With Carfilzomib Recovery Parameter Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Dosing (mg/m2) 20x1 then 27 27 20 20 27 20x1 then 27 Duration of Therapy (mos) 3 5 6 1 3 3 Total Cumulative Dose (mg/m2) 405 903 972 141 540 444 NYHA Class LVEF BNP (pg/mL) Troponin Worst NYHA Class I 50 – 55 N/A N/A III I 60 – 65 79† N/A II I 55 594*† < 0.05 III I 55-60 N/A N/A III I 58 N/A N/A III I 68 N/A N/A III Nadir of LVEF (%) 25 – 30 47 50 < 20 25 – 30 44 Highest BNP or NTproBNP† (pg/mL) 1837† 170† 2988† 2026 640 744 Highest Troponin < 0.05 < 0.05 < 0.05 2.5 0.01 < 0.05 Carfilzomib Discontinuation Permanent Temporary Permanent Permanent Permanent Temporary Heart Failure Therapy Initiated Beta-blocker; ACE-I; loop diuretic None Beta-blocker; ARB Beta-blocker; ACE-I Beta-blocker; aldosterone antagonist Beta-blocker; aldosterone antagonist; loop diuretic Best NYHA Class I II III I II II Highest LVEF Lowest BNP (pg/ml) 40 65 50 104 55 2032 50 39 48 470 68 110 HF, LV dysfunction Mild LV and RV dysfunction HF ACS, HF, QTc, LV dysfunction HF, LV dysfunction HF, LV dysfunction Summary of Cardiac Events A B Cardio-Oncology • The demographic profile for cancer patients being treated with chemotherapy is identical to typical cardiac patients • Optimal management of cardiac disease includes prevention, early detection and careful medication choices • Close collaboration between cardiology and oncology is feasible and essential • Ongoing research will further define the best collaborative practice Monitoring Cardiac Disease in Survivors Lenihan, D JCO 2012 www.icosna.org ICOS is: • A collection of interested providers focused on improving cardiac health in cancer patients • A mix of academic, practice, governmental, regulatory, and industry professionals • Committed to our patients wherever they are The International CardiOncology Society An Update • • • • • Exactly what does this society mean? How do we do things? What are our goals? How do we achieve them? Is there really a future for this? We do things in many ways: • • • • • • Day to day improvement in our practices Monthly webinars available to all Periodic presentations at major meetings Annual ICOS congresses Development of current “Best Practice” Data review for ongoing early phase and late phase clinical trials • Ongoing participation in major professional society efforts • Ongoing individual and multicenter research • Consistent involvement with regulatory agencies in many countries ICOS goals • Research – Engage large databases – Cardiac safety endpoint adjudication – Hypothesis testing research • Advocacy • Patients/families • Providers • Education – Provider case review – Patient directed – Professional meetings – Industry/regulatory webinars – Trainee organization • Be a Resource • Up to Date information • Identify Goals for the future • Provide innovation • Be an example of collaboration A Paradigm for Cardiology Oncology Cooperation Kouri M et al. Circulation 2012 ICOS= A public, private, patient, provider, regulatory, governmental PARTNERSHIP Come to Nashville (Music City USA) sometime!