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Cardio-Oncology: Can we make a difference?
Daniel J Lenihan, MD Professor, Division of Cardiovascular Medicine Director, Clinical Research Vanderbilt University
Presenter Disclosure Information Global Cardio-Oncology Summit 2016
Vancouver BC Canada, 9.30.16
• I will not discuss off label use or investigational use in my presentation.
• I have financial relationships to disclose: – Research support from: Acorda, Inc; Takeda, Inc.
– Consultant (modest): Roche, Amgen, Prothena, BMS
Significant reversibility of LV dysfunction with trastuzumab-related cardiac toxicity; Importantly, patients can continue trastuzumab treatment despite LV dysfunction
Journal of Clinical Oncology 2005,23;p 7820-6.
What is Cardio-‐oncology?
PubMed “Chemotherapy Cardiotoxicity”
Case study: Anti-VEGF therapy • 60 y/o F, with HTN and DM, presents with metastatic renal cell
cancer that led to L nephrectomy, radiation to pelvis and ribs, lung nodules (probable metastatic dz), and resection of R femur tumor with a femoral nail placed, who was started on sunitinib 2 months ago.
• MEDS: triamterene, losartan, sunitininb 37.5 mg, Zofran • PE: BP 168/92, P88, wt 178#, R16 • No JVD, lungs clear, loud S4, trace ankle edema • Labs: Cr 1.1, TC 227, LDL 129, HDL 31, BNP 18, LVEF 55 with
mild LVH • 5 weeks after starting sunitinib she developed BP 216/112 and
had therapy stopped
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
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.
Figure Legend:
In Renal Cell Cancer, renin-angiotensin inhibitors
are critical therapies
R McKay et al, Clin Cancer Res. 2015 Jun 1; 21(11): 2471–2479.
RAS inhibitors seem to be very important
R McKay et al, Clin Cancer Res. 2015 Jun 1; 21(11): 2471–2479.
Statins are helpful in renal cell cancer especially with anti-VEGF directed therapy
R McKay et al European Journal of Cancer 52 (2016) 155-162
OS Anti-VEGF
Statins: yes Statins: yes
So what happened with our patient?
• Control BP with what meds? stopped triamterene, continued losartan 50mg qd, used furosemide for edema, started carvedilol 25mg bid, amlodipine 10mg daily used hydralazine intermittently • How do we follow this patient going forward? periodic BNP, rarely EF measured only for dyspnea • Any other general recs? sodium restriction, exercise, lipid therapy, aspirin • She has had no disease progression for almost 6 years!! and
can walk ½ mile without stopping.
Case study: does cardiotoxicity mean the drug has to stop?
• 74 y/o F, with Multiple Myeloma initially in 2013 treated with velcade, adriamycin and decadron as well as s/p stem cell txp 2004, has relapsed disease. She was started on carfilzomib, pomalyst and decadron 12/2014.
• Prior hx of DM, HTN but told she had no cardiac problems • On atenolol 50mg qd, Lisinopril 20mg qd, no aspirin or statin • After 2 cycles of treatment developed NYHA class 3-4 symptoms • Hematologist stopped therapy and was not going to treat further
• PROTECT is a prospective, non-randomized, open-label, supportive care, multi-institutional study.
• 130 patients will be enrolled, who will be initiated with either (1) Bortezomib-based (BOR) or (2) Carfilzomib-based (CAR) therapy based on the hematologist’s decision.
PROTECT Study Design
Sites:
Vanderbilt University Medical Center
University of Pennsylvania (UPenn)
*Dana Farber at Harvard *University of Alabama
*pending
Patient with relapsed or
refractory multiple myeloma screened
for eligibility
Enrolled and initially treated with
Bortezomib-‐based chemotherapy
(N=65)
Enrolled and initially treated with
Carfilzomib-‐based chemotherapy
(N=65)
6 cycles of chemotherapy
6 cycles of chemotherapy
Ongoing monitoring for outcomes
Ongoing monitoring for outcomes
Cardiac Events reported in PROTECT (CTCAE v4.0)
Cardiac Event # of events # of individuals
BOR-treated patients
CAR-treated patients
CTCAE grade
Acute coronary syndrome (ACS) which includes MI 6 (13.9%) 6 (15.7%) 0 (0%) 6 (15.7%) grade 2 (n=3)
grade 3 (n=3)
Arterial and/or venous thromboembolism 3 (6.9%) 3 (7.8%) 2 (5.2%) 1 (2.6%)
grade 1 (n=1) grade 2 (n=1) grade 4 (n=1)
Dyspnea 2 (4.6%) 2 (5.2%) 0 (0%) 2 (5.2%) grade 1 (n=1) grade 2 (n=1)
Hypertension 13 (30.2%) 11 (28.9%) 2 (5.2%) 7 (18.4%) grade 3 (n=11) grade 4 (n=2)
Symptomatic arrhythmia requiring treatment 2 (4.6%) 2 (5.2%) 0 (0%) 2 (5.2%) grade 3 (n=1)
grade 5 (n=1)
Symptomatic heart failure 16 (37.2%) 13 (34.2%) 3 (7.8%) 10 (26.3%) grade 2 (n=6) grade 3 (n=10)
Other (syncope) 1 (2.3%) 1 (2.6%) 0 (0%) 1 (2.6%) grade 2 (n=0) grade 3 (n=1)
Total # of suspected cardiac events 43 38 (58.4%) 7 (18.4%) 29 (76.3%)
grade 1 (n=2) grade 2 (n=7)
grade 3 (n=25) grade 4 (n=3) grade 5 (n=1)
Chemotherapy doses were reduced for 4 patients due to cardiac events: • CAR-treated patients (n=3) • BOR-treated patient (n=1)
What happened with our second pa>ent? • She was placed on spironolactone, Lasix, carvedilol, aspirin, crestor and Lisinopril.
• She walks daily, without symptoms of HF, and is in remission nearly 3 years later
Guidelines and Education
Pocket Guidelines also available!
Preven:on and monitoring of cardiac dysfunc:on in survivors of adult cancers: ASCO Clinical Prac:ce Guideline
Click to edit Master >tle style
Mul:-‐disciplinary collabora:on
American Society of Clinical Oncology: Clinical Prac*ce Guideline
Oncology Cardiology
Radia:on Oncology
Family Medicine
Pa:ent Rep. Exercise
Physiology
ACC Rep. AHA Rep.
ASCO Rep.
Epidemiology
Click to edit Master >tle style Wri:ng Group
Saro Armenian Ana Barac Joseph Carver Louis S. Cons>ne Neelima Denduluri Susan Dent Pamela S. Douglas Jean-‐Bernard Durand Michael Ewer Carol Fabian Melissa Hudson
Mariell Jessup Lee Jones Bonnie Ky Chris>na LaccheP Javid Moslehi Erica L. Mayer Kevin Oeffinger Katharine Ray Kathryn Ruddy Daniel Lenihan
Can we identify training requirements? • What is Cardio-Oncology? It is a clinically-based discipline focused on the cardiovascular health of cancer patients and cancer survivors • Who is a cardio-oncologist? A health care provider who is focused on the prevention, early detection, management, and recovery of cardiovascular function potentially resulting from cancer therapies.
Lenihan, D et al, JCF 2016:p.465-471
http://www.acc.org/clinical-topics/cardio-oncology?w_nav=MN#sort=%40foriginalz32xpostedz32xdate86069%20descending
Pa>ent Informa>on
hUp://be.macmillan.org.uk/be/p-‐22060-‐heart-‐health-‐and-‐cancer-‐treatment.aspx
26
CML: Development of BCR-ABL Tyrosine Kinases Inhibitors
TKIs Have Expanded Treatment Options for Patients With CML
1. Wong et al. Annu Rev Immunol. 2004;22:247-306; 2. Nowell PC et al. J Clin Invest. 2007;117:2033-5; 3. Rowley JD et al. Nature. 1973;243:290-293.
1950 1960 1970 1980 1990 2000 2010
Resistance to BCR-ABL inhibitors identified1
Other therapeutic targets identified for development1
BCR-ABL kinase activity1
Discovery of Ph chromosome1-3
t(9:22)2,3
Tyrosine kinase inhibition1
27
CML: Common TKI-Related Adverse Events
1. Rea. Ann Hematol. 2015 Apr;94 Suppl 2:S149-58.
Cardiovascular toxicity
Metabolic and endocrine AE
Hepatic and pancreatic AE
Pulmonary toxicity
Fluid retention
Myelosuppression
Dermatologic AE
Gastrointestinal AE
Musculoskeletal symptoms
28
A Assessment of risk Antiplatelet therapy
B Blood pressure
C Cholesterol Cigarette/tobacco cessation
D Diet and weight management Diabetes prevention and treatment
E Exercise
Monitoring for CV/metabolic Risks in the General Population
CV = cardiovascular 1. Hsu et al. Clin Cardiol. 2013;36(7):383-93. 2. Moslehi et al. J Clin Oncol. 2015;10;33(35):4210-8.
While there are guidelines for assessing and monitoring CV/metabolic risk in the general population, additional research is needed to identify guidelines for assessing and monitoring CV/metabolic risk in the CML patient population
ABCDE approach to the assessment and management of CV risk1
Adapted from Hsu et al. Clin Cardiol. 2013;36(7):383-93.
In symptomatic patients or those with high cardiovascular risk, consider referral to cardiologist2
29
Proposed Cardio-Oncology Assessment Algorithm
CXR = chest x-ray; ECG = electrocardiogram. 1. Herrmann et al. Mayo Clin Proc. 2014;89(9):1287-1306. 2. Moslehi et al. J Clin Oncol. 2015;10;33(35):4210-8.
Outline of a general cardio-oncology algorithm1
Before treatment
During treatment
After treatment Cardiovascular review (incl. history, examination, CXR, ECG, and
echocardiogram) Cardiovascu
lar risk? Cardiovascu
lar complication
s?
Cardiovascular
complications?
Hematology/Oncology patient
Adapted from Herrmann et al. Mayo Clin Proc. 2014;89(9):1287-1306.
In symptomatic patients or those with high cardiovascular risk, consider referral to cardiologist2
Cardio-oncology consultation
Cardio-Oncology: can we make a difference?
• In the words of Meredith Durham, who opened our conference with an absolutely fantastic, uplifting and motivating patient presentation:
“How can we make a difference?!”
Topics include: • How to deliver a Cardio-‐Oncology service • Training in Cardio-‐Oncology • eHealth and Cardio-‐Oncology • How do I measure the quality of my service? • Role of primary care in cancer survivors • Immunotherapy and emerging cardiotoxicity • Personalised medicine & gene>cs • EP session –who should have abla>on, ICDs, CRT? • An>coagula>on and an>thrombo>c (AF, ACS) • Radia>on-‐induced cardiotoxicity • Managing cardiac issues during BMSC transplants • Cardiac tumours, carcinoid valvular disease, amyloid • Hormone therapy and CV risk
