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Cardio-Oncology
- Dawn of a New Era
Joerg Herrmann, Mayo Clinic Rochester
October 16, 2013
29th Annual Cardiology Conference, Sioux City, Iowa
©2012 MFMER | 3208984-1
Disclosure
Relevant Financial Relationship(s)
None
Off Label Usage
None
©2012 MFMER | 3208984-2
Cancer in the United States, 1990-2008
Surviving Rising, Mortality Decreasing
12
10
8
6
200
4
2
150
Number of Cancer Survivors
Millions
Cancer Mortality Rate
per 100,000
250
0
1990
1995
2000
2005
Data from the National Cancer Institute on estimated number of cancer survivors and age-adjusted
cancer deaths per 100,000 people
Estimated Number of Cancer Survivors in the
U.S. on January 1, 2008 by Site (n = 11.9 M)
Other
12%
Female Breast
22%
Lung
3%
Thyroid
4%
2.5 Million
Melanoma
7%
Urinary Tract
(Bladder Kidney,
Renal Pelvis)
7%
Hematologic
(HD, NHL, Leukemia,
ALL, Myeloma)
8%
1 Million
Prostate
20%
Gynecological
8%
Colorectal
9%
Howlander N, et al. SEER Cancer Statistics Review, 1975-2008, National Cancer Institute
http://seer.cancer.gov/csr/1975_2008/
U.S. Cardio-Oncology Centers 2011
University of Wisconsin
Madison, WI
Brigham and
Women’s Hospital
Boston, MA
Yale Cancer
Center
Mayo Clinic
New Haven, CT
Memorial
Sloan-Kettering
Cancer Center
New York City, NY
University of Kansas
Cancer Center
Kansas City, KS
MD Anderson
Houston, TX
U.S. Cardio-Oncology 2013
University of Michigan
Ann Arbor, MI
University of Rochester
Rochester, NY
University of Wisconsin
Madison, WI
Cleveland Clinic
Cleveland, OH
Brigham and
Women’s Hospital
Boston, MA
Yale Cancer
Center
Mayo Clinic
New Haven, CT
Memorial
Sloan-Kettering
Cancer Center
Cedars Sinai
New York City, NY
Los Angeles, CA
Washington Hospita
Center
University of Kansas
Cancer Center
Kansas City, KS
Washington, DC
MD Anderson
Duke Radiation
Oncology
Houston, TX
Durham, NC
Cardio-Oncology – Dawn of New Era
1.) Cardiomyopathies with chemotherapeutics
2.) Vasculopathies with chemotherapeutics
3.) Structural heart disease with radiation therapy
©2012 MFMER | 3208984-7
Cardio-Oncology – Dawn of New Era
1.) Cardiomyopathies with chemotherapeutics
2.) Vasculopathies with chemotherapeutics
3.) Structural heart disease with radiation therapy
©2012 MFMER | 3208984-8
Case #1
48 yo female
1995
left-sided breast cancer
left mastectomy + tamoxifen
1998
right-sided breast cancer
+ LN
right mastectomy + local radiation tx
+ 3 cycles taxol, cytoxan, adriamycin
2007
breast cancer metastases
to bones and liver
radiation therapy to spine and femur
+ 3 cycles taxol, cytoxan, and
adriamycin (lifetime dose 420 mg/m2)
2008
pathologic right hip fracture
THA
Initiation of Xeloda (capecitabine) and Tykerb (lapatinib)
Case #1
Ca 27.29 [U/mL]
180
160
140
120
100
80
60
40
20
0
SOB/ edema
3
4
5
5.5
Au
gu
st
Se
pt
em
be
r
O
ct
ob
er
2
Ju
ly
Ju
ne
ay
1
M
Ap
ri l
h
Cycle no.
ar
c
M
BNP [pg/mL]
1600
1400
1200
1000
800
600
400
200
0
Case #1
March 2008
EF 30-35%
Case #1
October 2008
EF 20%
Next Best Step in Management?
A) Coronary angiography
B) Cardiac MRI
C) RV biopsy
D) Stop chemotherapy
Chemotherapy-induced cardiotoxicity
E) Initiate Metoprolol 25 mg PO per day
Which Drug Caused the Cardiomyopathy?
A) Doxorubicin (Adriamycin)
B) Paclitaxel (Taxol)
C) Cylophosphamide (Cyotxan)
D) Capecitabine (Xeloda)
E) Lapatinib (Tykerb)
Chemotherapy
Changing paradigms
Chemotherapy
Non-targeted therapy
Targeted therapy
Old
New
Exp. Anthracyclines
Exp. Herceptin
Incidence of heart failure (%)
Herceptin Cardiotoxicity
Metastatic trial
NSABP B-31
BCIRG 006
NCCTG
N9831
HERA
FinHer
Post-anthracycline (days)
Anthracycline
Ewer MS and Ewer SM. Nat. Rev. Cardiol. 2010; 7,564–75
Herceptin on Cancer Cell and Cardiomyocyte
Breast Cancer Cell
Trastuzumab
Cardiomyocyte
Trastuzumab
ErbB2 ErbB3
ErbB2 ErbB4
NRG1
NRG1
P
P
Grb2
Sos
P
Akt
p85
Grb2
P13K
p110
Ras
Anthracyclines
P
Sos
P
P
FOXO3
P
Ras
P
Src
BAD
Bcl2
ERK
cyt c
Bax
Bcl-xs
Bcl-xL Bax
ERK
cyt c
Mitochondrion
proliferation↓ survival↓
P
BAD
P
Bcl-xL
Akt
??
FAK
p27
P
p85
P13K
p110
cyt c
contractility↓
cyt c
Mitochondrion
viability↓
Chen MH et al. Circulation 2008;118:84-95
Multiple Hit Theory
Adjuvant therapy
Direct Effects
Breast Cancer
Patient
Baseline CV
Risk Factors
Decreased CV Reserve
↑ Preclinical +
Clinical CVD
Indirect Effects
Modifiable Lifestyle Risk Factors
Jones LW et al. J Am Coll Cardiology 2007;50:1435-41
©2012 MFMER | 3208984-18
Herceptin Cardiotoxicity
Age ↑
Predictors
Hypertension
Prior anthracycline
therapy
Doxorubicin
>240 mg/m2
Diabetes mellitus
Genes ?
CAD
Epirubicin
>500 mg/m2
Cardiomyopathy
Prior chest irradiation
Arrhythmia
Martin M et al. The Oncologist 2009;14:1–11
Ewer MS and Ewer SM. Nat. Rev. Cardiol. 2010; 7,564–75
©2012 MFMER | 3208984-19
Mean LVEF (%)
Herceptin Cardiotoxicity
Prior to
trastuzumab
therapy
(n=38)
Following
trastuzumab
therapy
(n=38)
Following
Following
standard therapy trastuzumab
for heart failure
rechallenge
(n=32) or
(n=25; all on
observation standard therapy)
(n=6)
Ewer MS et al. J Clin Oncol 2005;23:7820-6
Herceptin Cardiotoxicity
Ewer MS et al. J Clin Oncol 2005;23:7820-6
HER2 Pathway Inhibitors (HER2-Is)
Pertuzumab
Trastuzumab
HER family receptors
HER2
HER2
HER2
HER1
HER2
HER3
HER4
HER1 HER2
Plasma
membrane
P
P
Tyrosine kinase
domain
P
HSP90
P13K
Ras
Akt
Raf
mTOR
Lapatinib
MEK
MAPK
Proliferation,
survival, invasion
Murphy CG and Morris PG. Anti-Cancer Drugs 2012, 23:765–76
HER2 Pathway Inhibitors
Herceptin
Pertuzumab
Lapatinib
Cardiotoxicity:
Cardiotoxicity:
Cardiotoxicity:
Overall: 2.2-18.1%
Overall: 3.4-6.9%
Overall: 1.4-2.2%
Symptomatic: 0.3-3.9%
Symptomatic: 0.3-1.1%
Symptomatic: 0.1-0.5%
Azim H et al. Cancer Treat Rev 2009;35:633–8
Lenihan D et al. Ann Oncol. 2012; 23:791-800
Chemotherapy-related Cardiomyopathy
Prototype
Ultrastructure
Mechanism
Type I
(damage)
Type II
(dysfunction)
Doxorubicin
Trastuzumab
vacuoles, necrosis
microfibrillar disarray
no abnormalities
Oxidative injury
mitochondrial function ↓
altered calcium homeostasis
altered cardiac gene expression
apoptosis of cardiomyocytes
ErbB2 signaling
inhibition
Ewer, Lippman J Clin Oncol 2005;23:2900-2
Anthracycline Cardiotoxicity
Acute cardiotoxicity
Chronic cardiotoxicity
Myofibrillar loss with Z-band remnants
Acute toxic myocarditis
with myocyte damage
(pyknotic debris) and
inflammatory infiltrate
Cardiomyopathy with
shrunken myocytes with
myofibrillar loss and with
sacrotubular distension
Swollen, dilated sarcotubules
Berry GJ, Jorden M. Pediatr Blood & Vancer 2005:44:630-7
Anthracycline Cardiotoxicity
Predictors
Anthracycline
cumulative dose:
Age (<15 or >65 yrs)
Doxorubicin >240 mg/m2
Epirubicin >500 mg/m2
Female gender
Genes
Anthracycline type and
rate of administration
Pre-existing CVD
Mediastinal radiation
Hypertension
Ewer MS and Ewer SM. Nat. Rev. Cardiol. 2010; 7,564–75
©2012 MFMER | 3208984-26
Clinical Heart Failure After Anthracyclines
Breast Cancer Patients
20
Percent developing CHF
20%
15
14%
10
11%
5
0
0 1
3
6
9
12
18 24
36
48
60
Months after last epirubicin administration
Jensen BV et al. Ann Oncol 2002 13:699-709
Proportion of Patients Surviving
Chemotherapy-related Heart Failure
Even More Malignant Than Cancer
1.00
Peripartum
0.75
Idiopathic
0.50
Doxorubicin therapy
Ischemic heart disease
Infiltrative myocardial disease
0.25
HIV infection
0.00
0
5
10
15
Years
Felker et al. NEJM 2000; 342:1077-84
Cumulative Probability of survival
Heart Failure - More Malignant Than Cancer
Probability of 30-Day and 5-Year
Case-Fatality Rates in Sweden 1999
Scotland 1991
1.0
Probability of Case
Fatality, %
0.9
0.8
Diagnosis
(index Admission)
0.7
0.6
Breast
0.5
0.4
MI
0.3
0.2
Bowel
Ovarian
Heart
Failure
0.1
0.0
Lung
0 6 12 18 24 30 36 42 48 54 60
Month of follow-up
60 Years
Old
80 Years
Old
Heart failure, 30 d
5.2
10.4
Heart failure, 5 y
24.5
52.4
AMI, 30 d
8.1
17.6
AMI, 5 y
15.7
55.6
Lung cancer, 30 d
12.9
22.6
Lung cancer, 5 y
79.7
86.3
Colorectal cancer, 30 d
2.0
6.8
Colorectal cancer, 5 y
38.9
56.9
Breast cancer, 30 d
0.6
2.6
Breast cancer, 5 y
17.4
36.1
Bladder cancer, 30 d
1.0
4.7
Bladder cancer, 5 y
21.7
55.2
Stewart S et al. European Journal of Heart Failure 2001;3: 315-22
Stewart S et al. Circ Cardiovasc Qual Outcomes 2010;3: 573-580
Response to Therapy and Outcome
Cardiac event free rate (%)
100
Death HF Arrhythmias
80
Responders
(n=85)
0%
0%
3%
Non-Responders
(n=90)
4%
8%
16%
Partial Responders
(n=26)
0%
4%
23%
60
40
20
0
0
3
6
9 12 15 18 21 24
Months
Cardinale D et al. JACC 2010,55:213-20
ACE Inhibitor Therapy
70
Digitalo-diuretic ACE-Inhibition Discontinuing
therapy
ACE-Inhibition
LVEF (%)
60
50
40
30
20
0
CHF
no 10
0
0
7
8
7 8
200 400
600 800 1,000
1
2
3
4
5 6
Cumulative dose (mg/m2)/
Months after start of therapy
8 10 10 7
1 3
6
9 12
5
15 18 21 24 27 30
3
33 36 39 42
Months after last epirubicin dose
Jensen BV et al. Ann Oncol 2002 13:699-709
ACE Inhibitor Therapy
(LVEF increase 15%)
Percent recovering
100
With ACE-inhibition:
88% (7/8)
80
60
P<0.0001
40
Without ACE-inhibition:
8% (1/33)
20
0
0 1
3
6
9
12
18 24
36
48
60
Months after cardiotoxic decline or start of ACE-inhibition
Jensen BV et al. Ann Oncol 2002 13:699-709
Response to Therapy
Critical Dependence on Time
100
Responders (%)
80
64%
60
40
28%
20
7%
0
0%
0%
0%
0%
1-2
2-4
4-6
6-8
8-10
10-12
>12
(n=75)
(n=35)
(n=20)
(n=8)
(n=7)
(n=7)
(n=44)
Months
Cardinale D et al. JACC 2010,55:213-20
Breast Cancer Chemotherapy
Time Course of Changes
LV Ejection Fraction
#
70
60
*
*
*
*
%
50
Peak Systolic
Longitudinal Strain
40
30
25
*
20
20
*
*
*
*
no drop
10
6
9
12
15
*
5
<19%
EF↓ to <55% in 32%, persistent 11%
0
EF↓ to <50% in 15%, persistent 45%
*
*
*
725 494 379 259
10
Time (months)
0
3
6
9
12
Time (months)
sensitivity
74%
87%
specificity
73%
53%
# P<0.05 vs baseline
PPV
53%
43%
*P<0.0001 vs baseline
NPV
87%
91%
15
pg/mL
3
%
0
Ultrasensitive cTnI
drop
15
0
>30 pg/mL
*
140
120
100
80
60
40
20
0
0
3
6
9
12
15
Time (months)
Sawaya H et al: Circ Cardiovasc Imaging 2012;5:596-603
Management Algorithm – Anthracyclines
Medical history and exam, ECG, LVEF (RNA, TTE?)
LVEF >50%
LVEF <50%
Initiation of anthracycline therapy
Reassessment prior to each cycle
Reassessment at 250-300 mg/k2
No high risk
High risk
Reassessment at 450 mg/k2
Reassessment at 400 mg/k2
Reassessment prior to each cycle
Discontinue if LVEF↓ ≥10%
and LVEF ≤50%
Discontinue if LVEF↓ ≥10%
or LVEF ≤30%
Schwartz RG et al. Am J Med 1987;82:1109–18
Management Algorithm
Outcome Implications
Probability of CHF-free survival
1
Patients managed in
accordance with algorithm
0.8
0.6
Patients not managed in
accordance with algorithm
0.4
0.2
P<0.05
0
0
600
1200
1800
2400
3000
Time [days]
Schwartz RG et al. Am J Med 1987;82:1109–18
Management Algorithm – HER2 inhibitors
Medical history and exam, ECG, RNA/TTE
LVEF >50%
No risk factors
LVEF <50%
Risk factors
Risk benefit analysis
Initiation of HER2-I therapy
RNA/TTE q12 wks
EF↓ <10%,
EF ≥50%, asympt.
RNA/TTE q8 wks
EF↓ ≥10%,
EF <50%, asympt.
RNA/TTE q4-6weeks
EF↓ ≥10%,
EF <40% +/- sympt.
EF <40%
or HF sympt.
EF >40%,
no sympt.
RNA/TTE q4-6weeks
Discontinue HER2-I therapy
Continue
EF >40%,
no sympt.
EF <40%
+/- sympt.
Heart failure therapy
Careful risk-benefit analysis
Resume if EF ≥40% and
symptom resolution
Continue
RNA/TTE q 4 weeks
Panjrath GS, Jain D. Nucl Med Commun 2007;28:69-73
Case Follow-up
11/08
EF 15%
- admitted and treated for decompensated heart failure
- lisinopril initiated and increased to 15 mg qd over 2 months
- capecitabine continued
02/09
EF 35%
- Coreg started and increased to 6.25 mg BID
06/09
EF 40-45%
- no further episodes of heart failure decompensation
Chemotherapy-related Cardiomyopathy
Anthracyclines
Doxorubicin (Adriamycin)
Epirubicin (Ellence)
Idarubicin (Idamycin PFS)
Alkylating agents
Cyclophosphamide (Cytoxan)
Ifosfamide (Iflex)
Antimetabolites
Clofarabine (Clolar)
Antimicrotubule agents
Docetaxel (Taxotere)
Incidence
(%)
Frequency
of use
3-26
0.9-3.3
5-18
+++
++
+
7-28
17
+++
+++
27
+
2.3-8
++
Yeh E, Bickford CL JACC 2009, 53:2231-47
Chemotherapy-related Cardiomyopathy
Monoclonal antibody-based
tyrosine kinase inhibitors (TKIs)
Bevacizumab (Avastin)
Trastuzumab (Herceptin)
Proteasome inhibitor
Bortezomib (Velcade)
Small molecule TKIs
Dasatinib (Sprycel)
Imatinib mesylate (Gleevec)
Lapatinib (Tykerb)
Sunitinib (Sutent)
Incidence
(%)
Frequency
of use
1.7-3
2-28
++
++
2-5
++
2-4
05-1.7
1.5-2.2
2.7-11
++
+
+
+++
Yeh E, Bickford CL JACC 2009, 53:2231-47
Cardiomyopathies with Chemotherapeutics
Key Points
1) Cancer and/or its therapy can reveal CV pathology (“multi-hit theory”)
2) Changing paradigm to “no futility” (for cancer and cardiotoxicity)
3) Changing paradigm of early recognition (strain imaging emerging)
4) Changing paradigm of early treatment
5) Consideration of preventive treatment in high-risk patients
Cardio-Oncology – Dawn of New Era
1.) Cardiomyopathies with chemotherapeutics
2.) Vasculopathies with chemotherapeutics
3.) Structural heart disease with radiation therapy
©2012 MFMER | 3208984-42
Case #2
83 yo male
- awoke with retrosternal chest pressure, 10/10 in intensity, at 4 a.m.
- also diaphoresis and dyspnea
- three SL nitroglycerine tablets resulted in partial relief of symptoms
- presents to the ED for further evaluation
©2012 MFMER | 3208984-43
Case #2
PMH
- CAD, s/p CABG 9 years ago
- Hyperlipidemia
- Hypertension
- Obesity
- COPD
- Esophageal adenocarcinoma (T3, N0, M0), FOLFOX started 2 days ago)
SH
FH
- quit smoking 15 years ago
- non-contributory
©2012 MFMER | 3208984-44
Case #2
Medications
-Atenolol 100 mg tablet 1 TABLET by mouth one time daily.
-Losartan 100 mg tablet 1 TABLET by mouth one time daily
-Furosemide 40 mg tablet 2 tablets by mouth one time daily.
-Simvastatin 80 mg tablet 1 TABLET by mouth one time daily.
-Spironolactone 25 mg tablet one-half tablet by mouth one time daily
-Cardura 4 mg tablet 1 TABLET by mouth one time daily.
-Multivitamin tablet 1 TABLET by mouth one time daily.
-Nexium 40 mg capsule enteric coated 1 capsule by mouth one time daily.
-Symbicort 160-4.5 mcg/Actuation HFA Aerosol 2 by inhalation inhale two times a day.
-Bactrim DS tablet 1 TABLET by mouth one time daily
-Fluorouracil [ADRUCIL] 5,850 mg intravenous via ambulatory pump over 46 hours.
©2012 MFMER | 3208984-45
Case #2
Physical Examination
BP: 141/82 mmHg, HR 124 BPM, RR 17 breaths per minute
General: alert, no acute distress
Heart: RRR, regular S1 and S2, no gallops, murmur, rubs
Lungs: diminished breath sounds, prolonged expiratory phase
Vessels: no JVD, reduced distal LE pulses bilaterally
©2012 MFMER | 3208984-46
ECGs
ECG during chest pain
ECG 8 days prior
©2012 MFMER | 3208984-47
ECGs
ECG during chest pain
ECG 15 minutes later, chest pain resolution with NTG
©2012 MFMER | 3208984-48
Laboratory Values
11.8
9.2
37.5
235
137
100
20
4.1
26
1.3
159
cTnT: 0.05 => 0.11 => 0.09 ng/mL
©2012 MFMER | 3208984-49
Coronary angiogram
©2012 MFMER | 3208984-50
Coronary angiogram
©2012 MFMER | 3208984-51
Coronary angiogram
©2012 MFMER | 3208984-52
Coronary angiogram
©2012 MFMER | 3208984-53
Coronary angiogram
©2012 MFMER | 3208984-54
Coronary angiogram
©2012 MFMER | 3208984-55
What is the diagnosis?
A) Acute myocardial infarction type 1 according to the Universal Definition
B) Acute myocardial infarction type 2 according to the Universal Definition
C) Acute ST segment elevation myocardial infarction
D) Unstable angina
E) Acute chest pain episode
How should this patient be managed?
A) Start Aspirin and Metoprolol, cardiac MRI to assess for LGE
B) Start Aspirin and Metoprolol, echocardiogram
C) Start Aspirin and Plavix, Metoprolol, non-invasive stress testing
D) Start Aspirin, Plavix, Metoprolol and Imdur, no further testing
E) Start Aspirin and Nitroglycerin drip, stop 5-FU, no further testing
What is the diagnosis?
A) Acute myocardial infarction type 1 according to the Universal Definition
B) Acute myocardial infarction type 2 according to the Universal Definition
C) Acute ST segment elevation myocardial infarction
D) Unstable angina
E) Acute chest pain episode
Universal Definition of Myocardial Infarction
Thysgesen K et al. EHJ 2012;33:2551-67
How should this patient be managed?
A) Start Aspirin and Metoprolol, cardiac MRI to assess for LGE
B) Start Aspirin and Metoprolol, echocardiogram
C) Start Aspirin and Plavix, Metoprolol, non-invasive stress testing
D) Start Aspirin, Plavix, Metoprolol and Imdur, no further testing
E) Start Aspirin and Nitroglycerin drip, stop 5-FU, no further testing
Fluorouracil (5-FU) Cardiotoxicity
Study
Type
N
Regimen
Cardiotoxicity
incidence
De Forni et al.
Prospective
367
5-FU high-dose
7.6%
Schober et al.
Retrospective
390
5-FU/leucovorin
3.0%
Meydan
Retrospective
231
5-FU
3.9%
Ng
Retrospective
153
Capecitabine
6.5%
Tsibiribi et al.
Retrospective
214
Capecitabine
1.9%
Jensen
Retrospective
668
5-FU
5-10%
FOLFOX4
18%
5-FU high dose
6.3%
Capecitabine
5.5%
Kosmas et al.
Prospective
644
Cardiotoxicity incidence:
5-FU
2-20%
Capecitabine
2-7%
Cernay J et al. Clinical Colorectal Cancer 2009;8:55-8
©2012 MFMER | 3208984-61
62 yo female with
- rectal adenocarcinoma
Chest pain
Dyspnea
BP 204/120 mmHg, HR 110 BPM, RR 20/min
JVP elevation, bilat. pulm. rales, bilat. LE edema
Kobayashi N et al. J Nippon Med Sch 2009;76:27-33
©2012 MFMER | 3208984-62
Fluorouracil (5-FU) Cardiotoxicity
Biomarker:
cTnT 0.82 ng/mL, CKMB 13 IU/L,
TTE:
BNP 1257 pg/mL
extensive LV apical akinesis
EF 28%
Sestamibi scan:
extensive LV apical akinesis
Apical ballooning syndrome
Kobayashi N et al. J Nippon Med Sch 2009;76:27-33
©2012 MFMER | 3208984-63
Baseline
Acetylcholine
Acetylcholine + 5-FU
Kobayashi N et al. J Nippon Med Sch 2009;76:27-33
©2012 MFMER | 3208984-64
5-FU Cardiotoxicity - Management
At the time of acute presentation
1. Stop administration of the drug
2. Use nitrates or CCB
3. Cardiac monitoring, CCU for pts with
cardiac biomarker elevation >2x URL for ≥ 72 hours
Re-challenge
1. 3-day course of nitrates or CCB, 24 hours before, during, and
after re-challenge
2. Continuous ECG monitoring on the day of drug administration
3. Avoid in patients with MI!
Cernay J et al. Clinical Colorectal Cancer 2009;8:55-8
©2012 MFMER | 3208984-65
Sorafenib-induced Myocardial Infarction
65 yo male with renal carcinoma
- worsening hypertension on sorafenib
- presenting with chest pain at rest
LGE
Biomarker:
cTnI 2.18 ng/mL, CKMB 31.8 IU/L
T2
Arima Y et al. J Cardiol 2009;54:512-5
©2012 MFMER | 3208984-66
Sorafenib and Inducible Vasospasm
Nitroglycerin
Ergonovine
Arima Y et al. Journal of Cardiology 2009;54:512-5
©2012 MFMER | 3208984-67
Target: The Endothelium
In a 70kg
man,
the total # of
endothelial
cells is
~ 1 trillion
The
endothelium
is
the largest
organ in
the body
In a
70kg man,
its total
surface area
is
~ 6 tennis
courts
In a
70kg man, its
total weight is
~ 1,800 g
(> the liver,
~ 5 hearts)
VEGF and Endothelial Nitric Oxide
Isenberg JS et al. Nat Rev Cancer 2009; 9:182-94
VEGF Signaling
Ras
VEGF
Extracellular
matrix
VEGFR
P
P
P
P
PLC-
Cytoplasm
p38
FAK
P13K
PIP2
PIP2
DAG
Raf
Paxillin
IP3
MAPKAPK2 and 3
PIP3
PKC
Ca2+
MEK
HSP27
Focal adhesion
turnover
eNOS
ERK
cPLA
NO
Gene expression
Cell proliferation
Prostaglandin
production
Vascular cell
permeability
Akt
Actin
reorganization
Cell migration
Angiogenesis
Caspase 9
BAD
Cell survival
VEGF Signaling Pathway Inhibition
VEGF
VEGF inhibitor
VEGFR
P
P
P
P
Capillary rarification
Extracellular
matrix
Cytoplasm
VEGF Signaling Pathway (VSP) Inhibitors
Cell survival
Angiogenesis
Prostaglandin production
NO production
Nazer B et al. Circulation 2011;124:1687-1691
VSP Inhibitors and Cardiovascular Events
Hypertension
Arterial
thromboembolism
All grade: 20-25%
Incidence: 1.4-3.8%
(cardiac>cerebral)
Grade 3/4: 6-8%
VEGF
Platelets
VSP inhibitors
RR: 1.5-3.0 (3-6 in RCC)
EC
Cardiomyopathy
Overall: 1.6-4.1%
High grade: 0.4-1.5%
(RR 3.3-4.8)
Cardiomyocyte
©2012 MFMER | 3208984-73
VSP Inhibitors and Hypertension
Hypertension
All grade: 20-25%
Grade 3/4: 6-8%
VEGF
VSP inhibitors
EC
Cardiomyocyte
©2012 MFMER | 3208984-74
Sunitinib AND Hypertension
Patients (%)
BP (mm Hg)
Hypertension
On antihypertensives
Grade-III hypertension
SBP
DBP
Cycle
mm Hg, SD
SBP
DBP
121 (22) 141 (19)
72 (13)
86 (11)
Cycle
141 (21) 134 (25)
86 (12)
80 (11)
132 (18)
80 (12)
Chu TF et al. Lancet 2007;370:2011-9
Hypertension Management Before Tx
Cancer
Hypertension
Cancer therapy options
Severity
(organ damage)
Secondary causes
Treatment
High hypertension risk:
Bevacizumab, Sorafenib,
Sunitinib, Cisplatin
Risk/benefit
assessment
Prohibitive
risk
Therapy initiation or intensification
(towards pre-existing goal of
<140/90 or <130/80 mmHg,
then cancer therapy)
Repeat
assessment
Treatment
w/close f/u
Maitland ML et al. J Natl Cancer Inst 2010;102:596-604
©2012 MFMER | 3208984-76
Hypertension Management During Tx
Cancer
Hypertension
Cancer therapy options
Severity
(organ damage)
Secondary causes
Treatment
High hypertension risk:
Bevacizumab, Sorafenib,
Sunitinib, Cisplatin
BP check weekly
with first cycle, then
every 2-3 wks
Therapy initiation or intensification
(towards goal of <140/90) Temporary
hold or dose reduction of cancer
therapy if >180/110 or shock
Maitland ML et al. J Natl Cancer Inst 2010;102:596-604
©2012 MFMER | 3208984-77
VSP Inhibitors and Acute Ischemic Events
Arterial
thromboembolism
Incidence: 1.4-3.8%
(cardiac>cerebral)
VEGF
Platelets
VSP inhibitors
RR: 1.5-3.0 (3-6 in RCC)
EC
Cardiomyocyte
©2012 MFMER | 3208984-78
VSP Inhibitors and Acute Ischemic Events
Expert Consensus
ECGs at baseline, 2-4 weeks, 8-12 weeks, then every 3 months
Nonspecific T-wave changes
Continue with frequent monitoring
Ischemic ST-T wave changes
Cardiac eval., continue at discretion
Angina (abn. stress test, angiogram)
Discontinue VSP inhibitor
Acute myocardial infarction
Discontinue VSP inhibitor
Steingart RM et al. Am Heart J 2012;163:156-62
VSP Inhibitors and Cardiovascular Events
VEGF
VSP inhibitors
EC
Cardiomyopathy
Overall: 1.6-4.1%
High grade: 0.4-1.5%
(RR 3.3-4.8)
Cardiomyocyte
©2012 MFMER | 3208984-80
Predictors of VSP Inhibitor Cardiotoxicity
CAD
RR 16-18
Hypertension
RR 2.5-3
Heart failure
RR ?
VSP inhibitors ?
©2012 MFMER | 3208984-81
VSP Inhibitors AND Heart Failure
No HF med
On HF meds
%
Deceased
On HF meds
1
2
3
4
5
6
On HF meds
Recovery rate: 60-80%
Telli et al. Ann Oncol 2008;19:1613
Di Lorenzo et al. Ann Oncol 2009;20:1535
Hypertension Summary
Incidence Frequency
(%)
of use
FDA approved
cancer therapy
Monoclon. aby-based TKI
Bevacizumab (Avastin)
4–35
++
Renal, colorectal,
lung
Small molecule TKI
Sorafenib (Nexavar)
Sunitinib (Sutent)
17–43
5-47
+++
+++
Renal, liver
Renal, pNET, GIST
Modified from Yeh E, Bickford CL JACC 2009, 53:2231-47
©2012 MFMER | 3208984-83
Myocardial Ischemia Summary
Incidence Frequency
(%)
of use
FDA approved
cancer therapy
Antimetabolites
5-Flourouracil (5-FU, Adrucil)
1–68
+++
Colon, Pancreas,
Gastric, head/neck
Capecitabine (Xeloda)
3–9
+++
Colorectal, breast
Antimicrotubule agents
Paclitaxel (Taxol)
Docetaxel (Taxotere)
<1-5
1.7
+++
++
Breast, ovarian, lung
Monoclon. aby-based TKI
Bevacizumab (Avastin)
0.6–1.5
++
Renal, colorectal,
lung
Small molecule TKI
Erlotinib (Tarceva)
Sorafenib (Nexavar)
2.3
2.7–3
+++
+++
Pancreas, lung
Breast, prostate,
gastric, head/neck
Renal, liver
Modified from Yeh E, Bickford CL JACC 2009, 53:2231-47
©2012 MFMER | 3208984-84
20% incidence, arterial events 3x more frequent
Vasculopathies with Chemotherapeutics
Key Points
1) Myocardial ischemia can be caused by chemotherapeutics
2) 5-FU can cause ACS and apical ballooning syndrome
3) VEGF inhibitors are emerging and so are their ischemic concerns
4) Hypertension – very common with VEGF inhibitors
5) Any CVD increases risk for VEGF inhibitor-induced cardiomyopathy
Cardio-Oncology – Dawn of New Era
1.) Cardiomyopathies with chemotherapeutics
2.) Vasculopathies with chemotherapeutics
3.) Structural heart disease with radiation therapy
©2012 MFMER | 3208984-87
Case #3
57 year old woman
- chronic dyspnea on exertion, but was able to walk slowly for hours
- prior to admission, sudden onset of lightheadedness and malaise
- heart rate in the low 40's, but normal blood pressure
- asked her family to call for EMS, then lost consciousness
- was noted to be in PEA arrest with slow rate and AV dissociation
- CPR was initiated with ROSC within minutes
- two more arrests on the way to local ER with successful CPR
- intubated and started on hypothermia protocol
Case #3
PMH
1. CAD, s/p CABG (LIMA to LAD, SVG to RCA and OM 10/3/12)
2. AS, s/p replacement (21-mm CarboMedics prosthesis 10/3/12)
3. Hyperlipidemia
4. Diabetes mellitus, type 2
5. Hodgkin’s lymphoma, s/p radiation and chemo (MOPP/ABVD) 1986-89
6. Breast cancer, s/p bilat. mastectomies and non-anthracycline CTX 2004
7. Hashimoto's thyroiditis
8. Hyperactive airway disease
9. Anxiety attacks
Case #3
Medications
Aspirin 325 mg one time daily.
Coumadin 2 mg as directed
Janumet 50-1,000 mg twice daily
Lasix 40 mg one time daily.
Lexapro 20 mg one time daily.
Lipitor 10 mg tablet mouth one time daily.
Lopressor 50 mg two times a day.
Oxycodone 5-10 mg every 4 hours PRN
Potassium chloride 20 mEq one time daily.
Synthroid 100 mcg one time daily.
Laboratory Values
11.3
10.3
34.6
262
135
102
20
4.2
17
0.7
200
ABG: 7.42/28/102/18
TSH 0.04
INR 6.7
cTnT: 0.09 ng/mL x3
©2012 MFMER | 3208984-91
ECGs
Admission ECG
ECG 6 months prior
©2012 MFMER | 3208984-92
Echocardiogram
- normal LV size and wall thickness, EF 25-30%
- regional wall motion abnormalities
- normal RV size, mild decrease in EF with preserved apical function
- right ventricular systolic pressure 32 mmHg
- calcification of aorto-mitral curtain, consistent with prior radiation treatment
- normal 21 mm aortic valve CarboMedics prosthesis
- mild-moderate TR
- normal IVC size, no inspiratory collapse
- no intracardiac mass or thrombus
- no pericardial effusion
- pleural effusion
Coronary angiogram
- 60% left main stenosis
- 30% proximal LAD lesion
- 30% proximal LCX lesion
- 80% ostial RCA stenosis, 30% mid and distal RCA lesion
- LIMA to mid LAD appears normal
- sequential SVG to distal RCA and OM1 appears normal
Cardiac catheterization
Aortic pressure
RA pressure
RV pressure
PA pressure
PCW pressure
90/54, MAP 68, HR 120 BPM
20/22, mean 24
53/14, EDP 25
49/23, mean 35
26/29, mean 30
Cardiac output 6.07 l/min
Cardiac index 3.17 l/min/m2
Etiology of patient’s out-of-hospital arrest?
1. VT related to myocardial ischemia
2. VT with a scar area serving as the substrate
3. PEA arrest due to acute myocardial infarction
4. PEA arrest secondary to acute pulmonary embolism
5. Bradycardic arrest as a consequence of intermittent complete heart block
Etiology of patient’s intermittent CHB?
1. Acute myocardial infarction
2. Thyroid dysfunction
3. Metoprolol
4. Prior chest radiation
5. Acute renal failure
Etiology of patient’s intermittent CHB?
1. Acute myocardial infarction
2. Thyroid dysfunction
3. Metoprolol
4. Prior chest radiation
5. Acute renal failure
Radiation-induced Heart Disease
Acute cardiac injury
(less common)
Acute pericarditis
Myocarditis
Radiation-induced
cardiac disease
Late cardiac injury
Constrictive pericarditis
Restrictive cardiomyopathy
Coronary artery disease
Valvular disease
Conduction disturbances
Modified from Groarke et al: Eur Heart J, 2013
Calcification of the Mitral-aortic Junction
Santoro F et al. Int J Cardiol 2012;155:e49-50
Outcome After Radiation and Chemotherapy
Hodgkin’s Lymphoma (Stage I-III)
Cumulative Hazard Event
0.45
0.40
Death
Cancer
Cardiac
Relapse
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
0
2
4
6
8
10
12
14
16
18
20
22
24
Years from Diagnosis
Lee CKK et al. Int. J Radiation Oncology Biol. Phys. 2000,48:169-79
Radiation-induced Heart Disease
Radiation therapy n=(48)
40 Gr (27-52)
at age 16.5 (6-25)
for Hodgkin’s Disease
14 year follow-up
(6-27.5 years)
Self-assessment: OK
Questionaire
19%
67%
25%
Fatigue
Dyspnea
Chest pain
40%
Dizziness
Adams MJ et al. JCO 2004,2:3139-48
Radiation-induced Heart Disease
30%
12%
75,00%
ECG abnormalities
Autonomic dysfunction
37%
VHD (>mild AR, MR, TR)
Diastolic dysfunction
42%
57%
Systolic dysfunction
Blunted exercise
response
Adams MJ et al. JCO 2004,2:3139-48
Chemotherapy and Radiation-related CHF
Breast Cancer
Cumulative risk (%)
30
No RT
RT vs no RT: HR=1.80 (95% CI=1.05 to 3.11)
RT + CT vs no RT: HR=3.60 (95% CI=2.00 to 6.51)
20
10
0
10
15
20
Follow-Up (years)
No. at risk
no RT
RT
RT + CT
591
1,195
594
393
905
406
35
131
47
Hooning MJ et al. J Natl Cancer Inst 2007;99:365-75
Cancer Diseases More Frequently
Treated With Mediastinal/Chest RT
• Hodgkin’s lymphoma
30-36 Gy
• Breast cancer
45-50 Gy
• Gastric carcinoma
45-50 Gy
• Esophageal carcinoma
45-50 Gy
• Lung cancer
50-60 Gy
• Thymoma
60 Gy
Courtesy Dianela Cardinale
Chest radiation exposure
Microvascular injury
accelerates age-related
atherosclerosis, leading to
coronary artery disease
(years/decades post-RT)
Reduced flow to a
myocardial
<< territory >>
Microvascular
injury
Reduces myocardial capillary
density (within months post-RT)
Reduced collateral
flow/vascular
reserve (often
subclinical)
Myocardial ischemia
Regional wall motion
abnormalities
Increased capillary
permeability of the
pericardium,
thickening,
adhesions
Valve endothelial injury
and dysfunction
Leaflet fibrosis,
thickening, shortening
and calcification
Valve regurgitation
and/or stenosis
Pericardial
effusion/constriction
Progressive myocardial
fibrosis
Progressive decline in
LV systolic and
diastolic function
Asymptomatic stage
Concomitant cardiotoxic
chemotherapy
LV volume/pressure
overload
Overt heart failure
European Heart Journal – Cardiovascular Imaging 14;721, 2013
Congestive heart failure
Myocardial infarction
Cumulative incidence
(%)
Cumulative incidence
(%)
Radiation-induced Heart Disease
15
12
9
6
3
0
15
12
9
6
3
0
No cardiac radiation
<500 cGy cardiac radiation
500 to <1500 cGy cardiac radiation
1500 to <3500 cGy cardiac radiation
3500 cGy cardiac radiation
0
10
20
30
0
Time since diagnosis (years)
10
20
30
Pericardial disease
Valvular disease
Cumulative incidence
(%)
Cumulative incidence
(%)
Time since diagnosis (years)
15
12
9
6
3
0
15
12
9
6
3
0
0
10
20
Time since diagnosis (years)
30
0
10
20
30
Time since diagnosis (years)
Mulrooney DA et al. BMJ 2009;339:b4606
©2012 MFMER | 3208984-107
Radiation-induced Heart Disease
Patchy fibrosis
does not correspond to
CAD pattern…
…even though CAD can
be prominent
(mantle field irradiation
pattern)
O h-Icí D, Garot J. Circ Heart Fail 2011;4:e1-e2
©2012 MFMER | 3208984-108
Mantle Field Radiation
Maraldo MV et al. Int J Rad Oncol Biol Phys 2012;83:1232-7
Breast Cancer Radiation
Zagar T M , Marks L B JCO 2012;30:350-352
Radiation-induced Coronary Artery Disease
Breast Cancer therapy
CAD location with left breast radiation therapy: LAD > RCA > LCX
CAD location with right breast radiation therapy: RCA > LAD > LCX
Correa C R et al. JCO 2007;25:3031-3037
Radiation-induced Coronary Artery Disease
Acceleration Pattern
Fibrosis Pattern
Weintraub et al. J Am Coll Cardiol 2010;55:1237-9
Histology images courtesy of Dr. William Edwards, Mayo Clinic
©2012 MFMER | 3208984-112
Radiation-induced Heart Disease
Darby SC et al. N Engl J Med 2013;368:987-98
Radiation-induced Heart Disease
Relative Hazard
10
5
2
1
0
0
10
20
30
40
Cumulative Radiotherapy Dose
(x 100 Gray)
Van der Pal HJ et al. J Clin Oncol 2012;30:1429-37
Darby SC et al. N Engl J Med 2013;368:987-98
Reduction in Mean Dose to Cardiac
Structures From 3-D Radiotherapy
1970s-2006
Year
Mean dose (Gy)
Left anterior
descending
Heart
artery
Right
coronary
artery
Circumflex
coronary
artery
1970s
13.3
31.8
9.1
6.9
1980s
4.7
21.9
2.0
2.8
2006
UK
2.3
83%
2.0
77%
1.2
7.6
77%
70%
Courtesy Dianela Cardinale
Evolution of RT Techniques
• Orthovoltage radiation
1970
• Megavoltage radiation
1980
• 2D – techniques
1990
•
•
•
•
•
•
•
2000
2010
RT modern era
Conformal 3D techniques
Involved Field
Intra Operative Radio Therapy
Intensity Modulated Radio Therapy
Breathing control devices
Modern stereotactic RT
Hadrontherapy
Total heart dose
Cardiac irradiated volume
1960
High precision and customized RT
Courtesy Dianela Cardinale
Algorithm for Post-Chest Radiotherapy F/u
Risk factors for post-radiation
cardiac complications
•Young age at radiation
•High radiation dose
•Higher cardiac volume exposed
to radiation
•Increasing interval from time of
radiation
•Traditional cardiac risk factors
•Adjuvant chemotherapy
No
Suspect
constrictive
pericarditis
Yes
Suspect
Suspect
radiotherapyassociated
cardiac injury
Supportive
symptoms/signs
zcoronary disease
No imaging advised
TTE ± CT or MR
ACS presentation
Invasive diagnostic coronary
angiogram ± functional imaging
Non-ACS symptoms
Functional imaging*: Stress Echo or
rest/stress MPI or stress MRI ± CCTA
Asymptomatic and
5 years post-RT
CT coronary Ca2+
score or CCTA or
functional imaging
Further studies only
if symptoms develop
No
Patients who received
mediastinal/thoracic
RT for treatment of
•Hodgkins lymphoma
•Breast cancer
(left > right)
•Others
Suspect valvular
disease
TTE starting at 10 years postRT, or earlier if supportive signs
or symptoms present
Valve
disease
Yes
Evaluation prior
to cardiothoracic
surgery (eg,
CABG/valve
surgery)
Repeat TTE
every 5 years
Follow ACC/AHA/
ESC guidelines
Obtain gated CT thorax to assess for mediastinal
fibrosis, porcelain aorta, etc, to guide
surgical risk assessment and technique
Modified from Groarke et al: Eur Heart J, 2013
Algorithm for Patient Management After
Chest Radiotherapy
Baseline pre-radiation
comprehensive
Echocardiography
Chest radiation exposure
Yearly targeted clinical history and physical examination
New murmur
Screen for
modifiable
risk factors
Correct risk
factors
Search for signs and symptoms suggestive of
• Pericardial effusion/constriction
• Valvular heart disease
• LV dysfunction/heart failure
• Coronary artery disease
• Carotid artery disease
• Conduction system disease
Asymptomatic
Screening Echocardiography 5 years
after exposure in high-risk patients
10 years after exposure in the others
Signs/symptoms
of heart failure
Echocardiography
CMR if suspicion
of pericardial
constriction
Angina
Neurological
signs/symptoms
Carotid US
Functional noninvasive stress test
for CAD detection (5-10 years after
exposure in high-risk patients)
Re-assess every 5 years
ASCI-ASE – ESC Expert Consensus
Structural heart disease w/radiation therapy
Key Points
1) Plethora of cardiac diseases,unknown how affected by technical changes
2) Most common: heart failure and valvular heart disease
3) CAD not infrequent, influenced by CV risk factors
4) Arrhythmias not common, but potentially fatal
5) Pericardial disease – a possibilty from the very beginning
E-mail: herrmann.joerg@mayo.edu
©2012 MFMER | slide-120