1. CARDIO ONCOLOGY
JOURNAL CLUB
17/05/2012
DR. R. RAJKUMAR
II YR POST GRADUATE
DEPARTMENT OF MEDICAL ONCOLOGY

2. CARDIO ONCOLOGY
DISCLAIMER
IT IS NOT BASED ON ANY
NCCN, ASCO, NICE, AHA/ACC
GUIDELINES.
OFF LABEL INDICATIONS ARE
USED.

3. CASE PRESENTATION
• MRS. X, 60/Female, cT4bNxM0
• Underwent Lt. Simple Mastectomy
(21/08/2011)
• HPE= IDC-GRADE II
• pT2NxM0 ER+PR-Her2neu+
• Lt.Axillary Dissection , 3/3 nodes+
• Co morbidity- Known case of CAD- 6
Yrs.
• ECHO- EF- 36% mod. LV dysfunction
(19/10/2011)

4. CASE PRESENTATION
CARDIAC RISK ASSESSEMENT
QUESTION
1. None
2. MILD
3. MODERATE
4. HIGH

5. CASE PRESENTATION
CARDIAC RISK ASSESSEMENT
QUESTION
MODALITY-
1. Echo
2. Muga Scan
3. Cardiac Bio-Markers
4. Tissue Doppler
5. Cardiac MRI
6. Combination
7. None

6. CASE PRESENTATION
Choice of Adjuvant Chemotherapy
1.Anthracycline based
2.Taxane based
3.Combination of anthracycline &
taxane based
4.Combination with trastuzumab
5.Non Anthracycline based

7. CASE PRESENTATION
Received 4 cycles Inj. Pacli 260 & CTX
1000mg
QUESTION
1. agree
2. don‟t agree
3. don‟t know

8. CASE PRESENTATION
Rpt ECHO- EF- 30 % Severe LV
Dysfunction
Symptomatic –NHYA class II — III
QUESTION-
1. continue same line of management
2. reduce the dose of drugs
3. choose different class of drugs
4. stop treatment

9. CASE PRESENTATION
Case discussed in the opd &
treatment changed to inj. Doce &
CTX
QUESTION-
1. agree
2. don‟t agree
3. don‟t know

10. CASE PRESENTATION
TREATMENT FOR CARDIAC FAILURE
QUESTION
1.cardiac glycosides
2.diuretics
3.beta blockers
4.ace inhibitors
5.statins
6.combination

13. 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

14. These are by far the two most common
disease conditions in the developed
world….
Women Men
Heart
Disease
No Heart Heart
Disease Disease
No Heart
Disease
•Lifetime risk of developing coronary heart disease at age 40 years (U.S.)
Women Men
Cancer
Cancer No Cancer
No Cancer
•Lifetime risk of developing cancer (U.S.)
American Cancer Society. Cancer facts &
figures 2007, Lancet 1999;353:89-92.

15. Five-year Relative Survival (%)* during
Three Time Periods By Cancer Site
SITE 1975-77 1984-86 1996-02
Site 1975-1977 1984-1986 1996-2002
• All sites 50 53 66
• Breast (female) 75 79 89
• Colon 51 59 65
• Leukemia 35 42 49
• Lung and bronchus 13 13 16
• Melanoma 82 86 92
• Non-Hodgkin lymphoma 48 53 63
†
• Ovary 37 40 45
• Pancreas 2 3 5
• Prostate 69 76 100
• Rectum 49 57 66
• Urinary bladder 73 78 82
*5-year relative survival rates based on follow up of patients through 2003. †Recent changes in classification of ovarian cancer
have affected 1996-2002 survival rates.Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of
Cancer Control and Population Sciences, National Cancer Institute, 2006.

16. In any patient, heart disease and cancer
are likely to overlap
Driver BMJ 2008:337:a2467

17. In breast cancer patients, heart
disease has a great impact….
JAMA. 2001;285:885-892

18. Baseline Characteristics of Breast
Cancer Cohort and Chemotherapy
Subgroups
Doyle JJ et al. J Clin Oncol. 2005 Dec 1;23(34):8597-605.

19. Even in early stage breast
cancer, cardiac disease does
matter…
• Patients
with early
stage
breast
cancer are
4x more
likely to die
of non-
cancer
conditions
(up to 45 %
are cardiac
in nature)
Hanrahan, et al. JCO 25: 4952-4960, 2007

20. CARDIO TOXICITY
DEF- “ toxicity that affects the heart”- NCI
Cardiac review & evaluation committee of
trastuzumab clinical trial-
1.cardiomyopathy-↓ LVEF- Global or Septum
2.Symptoms of Heart Failure
3.Signs- S3 gallop, tachycardia,or both
4.↓LVEF <5%(55%)- signs & symptoms of
H.F.
5.↓LVEF >10%(55%)-without signs or
symptoms of H.F.

26. ANTHRACYCLINES

27. ANTHRACYCLINES
• Anthracyclines have been used as
efficacious antineoplastic agents for
many haemopoietic and solid
cancers since they were first
isolated from the pigment-producing
Streptomyces peuctius early in the
1960s. However,dose-dependent risk
of cardiomyopathy and congestive
heart failure has restricted their
clinical utility.

28. ANTI TUMOR ACTIVITY
• ACTIVATION OF SIGNAL
TRANSDUCTION PATHWAYS
• GENERATION OF REACTIVE OXYGEN
INTERMEDIATES
• STIMULATION OF APOPTOSIS
• INHIBITION OF TOPOISOMERASE II

29. CARDIO TOXICITY
Acute or sub acute-
• abnormalities in vent.
repolarisation & electrocardio QT-
interval changes
• Supraventricular & ventricular
arrhythmias
• Acute coronary syndromes
• Pericarditis & / or myocarditis like
syndrome
• Upto 2 weeks

30. CARDIO TOXICITY
• Chronic –
early-<1 yr of chemotherapy
late ->1 yr of chemotherapy
• Typical sign- asymptomatic sys. &
or diast Lt. ventricular
dysfunction

31. CARDIO TOXICITY
• Mechanism-
Oxidative stress
Iron overload/Calicum overload
Anthracycline Metabolites-
Doxorubicinol
PAF Hypothesis
Down regulation of ß receptors
Neuregulin signaling

32. CARDIO TOXICITY

33. CARDIO TOXICITY

36. CARDIO TOXICITY
• The occurrence of CHF is dose- and
schedule-dependent.
• left ventricular dysfunction is more
frequently observed in women, in
patients with personal history of
cardiac disease, and after mediastinal
X-ray therapy .
• The risk of cardiotoxic adverse events
increases when anthracycline
chemotherapy is administered
concurrently or sequentially before
adjuvant therapy with trastuzumab.

41. CARDIO TOXICITY

47. CARDIO TOXICITY

48. CARDIO TOXICITY

49. How do we best detect cardiotoxicity
by Echo?
Sa = longitudinal (annular) systolic contraction, E = transmitral E wave velocity, A = transmitral A wave
velocity, Ea = longitudinal (annular) early diastolic relaxation velocity. *P < 0.05 compared to baseline. **P < 0.01 compared to
baseline. ***P < 0.001 compared to baseline. ****P < 0.0001 compared to baseline. #P < 0.05 compared to low dose.
Belham et al. Eur J Heart Failure. 2006: Oct 23 epub.

50. TISSUE DOPPLER IMAGING

51. Troponin I is valuable in detecting Cardiotoxicity
Cardinale et al. Circ. 2004;109:2749-2754

52. CARDIO TOXICITY

53. BNP, a marker of volume overload, may also be
an effective marker of subsequent myocardial
damage
No HF Developed HF
Okumura et. al. Acta Haematologica. 2000. 104:158-163.

55. CARDIO TOXICITY

56. CARDIO TOXICITY

59. Recovery of LV dysfunction with standard HF
therapy
Jensen, et al. Annals of Oncology. 2002. 13:499-709.

60. Significant Improvement in EF After Optimal HF Therapy
100
100
75
Percent of Patients
55
50
25
14
0
LVEF HF with EF
Decrease Normal Improved
After EF After
Chemo Optimal
Treatment
Lenihan et al, HFSA 2008

61. Carvedilol appears protective during adriamycin
based chemotherapy
Data expressed as mean values.
Kalay et al. JACC. Dec 2006. 48:2258-62

62. ACE Inhibition appears quite important for
prevention of toxicity
Cardinale D et al. Circulation. 2006;114:2474-2481

65. CARDIO TOXICITY
• Dose reductions limit the
incidence of early cardiac events
but not that of delayed sequelae,
possibly indicating that any dose
level of antitumor drugs would
prime the heart to damage from
sequential stressors.

66. The risk of developing cardiotoxicity is
mainly related to the total cumulative
dose of doxorubicin (1% to 5% up to
550 mg/m2, 30% at 600 mg/m2, and 50%
at 1g/m2 or higher) with individual
variation. The risk increases
proportionally to the total accumulated
dose in a nonlinear fashion, so that
there probably is no safe dose of
doxorubicin. It is increasingly
recognized that abnormalities in non
invasive studies can be found in greater
frequency and at a lower cumulative
dose than previously reported.

69. HF Risk Factors Taking the Congestion
No Heart disease A Out of Heart Failure
No symptoms
Stages in the evolution
Heart disease
B of Heart Failure
No symptoms
Asymptomatic
LV dysfunction
C
Prior or current
HF Symptoms
D
Refractory
Hunt SA, et al: AHA / ACC HF guidelines 2001 HF symptoms

70. Trastuzumab, Anthracyclines
Hypertension
Diabetes, Hyperchol. A
Family Hx
Cardiotoxins Clinical Stages in the
Evolution
Heart disease of Heart Failure
(any) B
Asymptomatic 4% in NSABP B-31
LV dysfunction
C
Dyspnea, Fatigue
Reduced exercise
14% in NSABP B-31 tolerance
D
Marked symptoms
Hunt SA, et al: AHA / ACC HF guidelines 2001 at rest despite
max. therapy

76. How Accurate is Clinician Reporting
of Chemotherapy Adverse Effects?
Journal of Clinical Oncology, Vol 22, No 17 (September 1), 2004: pp. 3485-3490

77. 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

78. Classic Triad of Heart
Failure
• Dyspnea
• Lower extremity edema
• Fatigue

79. Difficulties in diagnosing
“heart failure”
• Can be a wide range of
presentations
• Many of the symptoms of heart
failure overlap with other disease
states such as COPD, Obesity,
Nephrotic Syndrome, Drug induced
Edema, Cirrhosis, Sleep Apnea, and
Cancer
• How to effectively and efficiently
differentiate between these
entities?

80. Difficulties in diagnosing
“heart failure”
• Can be a wide range of
presentations
• Many of the symptoms of heart
failure overlap with other disease
states such as
COPD, Obesity, Nephrotic
Syndrome, Drug induced
Edema, Cirrhosis, Sleep Apnea, and
Cancer
• How to effectively and efficiently
differentiate between these
entities?

82. Detecting Cardiotoxicity
Summary of current methods
• The guidelines*at present suggest
a baseline EF measurement and a
repeat study at some time interval
(keep in mind that more than 1/3 of patients with heart
failure have a normal EF and their prognosis is similar to
those with systolic dysfunction)
• Symptoms are the mainstay of the
diagnosis of heart failure (and the utility of
that is in question)
• No recommendation for biomarker
testing or preventive therapy
*AHA,ACC,HFSA, and ASCO websites

83. COLLATERAL DAMAGE
“It‟s naïve to believe that, if
you inhibit a pathway to kill
a cancer cell, you won‟t kill
other healthy cells”.

85. www.msnbc.msn.com. Aug 2005.

86. First Report of Cardiotoxicity of
a Targeted Therapy
TRASTUZUMAB

87. Trastuzumab improves PFS and OS
in metastatic breast cancer
Slamon et al.: NEJM 2001;344:783-92.

88. BUT…..
EXCESS CARDIOTOXICITY
OBSERVED

89. Independent Cardiac Review &
Evaluation Committee (CREC)
Cardiotoxicity
H + AC AC H+T T
Cardiac dysfunction
27 8 13 1
events, %
NYHA Class III/IV CHF, % 16 4 2 1
Seidman A et al: J Clin Oncol 2002; 20:1215-21.

90. Phenotypic Analysis of erbB2
Knockout Mouse Myocardium
erbB2-floxed erbB2-CKO
Trichrome staining
Transmission EM
m =  mitochondria
Arrows =  vacuoles
Crone SA, et al. Nature Medicine. 2002;8:459-465.

91. A „two-hit‟ model of trastuzumab-
induced cardiotoxicity
• Trastuzumab -> loss of
ErbB2-mediated
signaling
– Interferes with ability
of the heart to respond
to stress
• When faced with
subsequent stress ->
ErbB2-deficient hearts
are more susceptible
to the cardiotoxic
effects of the stressor

92. Reversible or Just Treatment
Responsive?
90
80
Mean LVEF (%)
70
60
50
40
30
20
10
0
Prior to Following Following Following
Trastuzumab Trastuzumab Standard Therapy Trastuzumab
Therapy Therapy for Heart Failure Rechallenge
(n = 38) (n = 37) (n = 32) (n = 25)
Durand JB, et al: J Clin Oncol 2005;23:7820-7826

93. Adjuvant Trastuzumab Trials
NSABP B-31 & NCCTG N-9831
AC x 4 > Taxol x 4
AC x 4  Taxol x 4  H x 52
HERA
At least 4 cycles chemo  Observation vs. H 1yr vs. H
2yrs
BCIRG 006
AC x 4  Docetaxel x 4
AC x 4  Docetaxel x 4  H x 52
Docetaxel + Carboplatin x 6 + H x 52 (“TCH”)

94. Adjuvant Trastuzumab Trials
FinHER
Docetaxel x 3 + H x 9 wks > FEC x 3
Docetaxel x 3 > FEC x 3
Vinorelbine x 3 + H x 9 wks > FEC x 3
Vinorelbine x 3 > FEC x 3

95. Prospective Cardiac Monitoring
in the Adjuvant Trials
• Designed to minimize significant
cardiotoxicity
• Significant cardiac comorbidities
excluded
• Trials required normal baseline LVEF
• Protocol specified cardiac safety
analyses

96. Cardiac Monitoring Strategy
NSABP B-31 &NCCTG N9831
Timing of Baseline, post-AC, 6, 9, 18 months
Evaluation from randomization
Criteria for Symptomatic cardiac dysfunction
Discontinuation
Hold Criteria* Asymptomatic and:
1. LVEF drop  16% from baseline or
2. LVEF drop 10-15% from baseline to
< LLN
* Treatment was discontinued if LVEF did not recover to a level above hold
criteria after treatment stopped for 4 weeks

97. Cardiotoxicity in the Adjuvant Trials
NSABP B-31 NCCTG HERA BCIRG FinHER
N9831 006
NYHA III/IV NYHA III/IV Severe CHF: Grade 3/4 CHF/MI:
CHF or CHF or CHF:
cardiac death cardiac
at 3 years: death at 3yrs:
C: 0% ACT: C: 3.4%
C: 0.8% C: 0.3% H: 0.6% 0.3% H: 0%
H: 4.1% H: 3.5% ACTH:
1.6%
TCH:
0.4%

98. Additional B-31 Cardiotoxicity Data
• Symptomatic CHF not meeting
criteria for a cardiac event:
C: 1%
H: 5.1%
• 14% discontinued trastuzumab
secondary to asymptomatic declines
in LVEF
Tan Chiu et al: J Clin Oncol 2005;23:7811-9

99. NSABP B-31
Cardiac Risk Score
Factors associated with risk of developing a
cardiac event:
 Use of hypertensive medications
 Age >49
 Baseline LVEF <54
Risk Score = 100 x 7.4(0.03 x Age) – (0.10 + baseline LVEF) + (0.68 x C)
4.82
C = HTN medication status: none = 0; yes = 1
Rostagi P, Adjuvant Breast Oral Session, ASCO 2007

100. NSABP B-31
Cardiac Risk Score
Example:
62 yo woman on antihypertensive
medication
Baseline LVEF = 60%
Cardiac Risk Score =
0.20
82%
Predicted Cumulative Incidence
0.15
3-year predicted
incidence of
0.10
symptomatic heart
failure/cardiac death 
0.05
(0.04,62)
o
10%
(0.024,50)
o
0.00
0 20 40 60 80 100
Cardiac Risk Score

102. Cardiac Dysfunction Associated
With Trastuzumab
Trastuzumab Trastuzumab AC Trastuzumab P
Alone + AC Alone +P Alone
Any cardiac 3% to 7% 27% 8% 13% 1%
dysfunction
Class III-IV 2% to 4% 16% 4% 2% 1%
Seidman A, et al. J Clin Oncol. 2002;20:1215-1221.

103. There is significant reversibility of LV
dysfunction with trastuzumab-related
cardiac toxicity
Ewer, et al Journ of Clinical Oncology 2005,23;p 7820-6.

104. ANTHRA AND TRAZ
• Anthracyclines are the precipitating factor for
trastuzumab-induced cardiotoxicity
and, therefore, anthracyclines and
trastuzumab should not be given
synchronously
• Trastuzumab can usually be given safely
following completion of adjuvant
anthracycline based chemotherapy, and
trastuzumab-associated cardiotoxicity is
usually treatable and reversible
• Regular left-ventricular function monitoring
before and during therapy is mandatory in all
patients receiving adjuvant trastuzumab after
anthracyclines

105. ANTHRA AND TRAZ
• In patients with advanced disease, the clinical benefit
from trastuzumab needs to be balanced against
cardiotoxicity
• Trastuzumab in combination with nonanthracycline
chemotherapy does not seem to be associated with
any increased risk of cardiotoxicity
• The optimal duration for adjuvant trastuzumab therapy
suggested by current data is 1 year, although some
data support as little as 9 weeks of trastuzumab;
however, scheduling trastuzumab before initiating
adjuvant anthracycline therapy remains experimental
and might be risky because of the long half-life of
trastuzumab

111. Bevacizumab
• Bevacizumab is also associated with
hypertension and instances of
thromboembolism, pulmonary
hemorrhage, and pulmonary edema or
gastrointestinal tract bleeding.
• Antiangiogenesis class of drugs can
also harbor cardiovascular toxicity, as
indicated by a reduction of LVEF that
over the long term may result in CHF

112. Systemic Effects of Anti-VEGF
Therapy
Tumor Tissues Normal Tissues
(VEGF upregulated) (VEGF constitutively expressed)
Hypertensive remodeling
Lung cancer (bevacizumab) Microvascular rarefaction
Inhibition of tumor growth, tumor cavitation Cardiomyopathy (sunitinib and sorafenib)
Hepatocellular carcinoma (sorafenib)
1 2 3
Tumor necrosis
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

114. NCI Guidelines: Common
Toxicity Criteria, 2001, 1-12
GRADE 1 2 3 4 5
LV Systolic Asymptomatic AsymptomaticLVEF Symptomatic Refractory CHF Death
Dysfunction LVEF 40-50%: CHF responsive or LVEF <
50% to 60%; SF < 15% to 24% to intervention; 20%:
SF < 24% to EF < 20% to intervention
30% 40% such as VAD,
SF < 15% ventricular
reduction
surgery, or
heart transplant
indicated
NCI Guidelines: Common Toxicity Criteria. 2001; 1-12.

115. Cancer Therapy and Heart
Failure:
A Tale of 2 Diseases
• Danger of insults added to
injuries of the heart
• Silent progression of heart
failure
• Missing chapters in
cardiotoxicity story
• Tough trade of one fatal
disease for another
• Decisions about therapy
depend on absolute risks for
individual patients

116. Survival According to the Underlying
Cause of Cardiomyopathy
1.00
Peripartum
Proportion of Patients Surviving
0.75
1% Idiopathic
Due to
0.50 Due to
doxorubicin therapy
ischemic heart disease
Due to infiltrative myocardial disease
0.25
Due to HIV infection
0.00
0 5 10 15
Years
Felker GM, et al. N Engl J Med. 2000;342:1077-1084.

117. Cancer vs Heart Failure
HEART FAILURE
CANCER Bad outcome
• Bad outcome – Median survival class IV heart
• Bad way to die failure:
1.0-1.5 yrs
Bad way to die
– 80% of HF deaths since 2000
accompanied by severe
symptoms
– Pain, anorexia, constipation
common
– Anxiety and insomnia may be
aggravated by high central
dopamine levels

118. The Exchange of One for
Another
“And in the black prison of the
Conciergerie . . .
„Change that cravat for this of
mine, that coat for this of mine‟.”
A Tale of Two Cities

119. A Tale of Two Diseases
• Danger of insults added
to injuries of the heart
• Silent progression of
heart failure
• Missing chapters in
cardiotoxicity story
• Tough trade of one fatal
disease for another
• Decisions about therapy
depend on absolute risks
for individual patients

122. CARDIO ONCOLOGY TEAM
DR. HARI
&
DR. NITHYA

128. Supported in part by the Lance Armstrong
Foundation

130. PROTOCOL
INCLUSION CRITERIA –
• Patients undergoing chemotherapy in
the Dept. of Med onco , M.M.C. ,Chennai
from MAY 2012- MARCH 2013.
• Patient age 18-85 years
• Starting a new course of
chemotherapy that includes an
anthracycline (does not have to be
first-line therapy and previous
anthracycline use is allowed)
• Has a life expectancy greater than 3
months

131. Exclusion Criteria
• Unstable angina within the last 3
months
• Myocardial infarction within the
last 3 months
• LVEF less than 30%
• Decompensated HF in the last 3
months

132. METHODOLOGY
CARDIAC MONITORING-
ECG , CARDIAC TROP T/I
measurement, CRP
measurement , TISSUE
DOPPLER ECHO- Pre
Chemo, During Chemo, &Post
Chemo.

133. Cardiac Event
• Any new symptomatic cardiac arrhythmia
• Acute coronary syndrome
• Symptomatic HF
• Development of asymptomatic left
ventricular dysfunction (defined as LVEF
less than 50 % with a normal baseline or a
decrease of greater than 10% from
baseline)
• Sudden cardiac death (defined as rapid
and unexpected death from cardiac
causes with or without known underlying
heart disease).

134. PLANNED RECRUITMENT
• 100 Patients

135. Photo Album
by drraj