CARDIO ONCOLOGY

JOURNAL CLUB

17/05/2012

DR. R. RAJKUMAR II YR POST GRADUATE DEPARTMENT OF

MEDICAL ONCOLOGY

CARDIO ONCOLOGY

DISCLAIMER IT IS NOT BASED ON ANY

NCCN, ASCO, NICE, AHA/ACC GUIDELINES.

OFF LABEL INDICATIONS ARE USED.

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)

CASE PRESENTATION

CARDIAC RISK ASSESSEMENT

QUESTION 1. None 2. MILD 3. MODERATE 4. HIGH

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

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

CASE PRESENTATION

Received 4 cycles Inj. Pacli 260 & CTX 1000mg

QUESTION

1. agree 2. don’t agree 3. don’t know

CASE PRESENTATION

Rpt ECHO- EF- 30 % Severe LV Dysfunction

Symptomatic –NHYA class II — IIIQUESTION- 1. continue same line of management 2. reduce the dose of drugs 3. choose different class of drugs 4. stop treatment

CASE PRESENTATION

Case discussed in the opd & treatment changed to inj. Doce & CTX

QUESTION- 1. agree 2. don’t agree 3. don’t know

CASE PRESENTATION

TREATMENT FOR CARDIAC FAILURE

QUESTION

1.cardiac glycosides 2.diuretics 3.beta blockers 4.ace inhibitors 5.statins 6.combination

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

These are by far the two most common disease conditions in the developed world….

Heart Disease

No Heart Disease

Women

Heart Disease

No Heart Disease

Men

Women

No Cancer

Cancer

Men

No CancerCancer

•Lifetime risk of developing cancer (U.S.)

•Lifetime risk of developing coronary heart disease at age 40 years (U.S.)

American Cancer Society. Cancer facts &

figures 2007, Lancet 1999;353:89-92.

Five-year Relative Survival (%)* during Three Time Periods By Cancer

Site

*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.

 

 

 

Site 1975-1977 1984-1986 1996-2002 SITE 1975-77 1984-86 1996-02

• 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

†

In any patient, heart disease and cancer are likely to overlap

Driver BMJ 2008:337:a2467

In breast cancer patients, heart disease has a great impact….

JAMA. 2001;285:885-892

Baseline Characteristics of Breast Cancer Cohort and Chemotherapy Subgroups

Doyle JJ et al. J Clin Oncol. 2005 Dec 1;23(34):8597-605.

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

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.

ANTHRACYCLINES

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.

ANTI TUMOR ACTIVITY

• ACTIVATION OF SIGNAL TRANSDUCTION PATHWAYS

• GENERATION OF REACTIVE OXYGEN INTERMEDIATES

• STIMULATION OF APOPTOSIS• INHIBITION OF TOPOISOMERASE II

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

CARDIO TOXICITY

• Chronic – early-<1 yr of chemotherapy late ->1 yr of chemotherapy• Typical sign- asymptomatic sys.

& or diast Lt. ventricular dysfunction

CARDIO TOXICITY

• Mechanism- Oxidative stress Iron overload/Calicum overload Anthracycline Metabolites- Doxorubicinol PAF Hypothesis Down regulation of ß receptors

Neuregulin signaling

CARDIO TOXICITY

CARDIO TOXICITY

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.

CARDIO TOXICITY

CARDIO TOXICITY

CARDIO TOXICITY

How do we best detect cardiotoxicity by Echo?

Belham et al. Eur J Heart Failure. 2006: Oct 23 epub.

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.

TISSUE DOPPLER IMAGING

Cardinale et al. Circ. 2004;109:2749-2754

Troponin I is valuable in detecting Cardiotoxicity

CARDIO TOXICITY

BNP, a marker of volume overload, may also be an effective marker of subsequent myocardial

damage

Okumura et. al. Acta Haematologica. 2000. 104:158-163.

Developed HFNo HF

CARDIO TOXICITY

CARDIO TOXICITY

Recovery of LV dysfunction with standard HF therapy

Jensen, et al. Annals of Oncology. 2002. 13:499-709.

100

14

55

0

25

50

75

100

Pe

rce

nt

of

Pa

tien

ts

Significant Improvement in EF After Optimal HF Therapy

LVEF Decrease

After Chemo

HF with Normal EF

EF Improved After

Optimal Treatment

Lenihan et al, HFSA 2008

Carvedilol appears protective during adriamycin based chemotherapy

Kalay et al. JACC. Dec 2006. 48:2258-62Data expressed as mean values.

ACE Inhibition appears quite important for prevention of toxicity

Cardinale D et al. Circulation. 2006;114:2474-2481

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.

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 individualvariation. The risk increases proportionally to the total accumulateddose 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.

Heart diseaseNo symptoms

HF Risk FactorsNo Heart disease

No symptoms

AsymptomaticLV dysfunction

RefractoryHF symptoms

Prior or currentHF Symptoms

Taking the Congestion Out of Heart Failure

Stages in the evolutionof Heart Failure

A

B

C

D

Hunt SA, et al: AHA / ACC HF guidelines 2001

Heart disease(any)

HypertensionDiabetes, Hyperchol.

Family HxCardiotoxins

AsymptomaticLV dysfunction

Marked symptomsat rest despitemax. therapy

Dyspnea, FatigueReduced exercise

tolerance

Clinical Stages in the Evolution

of Heart Failure

A

B

C

D

Hunt SA, et al: AHA / ACC HF guidelines 2001

Trastuzumab, Anthracyclines

14% in NSABP B-31

4% in NSABP B-31

Journal of Clinical Oncology, Vol 22, No 17 (September 1), 2004: pp. 3485-3490

How Accurate is Clinician Reporting of Chemotherapy Adverse Effects?

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

Classic Triad of Heart Failure

• Dyspnea

• Lower extremity edema

• Fatigue

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?

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?

Detecting CardiotoxicitySummary 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

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”.

www.msnbc.msn.com. Aug 2005.

First Report of Cardiotoxicity of a Targeted Therapy

TRASTUZUMAB

Trastuzumab improves PFS and OS in metastatic breast cancer

Slamon et al.: NEJM 2001;344:783-92.

BUT…..

EXCESS CARDIOTOXICITY OBSERVED

Independent Cardiac Review & Evaluation Committee (CREC)

CardiotoxicityH + AC AC H + T T

Cardiac dysfunction events, % 27 8 13 1

NYHA Class III/IV CHF, % 16 4 2 1

Seidman A et al: J Clin Oncol 2002; 20:1215-21.

Phenotypic Analysis of erbB2Knockout Mouse Myocardium

Crone SA, et al. Nature Medicine. 2002;8:459-465.

erbB2-floxed erbB2-CKO

m = mitochondria

Arrows = vacuoles

Transmission EM

Trichrome staining

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

Reversible or Just Treatment Responsive?

908070605040302010

0

Mea

n LV

EF (%

)

Following Trastuzumab

Therapy(n = 37)

Prior to Trastuzumab

Therapy(n = 38)

Following Standard Therapy for Heart Failure

(n = 32)

Following TrastuzumabRechallenge

(n = 25)

Durand JB, et al: J Clin Oncol 2005;23:7820-7826

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”)

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

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

Cardiac Monitoring Strategy NSABP B-31 &NCCTG N9831

Timing of Evaluation

Baseline, post-AC, 6, 9, 18 months from randomization

Criteria for Discontinuation

Symptomatic cardiac dysfunction

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

Cardiotoxicity in the Adjuvant Trials

NSABP B-31 NCCTG N9831

HERA BCIRG 006

FinHER

NYHA III/IV CHF or cardiac deathat 3 years:

C: 0.8%H: 4.1%

NYHA III/IV CHF or cardiac death at 3yrs:

C: 0.3%H: 3.5%

Severe CHF:

C: 0%H: 0.6%

Grade 3/4CHF:

ACT: 0.3%ACTH: 1.6%TCH: 0.4%

CHF/MI:

C: 3.4%H: 0%

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

NSABP B-31Cardiac 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

NSABP B-31Cardiac Risk Score

Example:62 yo woman on antihypertensive medicationBaseline LVEF = 60%

0 20 40 60 80 100

0.0

00

.05

0.1

00

.15

0.2

0

Cardiac Risk Score

Pre

dic

ted

Cu

mu

lative

In

cid

en

ce

o

o(0.024,50)

(0.04,62)

Cardiac Risk Score = 82%

3-year predicted incidence of symptomatic heart failure/cardiac death 10%

Cardiac Dysfunction Associated With Trastuzumab

Seidman A, et al. J Clin Oncol. 2002;20:1215-1221.

Trastuzumab Alone

Trastuzumab+ AC

ACAlone

Trastuzumab+ P

PAlone

Any cardiac dysfunction

3% to 7% 27% 8% 13% 1%

Class III-IV 2% to 4% 16% 4% 2% 1%

There is significant reversibility of LV dysfunction with trastuzumab-related cardiac

toxicity

Ewer, et al Journ of Clinical Oncology 2005,23;p 7820-6.

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

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

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

Systemic Effects of Anti-VEGF TherapyNormal Tissues

(VEGF constitutively expressed)

Tumor Tissues

(VEGF upregulated)

Lung cancer (bevacizumab)Inhibition of tumor growth, tumor cavitation

Hepatocellular carcinoma (sorafenib)Tumor necrosis

Renal cell carcinoma (sunitinib)Tumor shrinkage, tumor cell necrosis

Colorectal cancer (bevacizumab)Deceleration of tumor growth

efficient chemotherapy delivery

1 2 3

Hypertensive remodelingMicrovascular rarefactionCardiomyopathy (sunitinib and sorafenib)

Microcirculation: 1. normal arteriole, 2. functional rarefaction(endothelial dysfunction,vasoconstriction), 3. anatomic rarefaction

Thrombotic microangiopathyGlomerulopathy / glomerulonephritisProteinuriaHypertensive nephropathy

NCI Guidelines: Common Toxicity Criteria, 2001, 1-12

GRADE 1 2 3 4 5

LV Systolic Dysfunction

AsymptomaticLVEF 50% to 60%; SF < 24% to 30%

AsymptomaticLVEF 40-50%:SF < 15% to 24%

Symptomatic CHF responsive to intervention;EF < 20% to 40% SF < 15%

Refractory CHF or LVEF < 20%: intervention such as VAD, ventricular reduction surgery, or heart transplant indicated

Death

NCI Guidelines: Common Toxicity Criteria. 2001; 1-12.

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

Survival According to the Underlying Cause of Cardiomyopathy

Felker GM, et al. N Engl J Med. 2000;342:1077-1084.

1.00

0.75

0.50

0.25

0.000 5 10 15

Years

Peripartum

Idiopathic

ischemic heart diseaseDue to

Due to HIV infection

Due to infiltrative myocardial disease

Due to doxorubicin therapy

1%

Prop

ortio

n of

Pati

ents

Sur

vivi

ng

Cancer vs Heart Failure

CANCER• Bad outcome• Bad way to die

HEART FAILUREBad outcome

– Median survival class IV heart 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

The Exchange of One for Another

“And in the black prison of theConciergerie . . .

‘Change that cravat for this of mine, that coat for this of mine’.”

A Tale of Two Cities

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

CARDIO ONCOLOGY TEAM

DR. HARI & DR. NITHYA

Supported in part by the Lance Armstrong Foundation

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

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

METHODOLOGY

CARDIAC MONITORING-

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

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).

PLANNED RECRUITMENT

• 100 Patients

Photo Album

by drraj