8/29/2017

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John Steuter, MD

Cardio-Oncology

Disclosures

None

Case presentation

28 year old male with no PMH, presents to his PCP with fevers, chills, and cough, found to have pancytopenia

CXR demonstrated significant mediastinal fullness, referred for CT scan which confirms the presence of significant mediastinal lymphadenopathy.

Patient referred for biopsy and ultimately diagnosed with Diffuse large b-cell lymphoma- grade IV

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Case presentation

His oncologist plans for R-CHOP chemotherapy

– Rituximab, cyclophosphamide, doxorubicin (hydroxydaunomycin)

vincristine (Oncovin ®), Prednisone

Questions

Does the patient need an baseline evaluation of left ventricle function?

Which do you order? ( nuclear, echo, MRI, strain)

Does the patient need a beta blocker, ACE, or other medications

How would your management change if the patient was 62 years old with a PMH CAD?

Outline

Types of Chemotherapy Related Cardiac Dysfunction

Mechanisms of toxicity

Risk Factors/Stratification

Risk Modification

Monitoring

Prognosis

Treatment

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Definition“Direct toxic effects of chemotherapy on the cardiovascular system”

Unified definition needed

Examples:

Reduction in LVEF from baseline of 1-5% in the presence of signs or symptoms or HF

Reduction in LVEF >10% without signs or symptoms of HF

American Society of Echo (ASE)

Decrease in EF by 10% to a value of less than 53%

Confirmed by repeat imaging,2-3 weeks later

Further defined by symptomatic or asymptomatic (reversible, irreversible)

Chemotherapy related cardiac dysfunction

Type I

(anthracycline-associated cardiac dysfunction)

Type II

(trastuzumab induced cardiac dysfunction, related to HER2 blockade)

Anthracyclines

Anthracyclines are a class of drugs used in cancer chemotherapy derived from Streptomyces bacterium

– Daunorubicin (liposomal form)

– Doxorubicin (liposomal form)

• Adriamycin

• R-CHOP (doxorubicin Hydrochloride)– Epirubicin

– Idarubicin

– Valrubicin

– Mitoxantrone (anthracycline analog)

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Mechanism of actionAnthracyclines has four mechanisms of action:

1. Inhibits DNA and RNA synthesis by intercalating between

base pairs of the DNA/RNA strand, thus preventing the

replication of rapidly-growing cancer cells.

2. Inhibits topoisomerase II enzyme,

3. Creates iron-mediated free oxygen radicals that damage the

DNA, proteins and cell membranes.

4. Induce histone eviction from chromatin that deregulates

DNA damage responses.

Cardiotoxicity

Doxorubicin administration is associated with a decrease in the presence of the endogenous antioxidants responsible for the scavenging of free radicals.

A decrease in antioxidants and an increase in oxidants (free radicals) result in increased oxidative stress, leading to myocardial damage.

Mitochondria

Lipid peroxidation of cell membranes

Cardiotoxicity

Topoisomerase- II enzyme:

Two types Top2-alpha and Top2-beta

Top2-alpha: known marker of cellular proliferation and overexpressed in tumor cells but not in quiescent tissues

(anti-tumor activity)

Top2-Beta: mammalian cardiomyocytes express Top2-Beta, but not alpha

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Top2-Beta

Doxorubicin interacts with Top2-Beta and the complex can induce DNA double strand breaks, leading to cell death.

Zhang et al, 2012. Cardiomyocyte-specific deletion of the gene Top2-Beta protects from development of adriamycininduced heart failure in mice.

Acute ToxicityRhythm disturbances (AFIB, AV block)

Acute LV dysfunction

Pericarditis/Myocarditis

Varying prevalence but most studies put around 3%

Unclear risk for further chronic toxicity

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Factors affecting the development of atrial fibrillation and atrial

flutter (AF/AFL) following autologous hematopoietic SCT

Bone Marrow Transplant. 2013 Jul;48(7):963-5. doi: 10.1038/bmt.2012.253. Epub 2012 Dec 10.Steuter J, Villanueva ML, Loberiza FR, Armitage JO, Bociek RG, Ganti AK, Tarantolo SR, Vose JM, Easley A, Bierman PJ.

Patients who developed AF/AFL were compared with a group of patients who received auto-HSCT within the same time period (April 1999 to May 2005) and were within 5 years of age. Of the 516 patients who underwent auto-HSCT at the University of Nebraska Medical Center 44 (8.5%) developed AF/AFL at a median time of 4 days (range, days 1-9) following auto-HSCT.

Risk factors for developing AF/AFL were

older age (65)

elevated serum creatinine level

history of previous arrhythmia

history of previous mediastinal irradiation

Chronic toxicity

Wide range of time from exposure to presentation

Peak at 3 months, can be as long as a decade

Exposure drives incidence

• <4% if dose <500mg/m2

• 18% if dose 500-600mg/m2

• 36% if dose > 600mg/m2

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Risk Factors

Age at time of exposure

Concomitant agents

• (paclitaxel, cyclophosphamide, trastuzamab)

Chest radation (prior or concurrent)

Pre-existing CVD

• CAD, HTN, PVD, DM

Type II CRCD

Exemplified by trastuzumab

Humanized monoclonal antibody utilized for the treatment of HER2 positive breast cancer

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Mechanism

Not as well defined

Epidermal growth signal pathway (HER2) in the heart is implicated (blockade)

In contrast to anthracyclines, trastuzumab induced cardiac injury is not related to cumulative dose

Often is reversible after discontinuation

Trastuzumab could be used again after recovery

Risk factors (type II)

Risk of cardiac injury if receive concurrent anthracyclinetherapy carries expected increased risk

Age >50, pre-existing cardiac dysfunction, high BMI

Patients with type II CRCD often present with a decrease in LV function and less often by overt heart failure symptoms

Risk Stratification (type I)Current NCCN (National Comprehensive Cancer Network) guidelines

state that it is “essential” for patients with mantle cell lymphoma, diffuse large B-cell lymphoma, lymphoblastic lymphoma, chronic lymphocytic

lymphoma, small lymphocytic lymphoma, Burkitt’s lymphoma, and

Hodgkin’s lymphoma to have an evaluation of left ventricle function prior to therapy

NCCN guidelines for breast cancer suggest left ventricle function

evaluation prior to therapy. These patients may receive doxorubicin and

cyclophosphamide with doses of doxorubicin achieving the 300 mg/m2

threshold.

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The evaluation of left ventricle function by echocardiogram and reevaluation of patients exposed to anthracyclinetherapy was given a class I recommendation by the task force of the ACC, AHA, and the ASE

Risk ModificationLimiting exposure dose

Longer infusion times

• No significant change, trend towards higher deaths rates in longer infusion from malignancy

Liposomal encapsulation

Cardio-protective agents

Dexrazoxane

Dexrazoxane ( an iron chelating agent )

Prevents formation of semiquinone-iron which leads to free radical formation

has shown some reduction in incidence

• (8% vs 1 %) Swain 1997, clinical trial

associated severe myelosuppression

may interfere with antitumor activity of doxorubicin??

• No change in overall survival and event free survival

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Monitoring

IMAGING:

• 2D echo

• 3D echo

• Strain

• MUGA

• Cardiac MRI

Echo strain

Visual estimation of LV wall analysis and EF can be quite subjective

Strain: “stretching” used in echo to describe “deformation”

Strain rate: rate by which the deformation occurs

Longitudinal, circumferential, radian strain

Global longitudinal strain:-16 to -22, -20 to -25 variation

Cardiac Magnetic Resonance Imaging for the Assessment of the Myocardium After

Doxorubicin-based Chemotherapy– American Journal of Clinical Oncology

– Lunning, et al 2013

10 patients enrolled received a cumulative dose of doxorubicin of 300 mg/m2. A comparison of pretreatment and posttreatment cMRI demonstrated 5 (50%) patients

with a >=10% decrease in LVEF (median, -8.4%; range, 1% to -17%; P=0.004). Three patients had at least 1 new or progressive segment of GD-DE. The global

circumferential strain was significantly lower in patients after treatment, as compared with values before treatment (P=0.018) and to normal controls (P=0.046).

Patients after treatment also had significantly lower global longitudinal strain than controls (P=0.035), and longitudinal strain values that tended to decrease compared

with pretreatment values (P=0.073).

“ Our data suggests that cMRI has the ability to assess both early structural and functional myocardial changes in association with doxorubicin-based

chemotherapy”

T1 mapping

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Troponin

Cardinale et al. Left ventricular dysfunction predicted by early

troponin I release after high-dose chemotherapy. JACC 2000

204 patients (troponin positive and troponin negative groups)

In cTnI+ patients, a close relationship between the cTnI

increment and the LVEF reduction was found (r = -0.87,

p<0.0001)

BNP

Elevation corresponds with diagnosis of decreased EF in patients with adriamycin cardiomypathy (Koh et al, 2004, Japanese Circulation)

However, only troponin not BNP elevation was positive prior to EF decrease and thus of clinical benefit in predicting development of cardiomyopathy

Myocardial Biopsy

Heart failure associated with suspected anthracyclinecardiomyopathy:

• Class IIa Level of evidence: C

The findings that have been suggested for the diagnosis of doxorubicin cardiomyopathy are loss of myofibrils, distention of sarcoplasmic reticulum, and vacuolization of the cytoplasm.

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Myofibril loss and vacuolization (adria cells)and Diffuse fibrosis

ASE Guidelines

ASE guidelines

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ASE guidelines

ASE guidelines

Prognosis

Cancer Prognosis:

Overall 5-year survival rate for patients with non-Hodgkin’s lymphoma is 63%

High risk NHL 3-year survival is 53%

Breast Cancer 5 year survival rate: stage IV :22%, III: 72% , II: 93%, I : 100%

CHF:

Framingham survival after onset (all class)

– 1 yr 55-60%, 5 yr 25%

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The only independent predictors of LVEF recovery

– time-to-HF treatment

– low NYHA functional class (class I or II)

Cardinale, et al. Clinical Relevance and Response to Pharmacologic Therapy. JACC 2010

Treatment

Maximal medical therapy

Mechanical assistance / Transplantation

Cardio-protective agents

ACE/ARB

Beta-blockers

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ACE inhibitors

Mechanisms of cardiac protection

a) maintain mitochondrial O2

b) prevent the depletion of cellular ATP content

c) lowering the mitochondrial free radical leak

Beta Blockers

-Patients with ACM had a baseline mean left ventricular ejection fraction (LVEF) of 28%, which improved to 41% (P = .041) after treatment with β-blockers.

-The control group had a baseline mean LVEF of 26%, which improved to 32% (P = .015) after treatment.

-The degree of improvement between the 2 groups was not significantly different.

-β-Blockers have a beneficial effect on cardiac function in patients with ACM, which is at least comparable with other forms of heart failure with systolic dysfunction

• β-Blockade in adriamycin-induced cardiomyopathy, Journal of Cardiac Failure. 2000

PRADA“Prevention of Cardiac Dysfunction during adjuvant breast cancer therapy”

-double-blind, placebo-controlled, 2 by 2 factorial design, single center trial

120 patients with early breast cancer

Randomized to

-Candesartan at a starting dose of 8mg and target dose of 32mg

-Metoprolol XL starting at 25mg and a target of 100mg

-placebo

After breast cancer surgery but before the start of anthracycline chemotherapy

Primary endpoint of change in LVEF from baseline

Follow up as short as 10 weeks and as long as 64 weeks, depending on coursed of trastuzumab

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Major Findings:

– 2.6% decline in LVEF from baseline in patients during adjuvant

therapy with anthracyclines with or without trastuzumab in

placebo group

– 0.6% decline in LVEF in the cadesartan group

– No significant difference in the Metoprolol XL arm

Limitations of PRADA

– Small sample size

– Extremely low cardiovascular risk patient cohort

• DM 1.5%, <7% with HTN, baseline EF 63%

Questions raised

-choice of beta blocker

-patient target on higher baseline cardiovascular risk

-outcome measure

Lenneman et al. Heart transplant survival outcomes for adriamycin-dilated cardiomyopathy. 2013, Am J Card

“ Patients who undergo OHT for DCA have favorable 10-year survival, making OHT a good therapeutic option for end-stage heart failure due to anthracyclines. Additionally, no increased risk of cancer-related deaths was found in the DCA group, demonstrating that recurrent malignancy does

not affect long-term survival.”

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Future

Identifying patients at the highest risk

Genetics

• Blanco J, et al. Journal of clinical oncology 2010

• Carbonyl reductases (CBRs) catalyze reduction of anthracyclines to cardiotoxic alcohol metabolites.

• Demonstrated increased anthracycline-related cardiomyopathy risk at doses as low as 101 to 150 mg/m.

• Homozygosis for G allele in CBR3 contributes to increased cardiomyopathy risk associated with low- to moderate-dose anthracyclines, such that there seems to be no safe dose for patients homozygous for the CBR3 V244M G allele.

• “These results suggest a need for targeted intervention for those at increased risk of cardiomyopathy””

“Ideal” risk stratification

Cancer diagnosis specified and optimal chemotherapy regimen proposed

Genetic screening of cancer patient for genetic markers or cardio-toxicity

Tailored Chemotherapy for individual patients

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Back to the case

Pre-treatment Imaging

Echo, MRI, Nuclear, strain?

Medical therapy

Pre and during chemotherapy?

Evaluation post chemo

Lab

Imaging

References1. Watts RG, George M, Johnson WH Jr. Pretreatment and routine echocardiogram

monitoring during chemotherapy for anthracycline- induced cardiotoxicity rarely

identifies significant cardiac dysfunction or alters decisions: a 5-year review at a single

pediatric oncology center. Cancer. 2012 April 1;118(7): 1919-24.

2. Conrad, A, McHugh V, Gundrum R. Utility of routine cardiac ejection fraction (EF)

measurement prior to anthracycline-based chemotherapy (ABC) in patients with diffuse

large b-cell lymphoma (DLBCL). Journal of Clinical Oncology. 2010 28:15.

3. Haq MM, Legha SS, Choksi J, et al. Doxorubicin-induced congestive heart failure in

adults. Cancer 1985; 56:1361-1365.

4. Volkova M, Russell R 3rd. Anthracycline cardiotoxicity: prevalence, pathogenesis and

treatment. Current Cardiology Review. 2011 November; 7(4): 214-220.

5. Eichenauer D, Engert A, Dreyling M. Hodgkin’s Lymphoma: ESMO Clinical Practice

Guidelines for diagnosis, treatment, and follow up. Annals of Oncology 2011;22(6):

55/58.

6. National Comprehensive Cancer Network (NCCN): Guidelines for evaluation and

treatment. 2013.

7. Tilly H, Walewski J, Gomes da Silva M, et al. Diffuse large B-cell lymphoma: ESMO

Clinic Practice Guidelines for diagnosis, treatment, and follow up. Annals of Oncology.

2012;23(7):78-82.

8. Cheitlin M, Armstrong W, Aurigemma G, et al. ACC/AHA/ASE 2003 guideline update

for the clinical application of echocardiography: summary article: a report of the

American College of Cardiology/American Heart Association Task Force on Practice

Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical

Application of Echocardiography). Circulation 2003; 108:1146.

9. Jensen BV, Skovsgaard T, Nielsen SL. Functional monitoring of anthracycline

cardiotoxicity: a prospective, blinded, long-term observational study of outcome

in 120 patients. Ann Oncol. 2002 May;13(5):699-709.

References

10. Zhang S, et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med

2012

11. Von Hoff DD, et al. Risk factors for doxorubicin induced congestive heart failure. Ann Intern Med

12. Blanco J, et al. Anthracycline-related cardiomyopathy in childhood cancer survivors and association

with polymorphisms in the carbonyl reductase genes. J clinical Oncology. 2010

13. Cardinale et al. Left ventricular dysfunction predicted by early troponin I release after high-dose

chemotherapy. JACC 2000

14. Cardinale, et al. Clinical Relevance and Response to Pharmacologic Therapy. JACC 2010

15. Ho et al. Survival after the onset of congestive heart failure in Framingham Heart Study subjects. Circulation 1998.

16. Lenneman et al. Heart transplant survival outcomes for adriamycin-dilated cardiomyopathy. 2013, Am J Card

17. Plana, J, et al. Expert Consensus for Multimodality Imaging Evaluation of Adult Patients during and after Cancer Therapy: A Report from the American Society of Echocardiography and the European Association ofCardiovascular Imaging. J Am Soc Echocardiogr 2014;27:911-39.