The Latest in Cardio-Oncology

Guidelines

Greg Armstrong, MD, MSCE

Department of Epidemiology and Cancer Control

Armenian SH, et al Lancet Oncol. 2015 Mar; 16(3)

Harmonizing Cardiomyopathy

Surveillance Recommendations

After Treatment of Childhood Cancer

Screening guidelines

Definitions: AHA/ACC

Stage A

High risk for HF but

w/o structural

disease or symptoms

Stage B

Structural heart

disease but w/o

symptoms of HF

Stage C

Structural heart

disease with

symptoms of HF

Stage D

Refractory HF

requiring

interventions

At Risk for Heart Failure (HF) Clinical Heart Failure (HF)

InterventionScreening

Childhood cancer survivorsTreated for cancer up to 21 years of age, regardless of current age

Anthracycline chemotherapyDoxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone

Chest radiationAny radiation in which the heart was in the field of treatment

-Mediastinal, thoracic, spinal, left or whole abdominal, TBI

Asymptomatic cardiomyopathyDecline in LV systolic function (abnormal EF, SF, wall stress)* or diastolic function (abnormal E/A, prolonged IVRT)* in the context of preserved EF, without corresponding symptoms of heart failure

Heart failure (HF)Symptomatic cardiomyopathy with evidence of cardiac dysfunction on imaging studies (ACC/AHA)

*JACCC 1995, 26:1039; J Clin Oncol 2007, 25:3635; J Am Soc Echocardiogr 2008, 21:922; Eur Heart Jour 2003, 24:320

Definitions

Grading system

Grade of

Recommendation

Conclusions of evidence

(based on GRADE* )

I

Strong

recommendation

to do

Benefits >>> risk &

burdens

IIa

Moderate

Recommendation

to do

Benefits >> risk & burdens

IIb

Weak

recommendation

to do

Benefits >= risks &

burdens

III

Recommendation

not to do

No benefit / Potentially

harm

A High level of evidence

Consistent evidence from well

performed and high quality studies

or systematic reviews (low risk of

bias, direct, consistent, precise).

Strong

recommendation

based on high level of

evidence

Moderate

recommendation based on

high level of evidence

Weak

recommendation

based on high level of

evidence

Recommendation based

on high level of evidence

B Moderate /Low level of evidence

Evidence from studies or systematic

reviews with few important

limitations.

Strong

recommendation

based on moderate/

low level of evidence

Moderate

recommendation based on

moderate/ low level of

evidence

Weak

recommendation

based on moderate/

low level of evidence

Recommendation based

on moderate/ low level of

evidence

C Very low level of evidence

Evidence from studies with serious

flaws.

Only expert opinion, or standards

of care.

Strong

recommendation

based on expert

opinion

Moderate

recommendation based on

very low level of evidence

Diverging expert opinions

Weak

recommendation

based on very low level

of evidence

Diverging expert

opinions

Recommendation based

on very low level of

evidence

Expert opinion

Wording in Recommendation We recommend…

Should be performed

Is recommended

Is indicated

Is useful

Is beneficial

Is effective

We suggest…

Is reasonable

Is probably recommended

Can be useful

Can be beneficial

Can be effective

We might suggest

Might be reasonable

Might be considered

Usefulness is unknown

We do not recommend

Should not be performed

Is not useful

Is not beneficial

Is not effective

Is potentially harmful

Who is at risk?

HF risk by anthracycline dose

Blanco JG, et al. J Clin Oncol. 2012 Van der Pal HJ, et al. J Clin Oncol. 2012

High

Moderate

Low

Who is at risk?

HF risk by RT dose

Mulrooney et al. BMJ 2009

No cardiac RT 1.0†

< 500 cGy 0.9 (0.6 to 1.4)

500 to < 1500 cGy 1.3 (0.7 to 2.5)

1500 to < 3500 cGy 2.2 (1.4 to 3.5)

> 3500 cGy 4.5 (2.8 to 7.2)

Cardiac RT dose and HF risk

Definition of risk

Risk GroupAnthracycline

(mg/m2)

Radiation

(Gy)Combined Rx

High> 250 > 35 ≥100 Anthracycline

+ ≥ 15 Radiation

Moderate 100 to < 250 > 15 to < 35 --

Low < 100 --

Cardiomyopathy surveillance is recommended for

survivors treated with high dose (≥ 250 mg/m2)

anthracyclines.

Cardiomyopathy surveillance is reasonable for survivors

treated with moderate dose (> 100 to < 250 mg/m2)

anthracyclines.

Who needs surveillance?Anthracyclines

Cardiomyopathy surveillance may be reasonable for

survivors treated with low dose (< 100 mg/m2)

anthracyclines.

Who needs surveillance?Chest radiation

Cardiomyopathy surveillance is recommended for

survivors treated with high dose (> 35 Gy) chest

radiation.

Cardiomyopathy surveillance may be reasonable for

survivors treated with moderate dose (> 15 < 35 Gy)

chest radiation.

No recommendation can be formulated for cardiomyopathy

surveillance for survivors treated with low dose (< 15 Gy)

chest irradiation with conventional fractionation.

Who needs surveillance?Anthracyclines + Chest radiation

Cardiomyopathy surveillance is recommended for survivors

treated with moderate-high dose anthracyclines (> 100 mg/m2)

and moderate-high dose chest radiation (> 15 Gy)

No recommendation can be formulated for surveillance:

- Younger (<5 years) age at exposure

- Dexrazoxane

- Different strategies by anthracycline analogue

Echocardiography is recommended as the primary cardiomyopathy

surveillance modality for assessment of cardiac function in survivors

treated with anthracyclines and/or chest radiation

What surveillance modality

should be used?

Radionuclide angiography or cardiac magnetic resonance imaging (CMR)

may be reasonable for cardiomyopathy surveillance in at risk survivors

for whom echocardiography is not technically feasible/optimal.

In instances where both imaging modalities are available, preference should be

given to CMR due to its lack of ionizing radiation exposure and potential for

additional information regarding cardiac structure and function.

What surveillance modality

should be used?

Assessment of cardiac blood biomarkers is not recommended as

the only strategy for cardiomyopathy surveillance in at risk

survivors.

- Poor correlation between cTn and asymptomatic

cardiomyopathy in long-term survivors

- NP’s: high negative predictive values (63-100%), low

sensitivity (0-32%) and PPV (12.5-37.5%) when used alone

Assessment of cardiac blood biomarkers (NPs) in conjunction

with imaging studies may be reasonable in instances where

symptomatic cardiomyopathy is strongly suspected or in

individuals who have borderline cardiac function during primary

surveillance.

At what frequency should surveillance be

performed?

High Risk survivors

Cardiomyopathy surveillance is recommended for High

Risk survivors to begin no later than 2 years after

completion of cardiotoxic therapy, repeated at 5 years

after diagnosis and continued every 5 years thereafter.

More frequent cardiomyopathy surveillance is reasonable

for High Risk survivors.

Lifelong cardiomyopathy surveillance may be reasonable

for High Risk survivors.

At what frequency should surveillance be

performed?

Pregnancy

Cardiomyopathy surveillance is reasonable prior to pregnancy or

in the first trimester for all female survivors treated with

anthracyclines and/or chest radiation

No recommendations can be formulated for the frequency of

ongoing surveillance in pregnant survivors who have normal cardiac

function immediately prior to or during the first trimester of

pregnancy.

“Health care providers should maintain a high index of suspicion for

cardiomyopathy in survivors treated with anthracyclines and/or radiation

who present with symptoms such as shortness of breath, fatigue, and ankle

swelling, as these are commonly reported during pregnancy.”

Cardiology consultation is recommended for survivors with

asymptomatic cardiomyopathy following treatment with

anthracyclines and/or chest radiation.

What should be done when abnormalities

are found?

Pediatric HF guidelines: J Heart Lung Transplant. 2004; 23: 1313

Adult HF guidelines: Eur J Heart Fail. 2008; 10(10): 933

Circulation. 2009; 119(14): e391

What are limitations for physical activity?

Regular exercise, as recommended by the AHA and ESC*,

offers potential benefits to survivors treated with

anthracyclines and/or chest radiation.

Regular exercise is recommended for survivors treated with

anthracyclines and/or chest radiation who have normal

cardiac function.

Cardiology consultation is recommended for survivors with

asymptomatic cardiomyopathy to define limits and

precautions for exercise.

* Circulation 2007, 116(9): 1081-93 ; Circulation. 2007; 115(17): 2358-68

What are limitations for physical activity?

• Individuals at risk for cardiomyopathy due to genetic disorders (i.e.: familial dilated cardiomyopathy, hypertrophic) but normal cardiac function

AHA & ESC recs: no restrictions on physical activity

- Circulation 2004, 109(22): 2807-16; Eur jour of cardiovasc prev and rehab 2006, 13(6): 876-85

Cardiology consultation may be reasonable for High Risk

survivors who plan to participate in high intensity* exercise

to define limits and precautions for physical activity.

*Circulation. 2004; 109(22): 2807-16

Role of modifiable CV risk factors*

*Blood 2012, 120:4505-4512; J Clin Oncol 2013, 31(29): 3673-80

Screening for modifiable CV risk factors (hypertension,

diabetes, dyslipidemia, obesity) is recommended for all

survivors treated with anthracyclines and/or chest radiation

so that necessary interventions can be initiated to help avert

the risk of symptomatic cardiomyopathy.

Jako Burgers and Kevin Oeffinger for critically appraising the

recommendations and the manuscript as external reviewers.

Experts of the International Late Effects of Childhood Cancer Guideline

Harmonization Group and PanCareSurfUp Consortium:

Smita Bhatia, Wendy Landier, Edit Bárdi, Eva Frey, Riccardo Haupt,

Claudia Kühni, Gisela Michel, Flora van Leeuwen, Cecile Ronckers, Berthe

Aleman, Gregory Armstrong, Eric Chow, Richard Cohn, Junichiro

Fujimoto, Satomi Funaki, Daniel Green, Tara Henderson, Lars Hjorth,

David Hodgson, Hiroyuki Ishiguro, Shunichi Kato, Chikako Kiyotani, Miho

Maeda, Michael Schaapveld, Jane Skeen, Charles Sklar.

Acknowledgements

Maron BJ, Chaitman BR, Ackerman MJ, et al: Recommendations for

physical activity and recreational sports participation for young patients with

genetic cardiovascular diseases. Circulation 109:2807-16, 2004

• Identify Working Groups to address 4 overarching Q’s - 10-12/11

• Refine clinical questions: Concordance, Discordance - 2/12

• Evidence tables (Concordance/Discordance) - 4/12

• Conclusion of the Evidence – 5/12

– Overall conclusions, Grading

• Formulation of Recommendations – 6/12-3/13

• Manuscript preparation – 4/13-10/13

• Expert panel external review – 11/13-12/13

• Submission for publication – 1/14

Steps to Harmonization: Timeline