optimizing cardiac health in cancer patients through...

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Optimizing Cardiac Health in Cancer Patients through Exercise

Jessica Scott, PhDExercise Oncology Service

Memorial Sloan Kettering Cancer [email protected]

Twitter: @cardiac_fitness

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No Disclosures

I have no financial relationships to disclose.

I will not discuss off label use and/or investigational use in my presentation.

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Increasing Number of Long Term Cancer Survivors

1920s

Radiation Therapy

1950s

Systemic Therapy

1970s

Screening

2000s

Targeted Therapy

Nu

mb

er o

f Su

rviv

ors

3.6M

16M

26M

2040

ICI

Increased risk of treatment late-effects

& competing causes of mortality

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Cancer Therapy-Induced Cardiovascular Disease

1. Heart Failure Reduced

Ejection Fraction

2. Coronary Artery Disease

3. Heart Failure Preserved

Ejection Fraction

Scott et al. Can J Cardiol., 2016

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Bone Demineralization

Gastrointestinal Events

Immune Dysfunction

Cardiac Atrophy

Skeletal Muscle Atrophy

Exercise Intolerance

Cognitive Impairments

Anemia ‘Direct’ HitCancer / Cancer therapy

‘Indirect’ HitSecondary to cancer /

therapy(e.g., deconditioning)

Baseline risk factorsSmoking, hypertension, age

Cancer Patient

Multiple Hit-Induced Multisystem Deconditioning

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“Accelerated” Cardiovascular Aging

Koelwyn& Jones. J ClinOncol, 2012

10%-20% decrease in VO2peak during treatment

VO2peak remains 30% lower compared to

controls

Long-term cancer survivors 20%-50% increase in CV

events

Multisystem Toxicity Across the Cancer Continuum

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Pulmonary diffusion • no change

Cardiac function • stroke volume• heart rate• cardiac output

Arterial/endothelial function• nitric oxide• angiogenic factors

Skeletal muscle function• mitochondrial size & number• capillarization

Exercise Training to Off-Set the Multiple-Hit

Lakoskiet al.. Nature Rev Clin Oncol, 2012

↑ Cardiorespiratory fitness↓ Fatigue↓ CV risk factors

↓ Chronic morbidity↓ Overt CVD

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Exercise: Standard of Care

Heart disease

Astronauts

Diabetes

Chronic lung disease

Cancer

✓

?

✓

✓

✓

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‘Direct’ HitMicrogravity

‘Indirect’ HitSecondary to microgravity

(e.g., deconditioning)


Bone Demineralization

Gastrointestinal Events

Immune Dysfunction

Cardiac Atrophy

Skeletal Muscle Atrophy

Exercise Intolerance

Cognitive Impairments

Anemia ‘Direct’ HitCancer / Cancer therapy

‘Indirect’ HitSecondary to cancer /

therapy(e.g., deconditioning)


Astronaut Cancer Patient

Multiple Hit-Induced Multisystem Deconditioning

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Spaceflight Countermeasures Program: 1960s1. Phenotyping 2. Exercise During Spaceflight

1965 intervention: 3x10 minutes/day for 14 days

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Spaceflight Countermeasures Program: Current1. Phenotyping

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Spaceflight Countermeasures Program: Current

Prehabilitation

Exercise to

augment reserve

Habilitation

Exercise to

mitigate decline

Rehabilitation

Exercise to return to

baseline levels

1. Phenotyping 2. Exercise Across the Spaceflight Continuum

EXONC SERVICEKoelwyn & Jones J Clin Oncol, 2012

2. Can exercise during therapy mitigate decline / improve

outcomes?

3. Can exercise after therapy or advanced

disease reverse decline / improve outcomes?

4. What is optimal exercise dose / delivery?

% P

hys

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al

Res

erv

e

1. Can exercise prior to therapy augment reserve / improve

outcomes?

Major Gaps in Exercise Oncology


% P

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1. Can exercise prior to therapy augment reserve / improve

outcomes?

Major Gaps in Exercise Oncology

EXONC SERVICEMoore et al. JAMA Intern Med, 2016

Cancer Prevention

Observational Evidence: Cancer and Cardiovascular RiskPre-Diagnosis

Non-Metastatic Breast Cancer (n=4,015)

0

0.2

0.4

0.6

0.8

1

Haz

ard

Rat

io (

CV

D E

ven

ts)

<2.5 2.51-8.6 8.7-18.0 >18.0

37%

Palomo et al. ACC, 2017

CVD Prevention

Favors exercise Favors inactivity

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-10 0 10 20

• n=5 studies

• 205 patients

• 78% male

• GI, NSCLC, Liver, Bladder,

Prostate

• Median 4 week intervention

Scott et al., J Clin Oncol. 2018

Favors exerciseFavors control

Meta-Analysis: VO2peak Pre-therapy

Exercise improves

VO2peak:

MWD: +2.36 mL/kg/min

Pre-therapy

Laukkanenet al., Mayo Clin Proc. 2016

1.0 mL/kg/min increase in VO2peak associated with an

adjusted 9% reduction in

all-cause mortality

EXONC SERVICESebioGarcia. et al., Interact Cardiovasc ThoracSurg, 2016

Exercise reduces post-operative complications:

55% reduced risk

Meta-Analysis: Post-Operative ComplicationsPre-therapy

• n=7 studies

• 548 patients

• 62% male

• Lung cancer


Exercise decreases hospital stay: 5 fewer days


2. Can exercise during therapy mitigate decline / improve

outcomes?

% P

hys

iolo

gic

al

Res

erv

eMajor Gaps in Exercise Oncology

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-10 0 10 20

• n=14 studies

• 980 patients

• 31% male

• Breast, prostate, lung, hematological




Meta-Analysis: VO2peak During therapy

Exercise improves

VO2peak:

MWD: +1.37

mL/kg/min

Pre-therapy

During therapy

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• n=13 studies

• 1152 patients

• 43% male

• Breast, prostate


Meta-Analysis: Muscle During therapy

Exercise improves

muscle strength:

MWD: +26 kg

Exercise improves

lean body mass:

MWD: +0.8 kg

Padilhaet al. J Cancer Surviv,2017


3. Can exercise after therapy or advanced

disease reverse decline / improve outcomes?

% P

hys

iolo

gic

al

Res

erv


EXONC SERVICESchmid et al., Ann Oncol, 2014

Breast

RR for All-Cause Mortality, 95% CI

0.0 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.0

Colorectal

Irwin et al., 2008

Holick et al., 2008

Irwin et al., 2011

Beasley et al., 2012

Kuiper et al., 2012

Meyerhardt et al., 2006

Campbell et al., 2013

Meyerhardt et al., 2009

Baade et al., 2011

Meyerhardt et al., 2006Limitations

▪ Small sample sizes (mean, ~3,000 patients)▪ Limited follow-up (<4 years from diagnosis) ▪ Few assessed change in exercise

Observational Evidence: Exercise and Mortality

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• n=15,450 adult survivors of childhood cancer• ~18 years post-diagnosis at baseline• Cumulative incidence at 15 years

0 MET-hrs/weekN=5059

15-18 MET-hrs/weekN=1669

Death from any cause 5.7%11.7% P<0.001

Death from recurrence/progression 1.4% 1.0%P=0.10

Death from health-related causes 8.7% 4.1%P<0.001

Post-Diagnosis Exercise and Cause-Specific Mortality

Scott et al., JAMA Oncol., 2018

Exercise in early adulthood associated with a 42% reduction in all-cause mortality

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Change in Exercise and All-Cause Mortality

Referent

RR for all-cause mortality, 95% CI

0.0 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.0

1.01 (0.81 to 1.27)

Low maintenance (n=1677)

Decreased exposure (n=2279)

0.60 (0.44 to 0.82)Increased exposure (n=1174)

0.56 (0.36 to 0.88)High maintenance (n=559)

•n=5,689• 8 yrs

Scott et al., JAMA Oncol., 2018

0

-6

+6

0

MET-hrs/week change

Baseline Follow up 2

Increased or high exercise over 8 years associated with ~40% reduction in

all-cause mortality

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-10 0 10 20

• n=27 studies

• 1774 patients

• 26% male

• Breast, colorectal, prostate, lung,

testicular, brain




Pre-therapy

During therapy

Post-therapy

Exercise improves

VO2peak:

MWD: +2.45

mL/kg/min

Meta-Analysis: VO2peak Post-therapy

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Exercise RCT in Metastatic Breast CancerAdvanced disease

Safety:- Serious AE: 0%- Non-serious AE (fatigue, pain): 10%

Feasibility:- Dose modification: 49%- Dose interruption: 46%- Relative dose intensity: 61%

Aerobic training at the dose and schedule tested is safe but not feasible for a significant proportion of

patients with metastatic breast cancer

Scott et al., Cancer, 2018

EXONC SERVICEKoelwyn& Jones. J ClinOncol, 2012

5%-10% increase in VO2peak pre/during

treatment

10-20% increase in VO2peak post treatment

20%-40% decreased risk of CV events

Summary I: Exercise Training Across the Cancer Continuum

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Existing

CVDNone

Impairment in Physical

Functioning - Speech

Cardiac

SymptomsHx MI or PCI/CABG,

↓LVEF, valvular dxNone

Low-dose

anthracycline

+ trastuzumab

Low-dose anthracycline

or trastuzumab + ≥2 RF,

or age ≥ 60 yrs

High-dose

anthracycline/

radiotherapy*

None

or

other

Cardiopulmonary

exercise test

Oncology/Cancer

rehabilitationCardio-oncology

rehabilitation exercise

(CORE)

Community-based

programs for cancer

patients

CV

consult

PT /OT / speech

consult

No symptoms/dxAfter exposure, assess symptom/dx

No symptoms/dx

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NCCN: Delingeret al. NCCN2014

ACS: Rock et al. CA Cancer J Clin, 2012

ACSM: Schmitz et al. Med SciSports Exer, 2010

ACS...Avoid inactivity

....≥150 mins/wk of mod-

intensity or ≥75 mins/wk

vig-intensity aerobic

activity

....greater benefits: ≥300

mins/wk of mod-intensity

or ≥150 mins/wk vig-

intensity aerobic activity

“ ”“

”“

”

ONE SIZE, FITS ALL!

Research Gaps

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Current Practice“One size fits all”

Positive responders

Non responders

Personalized MedicinePrecision exercise prescription

Risk stratification

Risk Stratification and Precision Exercise

One size fits all

Positive responders

Scott et al., Circulation, 2018


4. What is optimal exercise dose / delivery?

% P

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External Load Internal Load

Non-Cancer

Internal Exercise LoadCycling at 350W

(75% VO2peak) for 60 min

Patient

External Load Internal Load

Exercise Training Load –Adaptation ResponseExercise dosing

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Desired Physiological Adaptation or Study

Outcome

Effects of theDisease/Therapy

Patient Limitations

Comorbidities / Confounders

Exercise Training Prescription

Exercise Program Design Considerations Exercise dosing

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Principles of Exercise TrainingExercise dosing

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Cardiac Function

Blood Volume

&RBCs

Vasodilatory

Signaling

Neuromuscular Function

Metabolic

Adaptation

Mitochondrial Biogenesis

Autonomic Regulation

VT1/ LT1 VT2/ LT2 VO2peak

Zone 1 – Recovery Zone 2 – LSD Zone 3 – Tempo Zone 5 – IntervalsZone 4 – Threshold

CapillaryDensity

Exercise SpecificityExercise dosing

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% In

ten

sity

50

100

0

0 63

Months

Non-linear

% In

ten

sity

50

100

0

0 63

Months

Linear, moderate intensity

100

00 63

Months

50

Linear, high intensity

? Safe ✓ Moderate efficacy

Current guidelines Alternative 1 Alternative 2

X Questionable safety ✓High efficacy

✓ Adheres to principles of exercise training

% In

ten

sity

Exercise SequencingExercise dosing

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1. Multisystem Physiologic Characterization

2. Individualized Exercise Prescription

3. Supervised Physiologic Monitoring and Data Capture

Vascular

Blood

Cardiac

VO2peak

MSK Exercise Oncology Approach

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Risk Stratification Prescription

Standard exercise guidelinese.g., 3d/wk, 30-60 min/session at 70%-80% of peak heart rate

VO2peak-based prescriptione.g., 3d/wk, 30-60 min/session with each session at individualized VO2-based intensity zones

High CV risk + CPETe.g., clonal hematopoiesis

ASCO cardiotoxicity guidelinese.g., patients receiving high-dose anthracycline

Scott et al. Circulation, 2018

Future Directions

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Bone Marrow

Normal HSC

HSC + 1 Mutation

HSC + 2 Mutations

Extrinsic: Radiation, Chemotherapy

Intrinsic: Aging

...

....

..

......

...

High CV Risk: Clonal Hematopoiesis (CH)

..

..

..

..

..

..

Peripheral Blood

Myeloid cells

Lymphoid cells

. .. ... ..

....

.. . .

Proinflammatory

mediators

Organs

HFrEF

CAD

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Baseline Follow-Up

EXERCISE

Study Cohort

- Confirmed CH

- Completion of therapy

for solid tumors

- Inactive (<150 min/wk)

DYNAMIC LIFESTYLE MONITORINGASSESSMENTS ASSESSMENTS

6

MONTHS

Exercise as Interception Therapy for CHFuture directions

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4

2

A K T I V A G A I N S T

C A N C E R E X E R C I S E

O N C O L O G Y C E N T E R

M A N H A T T A N

42

Exercise Training Delivery

3 days/week, for 20-60 mins

Future directions

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Delivery Set-up and Device Integration Real-Time Monitoring

Tele-ExerciseFuture directions

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R O C K V I L L E C E N T R E

M O N M O U T H

B R O O K L Y N

C O M M A C K

H A U P P A U G EB E R G E N

W E S T C H E S T E R

B A S K I N R I D G E

A K T I V A G A I N S T

C A N C E R E X E R C I S E

O N C O L O G Y C E N T E R

M I S S I O N C O N T R O L

Exercise Training DeliveryFuture directions

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Conclusions

• Cancer treatment :

– accelerates cardiovascular aging

– increases risk of competing causes of morbidity & mortality

• Exercise therapy:–mitigates accelerated cardiovascular aging

– one size does not fit all

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MSK• Lee Jones

• Chau Dang

• Anthony Yu

• Pedram Razavi

Exercise-Oncology Team

Acknowledgments

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Optimizing Cardiac Health in Cancer Patients through Exercise

Jessica Scott, PhDExercise Oncology Service

Memorial Sloan Kettering Cancer [email protected]

Twitter: @cardiac_fitness

optimizing cardiac health in cancer patients through...

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