MTF research Outline panel: Cancer and massage...MCRF collaborators • Mark H. Rapaport MD • Becky Kinkead PhD • Pamela Schettler PhD ... Berger 2015, Lee 2015, Listing 2009,

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MTF research

panel: Cancer

and massage

Mark Hyman Rapaport,

MD

Outline

• Context

• Massage for cancer-related fatigue

– MCRF

– CRF prostate pilot study

• Relevance

Collaboration

• Collaborative partnership between

– Emory University School of Medicine

– Atlanta School of Massage

reference

MCRF collaborators

• Mark H. Rapaport MD

• Becky Kinkead PhD

• Pamela Schettler PhD

• Sherry Edwards BS

• Boadie Dunlop MD, MS

• Jeffery Rakofsky MD

• Becky Kinkead PhD

• Andrew Miller MD

• Mylin Torres MD

• Erika Larson MS, LMT

• Leticia Allen BA

• Dedric Carroll LMT

• Brittney Turner LMT

• Grace Prior LMT

• Melissa Comer LMT

• Shanese Armstrong-Mark LMT

• Sarah Istambouli LMT

• Suzanne Ledoux BS, LMT

• Aaron Gunn BS, LMT, CPT

• Margaret Sharenko, LMT, CPT

• James Nettles PhD, LMT

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Research personnel

• Principal investigator

• Study physicians

• Oncologist

• Scientists

• Biostatistician

• Research coordinator

• Liaison for Atlanta School of Massage

• Research massage therapists

Kinkead 2018

Funding & ethics

• Grant R21AT007090

– National Center for Complementary &

Integrative Health

– National Cancer Institute

• Ethical approval

– Emory University Institutional Review Board

– Winship Cancer Institute Clinical Translational

Research Committee

Kinkead 2018

Cancer-related fatigue (CRF)

• “a distressing persistent, subjective sense of physical, emotional, and/or cognitive exhaustion related to cancer or its treatment that is not proportional to recent activity” (National Comprehensive Cancer Network)

• Prevalent

• Complex

• Troublesome and disruptive

Berger 2015, Lee 2015, Listing 2009, Narayanan 2017

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Current treatment options for CRF

• Stimulant medication

• Exercise

• Cognitive Behavioral Therapy

• Yoga

reference

Challenges with the current

treatments

• Very small evidence base

• Small clinical effects

• Limited options for the patient

reference

Couzin-Franke 2010, Gorman 2004

Innate immunity/inflammation

reference

Macrophage

Local

Systemic

Local Effects- Increased vascular permeability

- Vasodilation

- Chemokine production

- Expression of adhesion molecules

- Pain

Effects on Brain- Fever

- Fatigue

- Anorexia

- Anhedonia

- Altered sleep

Acute Phase Response

- C-reactive protein

- serum amyloid A

- haptoglobin

- alpha 1-antichymotrypsin

Effects on Liver

Chemokines

Stromal

cell

Endothelial

cell

TNF, IL-1, IL-6, IFN-alpha

Adhesion

molecules

Leukocyte

Diapedesis

Toll-like

receptors

(TLRs)

TNF

IL-1

IL-6

IFN-alpha

NF-κB

sickness behavior

tumorrubor

calor

dolor

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IFN-alpha Alters Basal Ganglia Resting State Glucose Metabolism

Mayberg 2002nce

Cortex

Unipolar Major Depression

+4z

- 4zBasal

Ganglia

Parkinson’sDepression

Parkinson’s and Unipolar PET Scans courtesy of HS Mayberg 2002

F9Cg

P40 P40

insgp

cd

F9Cg

pth ins

P40

IFN-alpha(Post-Pre 4 weeks)

gp

p

th

F9Cg

Correlates with

reduced energy

and activity/fatigue

FDG PET Scans

Basal Ganglia Glutamate Increases Are Associated withDecreased Motivation and Motor Speed in Depression

Haroon 2016

Rationale for use of massage

• Massage can decrease fatigue, pain,

anxiety

• Massage can increase QOL

• People with CRF already utilizing

massage

• Gap in body-of-knowledge

Backus 2016, Bower 2014, Cowen 2017, Finnegan-John 2013, Listing 2009, Vapiwala 2006

Objective & hypothesis

• To investigate effects of 6 weeks of therapeutic massage/bodywork on persistent CRF in survivors of breast cancer

– Primary outcome: MFI

• Hypotheses

– Treatment better than no treatment

– 6 weeks of SMT would improve CRF

– Interventions would be acceptable to subjects

reference

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Experimental design

6 weeks

6 weeks

subjects

WLC

SMT LT

LTSMT

reference

Subject recruitment

• Strict exclusion/inclusion parameters

– Survivors of breast cancer with persistent

CRF

– Surgery plus radiation and/or

chemotherapy/chemoprevention

– Minimal experience with massage therapy

• Active recruitment: Jan 2014 – Feb 2016

• Informed consent

Mendoza 1999

Randomization

• Lists maintained by biostatistics group at Emory University

• Randomly permuted block sizes

• Stratified by BFI item 3

– “Please rate your fatigue (weariness, tiredness) by circling the one number that best describes your WORST level of fatigue during past 24 hours.”

• ≥7 = severe fatigue

• <7 = moderate fatigue

Mendoza 1999

Subject flow

Randomized (n = 66)

Evaluable (n = 57)

Prescreened (n=785)

Screened (n=101)

SMT (n=22)

evaluable (n=20)

LT (n=22)

evaluable (n=20)

WLC (n=22)

evaluable (n=17)

Kinkead 2018

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Assessment scheduleWeek 1 Week 2 Week 3 Week 4 Week 5 Week 6*

BFI

MFI

blood

CPES

CEQ

PROMIS

Q-LES-Q

safety

vitals

AEs

active treatment (SMT, LT) WLC SMT, LT, WLC

*WLC subjects end the no-treatment period and begin 6 weeks of active treatment in week 6, following the above assessment schedule

Outcome measures

• Fatigue– Multi-dimensional Fatigue Inventory (MFI)

– PROMIS Fatigue Short Form 7a (PROMIS)

• Quality of life– Quality of Life Enjoyment & Satisfaction

Questionnaire (Q-LES-Q)

• Preference, credibility, & expectancy– Condition preference/expectancy scales (CPES)

– Credibility/expectancy questionnaire (CEQ)

Interventions

• Manualized, 45-minutes, weekly for 6

weeks

– The Massage Therapy Pressure Scale

– SMT: effleurage, petrissage, tapotement;

primarily pressure level 3 [level 1 – level 3];

unscented, hypoallergenic lubricant

– LT: light contact (pressure level 1), each

position held 5 seconds

Rapaport 2016, Walton

Visit overview

• Meet with research coordinator

– Review of systems, vitals, blood draw, MFI,

PROMIS, Q-LES-Q, safety assessments

• (Baseline visit meet with study physician)

• Receive treatment intervention

• Meet with research coordinator

– Vitals, AEs, questions

• Meet with study physician

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Quality control measures

• Review of session audio recordings

• Quarterly research massage therapist retraining sessions

• Discussions at weekly research personnel meetings

– Treatment notes from research massage therapist

– Subject comments

– Research coordinator feedback

Rapaport 2016

Statistical analysis

• SAS 9.2 software

• Group baseline characteristics

– Analysis of variance (ANOVA) for continuous

measures

– Chi squared

– Fisher’s exact tests

Statistical analysis (cont’d)

• Within & between group changes for fatigue

and QOL outcome measures

– Mixed model repeated measures (MMRM)

– Autoregressive covariance

– Standardized treatment effect sizes

• CEQ computed as recommended & analyzed

in relation to change in MFI within group

• 2-tailed alpha .05 for statistical significance

Subject demographics

Kinkead 2018

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Baseline assessments

• Measure: mean (standard deviation)

[range] all (n=57 ) SMT (n=20) LT (n=20) WLC (n=17)

MFI 59.40(12.42)[32-86]

62.95(9.54)

[44-82]

55.00(12.48)[32-86]

60.41(14.34)[39-84]

PROMIS 22.47(4.04)

[13-33]

22.25(2.77)

[17-28]

22.05(4.42)

[16-33]

23.24(4.91)

[13-33]

Q-LES-Q 66.35(13.80)

[30.4-92.9]

65.26(11.99)

[42.9-85.7]

68.74(9.52)

[50.0-89.3]

64.82(19.43)

[30.4-92.9]

Kinkead 2018

Treatment outcomes

SMT(n=20)

LT(n=20)

WLC(n=17)

F df p

MFI -16.50 (6.37) -8.06 (6.05) +5.88 (6.48) 24.31 2144 < .0001

PROMIS -5.49 (2.53) -3.24 (2.57) -0.06 (1.88) 7.55 2144 = .0008

Q-LES-Q +8.11 (8.20) +1.85 (8.37) -5.78 (8.24) 6.54 2137 = .0019

SMT vs WLC LT vs WLC SMT vs LT

MFI-3.39

(-4.42 to -2.37)-2.09

(-2.90 to -1.28)-1.28

(-1.96 to -0.60)

PROMIS-2.06

(-2.87 to -1.25)-1.20

(-1.90 to -0.49)-0.86

(-1.51 to -0.21)

Q-LES-Q1.64

(0.89 to 2.40)1.64

(0.21 to 1.57)0.74

(0.10 to 1.38)

Change from baseline to week 6 TreatmentXtime interaction

Standardized effect size at week 6 (95% CI)small < .30moderate .30 to .59large ≥ .60

Ranges appropriate for early-phase study of feasibility, efficacy, and safety

Cohen 1992, Kinkead 2018, Nordin 2016, Purcell 2010, Yost 2011

Credibility, expectancy, preference

• Preference for SMT to LT

– 52 (78.8%) of 66 randomized subjects

– 44 (77.2%) of 57 evaluable subjects

• SMT ranked as more logical therapy for

decreasing CRF

• Expectancy of assigned intervention to

improve CRF not significantly higher for

SMT

Safety

• AEs assessed each visit

– Bruising at venipuncture site (12/39)

– Hyperextension from lying on massage table

(2/39)

– no difference between treatment groups

• No SAEs reported

Cambron 2007

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Limitations

• Small early-phase study of feasibility,

efficacy, and safety

• Fatigue is highly subjective and complex

– May be related to factors not assessed

• Focused on short-term effects

• Research massage therapy vs community

massage practice

Treatment outcome overview

• Change from baseline to week 6

• Significant treatment-by-time interaction

• Large standardized treatment effect sizes

SMT(n=20)

LT(n=20)

WLC(n=17)

MFI * * *

PROMIS * * no change

Q-LES-Q

fatigue

QOL

*Indicates statistical significance

Experimental design

6 weeks

6 weeks

subjects

WLC

SMT LT

LTSMT

reference

Pilot study: CRF

• To investigate effects of 6 weeks of therapeutic massage/bodywork on persistent CRF in survivors of prostate cancer

– Primary outcome: MFI

• Hypotheses

– Treatment better than no treatment

– 6 weeks of SMT would improve CRF

– Interventions would be acceptable to subjects

reference

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Pilot study: CRF

• Similar experimental design to MCRF

• Incorporating technology

– Activity monitor

– Self-report questionnaires

reference

“Your Fantastic Mind”

• Episode 3.2 "Massage Therapy for

Anxiety, Depression and Cancer Fatigue”

Emory University & Georgia Public Broadcasting 2019

https://youtu.be/faW57xzY6H4

Relevance

• More individuals with CRF may seek

massage as a treatment option

– Safely translating to community practice?

• Collaboration beneficial

– Scientists and massage therapists

– Potential for inclusion of massage therapy in

oncology group

Cowen 2017

Future directions

• Conduct a larger trial as a definitive test of

efficacy and safety of massage for persistent

CRF in survivors of breast cancer

• Investigate other cancer types

• Include a follow-up period to determine

duration of effects

• Further characterization of fatigue

• Expand role of research massage therapists

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Thank you NCCIH for funding

this work