MTF research Outline panel: Cancer and massage...MCRF collaborators • Mark H. Rapaport MD •...
Transcript of MTF research Outline panel: Cancer and massage...MCRF collaborators • Mark H. Rapaport MD •...
10/15/2019
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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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References
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Thank you NCCIH for funding
this work