Physical-Based Therapeutic Approaches for Cancer-Related Pain

Physical-Based Therapeutic Physical-Based Therapeutic Approaches for Cancer-Related PainApproaches for Cancer-Related Pain

Lee W. Jones, Ph.DLee W. Jones, Ph.DDepartment of SurgeryDepartment of Surgery

Duke University Medical CenterDuke University Medical Center

22ndnd Annual Pain Management Symposium Annual Pain Management SymposiumJune 6June 6thth, 2008, 2008

Presentation Outline

• Brief Overview of Cancer-Related Pain (CRP)Brief Overview of Cancer-Related Pain (CRP)• Management of CRPManagement of CRP• Role of Physical-Based Approaches for CRPRole of Physical-Based Approaches for CRP• Future Directions Future Directions

Brief Overview of CRP

Overview of CRP• 30% to 50% undergoing therapy30% to 50% undergoing therapy• 70% to 90% advanced disease70% to 90% advanced disease• Bone pain most common (>75% related to Bone pain most common (>75% related to

neoplastic invasion)neoplastic invasion)• CRP SyndromesCRP Syndromes

• NociceptionNociception - damage to pain receptors - damage to pain receptors• NeuropathicNeuropathic - nerve damage (peripheral - nerve damage (peripheral

neuropathy)neuropathy)• Treatment-related painTreatment-related pain – damage to – damage to

receptors by Sx, RT, CT, & ETreceptors by Sx, RT, CT, & ET

The Symptom Cluster

PAINPAIN

FATIGUEFATIGUE

DISTRESSDISTRESS

FUNCTIONFUNCTIONDECLINEDECLINE

↓↓↓↓ QOLQOL

Management of CRP

Management of CRPPharmacologic ApproachesPharmacologic Approaches

• Opoids / Analgesics / NSAIDs Opoids / Analgesics / NSAIDs • Bisphosphonates / new approachesBisphosphonates / new approaches• Inadequate pain reliefInadequate pain relief• Not benign (GI toxicity / cog dysfunction)Not benign (GI toxicity / cog dysfunction)

Non-Pharmacologic ApproachesNon-Pharmacologic Approaches• Surgery / psychological (grp Surgery / psychological (grp

psychotherapy / stress management, etc.)psychotherapy / stress management, etc.)• Address physical dimensions??Address physical dimensions??

Role of Physical-Based Approaches for CRP

Types of Physical-Based Approaches• YogaYoga

• mediation, gentle postures, breathing exercises mediation, gentle postures, breathing exercises • Tai ChiTai Chi

• Meditative form of exercise & postures Meditative form of exercise & postures • Structured Exercise TrainingStructured Exercise Training

• Bodily activity aim of improving fitness & healthBodily activity aim of improving fitness & health• Physical / Rehabilitation TherapyPhysical / Rehabilitation Therapy

• Prevention, management, & tx of movement Prevention, management, & tx of movement disordersdisorders

Review of Literature

• >50% of exercise studies conducted in early-stage >50% of exercise studies conducted in early-stage breast cancer patientsbreast cancer patients

• >50% completed during treatment>50% completed during treatment

• Majority tested aerobic-based interventionsMajority tested aerobic-based interventions

• Cycle ergometry/treadmill walking Cycle ergometry/treadmill walking

• 3d.wk for 6-24 weeks, moderate intensity3d.wk for 6-24 weeks, moderate intensity

• Adherence levels (if reported) > 70%Adherence levels (if reported) > 70%

Jones & Demark-Wahnefried. Lancet Oncol 2007

Review of Literature• All reported significant benefits• No adverse events

• Multiple Biopsychosocial Outcomes

Physiologic Outcomes – exercise capacity, body comp, NK activity, flexibility

Tx-Related Symptoms – fatigue, pain, nausea, diarrhea, platelet transfusion, hospital stay

QOL Outcomes – overall, PWB, FWB, SWB, SWL, anx/dep

Jones & Demark-Wahnefried. Lancet Oncol 2007

Prior Work• Examined potential role of exercise in the following:Examined potential role of exercise in the following:

DescriptiveDescriptive InterventionIntervention

Early-Stage Breast Cancer Early-Stage Breast Cancer Metastatic BreastMetastatic Breast

Non-Hodgkins LymphomaNon-Hodgkins Lymphoma Inoperable NSCLCInoperable NSCLC

Multiple MyelomaMultiple Myeloma Preoperative NSCLCPreoperative NSCLC

Primary Brain CancerPrimary Brain Cancer Neoadjuvant BreastNeoadjuvant Breast

EndometrialEndometrial Adjuvant NSCLCAdjuvant NSCLC

ColorectalColorectal Anemic Cancer PtsAnemic Cancer Pts

ProstateProstate NHL NHL

Prior Clinical TrialsPrior Clinical Trials

REHAB Trial• Examined the effects of endurance training on

exercise capacity, QOL, & biologic outcomes in PM breast cancer survivors

Courneya, Jones et al. Courneya, Jones et al. JCO JCO 20032003

Aims

• Effects on QOL (FACT-B) and exercise capacity (VO2peak)

• Effects on metabolic hormones (insulin, IGF-1, IGFBPs), & CV risk factors (BP, CRP, etc.)

REHAB Trial

MethodPatients and Eligibility

• Histologically confirmed (stage I-IIIa) breast cancer

• No evidence of metastatic or recurrent disease

• Completion of primary adjuvant therapy

• Postmenopausal

• No significant or recent CV disease

• Recruitment letter sent to all potentially eligible participants following physician approval


REHAB Trial

Patient CharacteristicsAll Cases

n=53Exercise

n=24Control n=28

Mean / % Mean / % Mean / %

Mean Age (yrs) 59 59 58

BMI (kg/m2) 29 29 29

Stage I 40% 42% 39%

Chemotherapy 40% 42% 39%

Radiotherapy 71% 67% 75%

Endocrine 46% 46% 46%


REHAB Trial

Results – Exercise Capacity - ITT

10

15

20

25

30

VO2 (mL.kg.min)

Baseline 15 weeks

EGCG

2.7 mL.kg.min within group (↑ 17.4%) (p<.001)3.4 mL.kg.min between groups


REHAB Trial

Results – QOL

100

105

110

115

120

125

FACT-B (0-140)

Baseline 15 weeks

EGCG

+9.1 points within group (clinically meaningful) (p<.001)+8.8 between groups


REHAB Trial

Results – Fatigue

5

10

15

20

FACT - Fatigue (0-52)

Baseline 15 weeks

EGCG

-9.3 points within group (clinically meaningful) (p<.006)-7.3 between groups

EG ↑ fatigue (adjusted analyses)


REHAB Trial

Other ResultsMetabolic Hormones (Fairey et al. CEBP, 2003)

• No differences in fasting insulin, glucose, insulin resistance, or IGFBP-1

• Differences in IGF-1 & IGFBP-3

CVD Risk Factors (Fairey et al. Brain Behav Immun 2005)

• Non-significant reductions in CRP (↓ 1.39 mg/L)

• Non-significant reductions in SBP (↓ 5.5 mm Hg), DBP (↓ 3.6 mm Hg), & HDL-C (↑ 0.05 mmol/L)

EXTRA Trial• Determine if a 12-week endurance exercise

training program can improve QOL in anemic pts receiving Aranesp

Sponsored by Amgen Inc,

Aims

• Effects on QOL (FACT-An), fatigue, exercise capacity (VO2peak)

• Effects on Hb response & dosing requirement

EXTRA Trial

MethodPatients and Eligibility

• Histologically confirmed solid tumors

• Hb level between 80 & 110 g/L

• Expected survival ≥3 months

• No significant or recent CV disease

• Identified via central screening

EXTRA Trial

Participant Characteristics

All Casesn=55

DA Alonen=29

DA+EX n=26

Mean / % Mean / % Mean / %

Mean Age (yrs) 56 54 58

Breast Cancer Dx 60% 62% 58%

Stage IV 47% 38% 57%

Chemotherapy 92% 90% 96%

Prior transfusion 20% 24% 15%

Heart Disease 16% 17% 14%

EXTRA Trial

Results – Exercise Capacity - ITT

10

15

20

25

30

VO2 (mL.kg.min)

Baseline 12 weeks

DA+ EXDAL

3.5 mL.kg.min within group (↑ 22%) (p<.001)3.0 mL.kg.min between groups

Courneya, Jones et al. Courneya, Jones et al. JCO JCO SubmittedSubmitted

EXTRA Trial

Results – QOL

115

120

125

130

135

140

145

150

FACT-An (0-188)

Baseline 12 weeks

DA+ EXDAL

+13.4 points within group (clinically meaningful) (p=.637)-6.9 between groups

Courneya, Jones et al. Courneya, Jones et al. JCO JCO SubmittedSubmitted

EXTRA Trial

Results – Hb Outcomes

NSCLC Pre-Op Study

• Determine the feasibility of pre-operative exercise training for patients undergoing surgical resection for NSCLC

Aims

• Determine feasibility of exercise training

• Determine the effects of exercise training on exercise capacity, QoL, & biologic outcomes

Jones et al. Cancer 2007


Pre-Op Study

MethodsPatients and Eligibility

• Suspected stage I-IIIa NSCLC with or without preoperative histologic confirmation

• Surgery for curative intent

• No contraindications to CPET

Pre-Op

Patient FlowNumber of Patients ScreenedNumber of Patients Screened

N=43N=43

Number of Patients EligibleNumber of Patients EligibleN=35 (35/43 = 81%)N=35 (35/43 = 81%)

Baseline Tests CompletedBaseline Tests CompletedN=25 (25/35 = 71%)N=25 (25/35 = 71%)

Patients Becoming IneligiblePatients Becoming IneligibleN=5 (5/25 = 20%)N=5 (5/25 = 20%)

Pre-Surgery Tests CompletedPre-Surgery Tests CompletedN=18 (18/20 = 90%)N=18 (18/20 = 90%)

Post-Surgery Tests CompletedPost-Surgery Tests CompletedN=13 (13/18 = 72%)N=13 (13/18 = 72%)

Reasons for Non-Eligibility (n=8)Reasons for Non-Eligibility (n=8)

Geographical Location (n=6)Geographical Location (n=6)

Reasons for Non-Consent (n=10)Reasons for Non-Consent (n=10)

Not Interested (n=6)Not Interested (n=6)

Reasons for Drop Out (n=2)Reasons for Drop Out (n=2)

No transportation (n=1)No transportation (n=1)Work Commitments (n=1)Work Commitments (n=1)

Reasons for Drop Out (n=5)Reasons for Drop Out (n=5)Died (n=2)Died (n=2)Sx complicationsSx complications

Reasons for Non-Eligibility (n=5)Reasons for Non-Eligibility (n=5)

Became inoperable (n=4)Became inoperable (n=4)



Pre-Op Study

Participant Characteristics (n=20)No. %

Age, mean - yrs 65±10

Male, % 6 30

BMI, mean 27±4

NSCLC Diagnosis 13 65

Lobectomy 15 75

FEV1, Liters 1.9±0.6 (73%)

VO2peak, mL.kg.min-1 15.7±3.6 (70%)

6MWD, meters 427±89 (68%)

Pre-Op Study

Results – VO2peak -ITT

10

12

14

16

18

20

VO2 (mL.kg.min)

Baseline Pre-Surgery

2.4mL.kg.min (↑ 15%) (p=.002)


Pre-Op Study

Results – VO2peak (adherence)

10

12

14

16

18

20

VO2 (mL.kg.min)

Baseline Pre-Surgery

> 80%< 80%

≥80% adherence: 3.3mL.kg.min (↑ 20%) (p=.006)

<80% adherence: 0.8mL.kg.min (↑ 5%) (p=.129)


Pre-Op Study

Results – VO2peak (n=13)


10

12

14

16

18

20

VO2 (mL.kg.min)

Baseline Pre-Surgery Post-surgery

↑ 18% ↓ 18%

~0%

Current Clinical TrialsCurrent Clinical Trials

Duke InfrastructureDuke InfrastructureExercise TrainingExercise Training

Exercise TestingExercise Testing

• Determine the feasibility of exercise training among 20 postsurgical NSCLC patients

Funded by the Lance Armstrong Foundation

Aims

• Determine feasibility of exercise training

• Determine the effects of exercise training on exercise capacity, tx completion rates, toxicity & QoL

• Cycle ergometry (3x/wk for 20-45mins, 60-100% VO2peak) for 14 weeks

• N=20 patients recruited; 19 completed; 1 on study

Jones LW, Crawford J, Garst J, Kraus WE, Peterson B

NSCLC Post-Op Study

NSCLC Post-Op Preliminary Results• 79% adherence

• 2 drop out (10%)

• Baseline - 15.3 ml.kg.min (30% ↓ age-matched predicted)

• Postintervention – 16 ml.kg.min (↑ 7%)

• No adverse events

• Abstract submitted to ASCO

• Effects of exercise training on tumor response to Effects of exercise training on tumor response to chemotherapy among 20 breast cancer patients chemotherapy among 20 breast cancer patients undergoing neoadjuvant chemotherapyundergoing neoadjuvant chemotherapy

Sponsored by US DOD Breast Cancer Research Program

AimsAims

• Effects of exercise on exercise capacityEffects of exercise on exercise capacity

• Examine effects of exercise on tumor physiology, tx Examine effects of exercise on tumor physiology, tx response, QoL, cardiac function, & blood markersresponse, QoL, cardiac function, & blood markers

• Cycle ergometry (3x/wk, 30-45mins, 60-100% VOCycle ergometry (3x/wk, 30-45mins, 60-100% VO2peak2peak for 12 weeks) for 12 weeks)

• 6 patients completed; 4 on study6 patients completed; 4 on study

Jones LWJones LW, Marcom PK, Dewhirst, M, Blackwell K, Allen J, Douglas PD, Kraus WE, Peterson, , Marcom PK, Dewhirst, M, Blackwell K, Allen J, Douglas PD, Kraus WE, Peterson, BB

Breast Neoadjuvant Study

• To prospectively assess changes in exercise capacity To prospectively assess changes in exercise capacity and skeletal muscle function across primary brain and skeletal muscle function across primary brain tumor therapy (n=25 HGG; n=10 LG)tumor therapy (n=25 HGG; n=10 LG)

• Baseline (pre chemo/XRT; 6 weeks; 6 months)Baseline (pre chemo/XRT; 6 weeks; 6 months)

Funded by NCI – R03

AimsAims

• Examine Examine feasibilityfeasibility of exercise capacity & skeletal muscle of exercise capacity & skeletal muscle function assessmentsfunction assessments

• Assess Assess changeschanges in these outcomes & QOL in these outcomes & QOL

• Disease progression & overall survivalDisease progression & overall survival

Jones LWJones LW, Reardon D, Friedman HS, Friedman A, Major N, Kraus WE, Peterson , Reardon D, Friedman HS, Friedman A, Major N, Kraus WE, Peterson BB

Glioma Profiling Study

Assessments

• Exercise CapacityExercise Capacity

• Skeletal Muscle FunctionSkeletal Muscle Function• Muscle sizeMuscle size• Muscle strengthMuscle strength

• Body CompositionBody Composition

Preliminary Results

• 105 screened; 50 (48%) eligible; 24 (48%) recruited

• 16 HGG; 8 LG

• N=24 completed baseline; n=20 completed 6 week assessment; n=7 completed 6 month

• 2 pts loss to follow-up (deceased, DVT)

• Baseline exercise capacity = 15.45 mL.kg.min (~45% below age-sex predicted)

• 6 week = 15.74 mL.kg.min

Forthcoming StudiesForthcoming Studies

Pre-Clinical InvestigationsPre-Clinical Investigations

• Determine the effects of exercise training on Determine the effects of exercise training on antitumor efficacy of doxorubicin (DOX) in MDA-antitumor efficacy of doxorubicin (DOX) in MDA-MB-231 breast cancer xenograftsMB-231 breast cancer xenografts

• Funded by US Dept of Defense BCRP - Concept Funded by US Dept of Defense BCRP - Concept AwardAward

Exercise/Chemotherapy InteractionExercise/Chemotherapy Interaction

PurposePurposeJones LW, Eves ND, Courneya KS, Baracos VE, Hanson J, & Mackey JR

MethodAthymic FemaleAthymic Female

HSD Mice (3-4wks)HSD Mice (3-4wks)N = 84N = 84

All Mice S.C. All Mice S.C. Implanted MDA-Implanted MDA-MB-231 (5x10MB-231 (5x1066))

Acclimatization Acclimatization for 10 Daysfor 10 Days

Doxorubicin Only Doxorubicin Only (n=21)(n=21)

R

Exercise Only Exercise Only (n=21)(n=21)

Exercise + Exercise + Doxorubicin Doxorubicin

(n=21)(n=21)

No Intervention No Intervention Control (n=21)Control (n=21)

Tumor Tumor Establishment for Establishment for

14 Days14 Days

Exercise InterventionExercise Intervention• Forced running on Treadmill (6 chambers)Forced running on Treadmill (6 chambers)

• 2nd treadmill ‘sham exercise training’2nd treadmill ‘sham exercise training’

• 18m/min @ 0% grade for 45 mins, 5d.wk, 8 wks18m/min @ 0% grade for 45 mins, 5d.wk, 8 wks

• 70-75% VO70-75% VO2max2max

Results

0

10

20

30

40

50

60

70

80

90

100

6 12 18 24 30 36 42 48 54

% S

urvi

ving

Days

Control Control N=21N=21 Events=14Events=14 Median Growth Delay=25 Median Growth Delay=25

Ex Only Ex Only N=21N=21 Events=16Events=16 Median Growth Delay=25 Median Growth Delay=25Ex + CTEx + CT N=21N=21 Events=16Events=16 Median Growth Delay=36 (>C0 p=0.029; Ex Only p=0.080) Median Growth Delay=36 (>C0 p=0.029; Ex Only p=0.080)CT Only CT Only N=21N=21 Events=13Events=13 Median Growth Delay=42 (>C0 p=0.0084; Ex Only p=0.029) Median Growth Delay=42 (>C0 p=0.0084; Ex Only p=0.029)

Log Rank P=0.015Log Rank P=0.015

35%35%

20%20%16%16%

Discussion

• Moderate intensity TM running does not significantly Moderate intensity TM running does not significantly influence DOX-induced tumor growth delay in MDA-influence DOX-induced tumor growth delay in MDA-MB-231 xenograftsMB-231 xenografts

• Trend for longer survival in DOX only suggests that Trend for longer survival in DOX only suggests that TM running may partially inhibit the efficacy of DOX TM running may partially inhibit the efficacy of DOX therapytherapy

• Clinical trial underway (DOD funded study)Clinical trial underway (DOD funded study)

Summary

Growing interest in role of exercise for cancer Growing interest in role of exercise for cancer survivorssurvivors

Preliminary evidence – safe, feasible, & Preliminary evidence – safe, feasible, & beneficial supportive interventionbeneficial supportive intervention

Current/forthcoming research addressing Current/forthcoming research addressing fundamental questionsfundamental questions

Integral part of comprehensive cancer careIntegral part of comprehensive cancer care

Documents

Physical-Based Therapeutic Approaches for Cancer-Related Pain