PhysicalBased Therapeutic Approaches for CancerRelated Pain

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Physical-Based Therapeutic Approaches for
Cancer-Related Pain
Lee W. Jones, Ph.D
Department of Surgery Duke University Medical
Center 2nd Annual Pain Management
Symposium June 6th, 2008
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Presentation Outline

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

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Brief Overview of CRP
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Overview of CRP

• 30 to 50 undergoing therapy
• 70 to 90 advanced disease
• Bone pain most common (gt75 related to neoplastic
  invasion)
• CRP Syndromes
• Nociception - damage to pain receptors
• Neuropathic - nerve damage (peripheral
  neuropathy)
• Treatment-related pain damage to receptors by
  Sx, RT, CT, ET

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The Symptom Cluster
PAIN
FATIGUE
?? QOL
DISTRESS
FUNCTION DECLINE
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Management of CRP
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Management of CRP

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

• Non-Pharmacologic Approaches
• Surgery / psychological (grp psychotherapy /
  stress management, etc.)
• Address physical dimensions??

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Role of Physical-Based Approaches for CRP
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Types of Physical-Based Approaches

• Yoga
• mediation, gentle postures, breathing exercises
• Tai Chi
• Meditative form of exercise postures
• Structured Exercise Training
• Bodily activity aim of improving fitness health
• Physical / Rehabilitation Therapy
• Prevention, management, tx of movement disorders

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Review of Literature

• gt50 of exercise studies conducted in early-stage
  breast cancer patients
• gt50 completed during treatment
• Majority tested aerobic-based interventions
• Cycle ergometry/treadmill walking
• 3d.wk for 6-24 weeks, moderate intensity

• Adherence levels (if reported) gt 70

Jones Demark-Wahnefried. Lancet Oncol 2007
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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
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Prior Work

• Examined potential role of exercise in the
  following
• Descriptive Intervention
• Early-Stage Breast Cancer Metastatic Breast
• Non-Hodgkins Lymphoma Inoperable NSCLC
• Multiple Myeloma Preoperative NSCLC
• Primary Brain Cancer Neoadjuvant Breast
• Endometrial Adjuvant NSCLC
• Colorectal Anemic Cancer Pts
• Prostate NHL

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Prior Clinical Trials
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REHAB Trial

• Examined the effects of endurance training on
  exercise capacity, QOL, biologic outcomes in PM
  breast cancer survivors

• Aims
• Effects on QOL (FACT-B) and exercise capacity
  (VO2peak)
• Effects on metabolic hormones (insulin, IGF-1,
  IGFBPs), CV risk factors (BP, CRP, etc.)

Courneya, Jones et al. JCO 2003
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REHAB TrialMethod

• Patients 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

Courneya, Jones et al. JCO 2003
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REHAB TrialPatient Characteristics
Courneya, Jones et al. JCO 2003
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REHAB TrialResults Exercise Capacity - ITT
2.7 mL.kg.min within group (? 17.4) (plt.001) 3.4
mL.kg.min between groups
Courneya, Jones et al. JCO 2003
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REHAB TrialResults QOL
9.1 points within group (clinically meaningful)
(plt.001) 8.8 between groups
Courneya, Jones et al. JCO 2003
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REHAB TrialResults Fatigue
EG ? fatigue (adjusted analyses)
-9.3 points within group (clinically meaningful)
(plt.006) -7.3 between groups
Courneya, Jones et al. JCO 2003
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REHAB TrialOther Results

• Metabolic 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)

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EXTRA Trial

• Determine if a 12-week endurance exercise
  training program can improve QOL in anemic pts
  receiving Aranesp

• Aims
• Effects on QOL (FACT-An), fatigue, exercise
  capacity (VO2peak)
• Effects on Hb response dosing requirement

Sponsored by Amgen Inc,
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EXTRA TrialMethod

• Patients 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

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EXTRA TrialParticipant Characteristics
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EXTRA TrialResults Exercise Capacity - ITT
3.5 mL.kg.min within group (? 22) (plt.001) 3.0
mL.kg.min between groups
Courneya, Jones et al. JCO Submitted
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EXTRA TrialResults QOL
13.4 points within group (clinically meaningful)
(p.637) -6.9 between groups
Courneya, Jones et al. JCO Submitted
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EXTRA TrialResults Hb Outcomes
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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
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Pre-Op StudyMethods

• Patients and Eligibility
• Suspected stage I-IIIa NSCLC with or without
  preoperative histologic confirmation
• Surgery for curative intent
• No contraindications to CPET

Jones et al. Cancer 2007
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Pre-OpPatient Flow
Number of Patients Screened N43
Reasons for Non-Eligibility (n8) Geographical
Location (n6)
Number of Patients Eligible N35 (35/43 81)
Reasons for Non-Consent (n10) Not Interested
(n6)
Baseline Tests Completed N25 (25/35 71)
Patients Becoming Ineligible N5 (5/25 20)
Reasons for Non-Eligibility (n5) Became
inoperable (n4)
Pre-Surgery Tests Completed N18 (18/20 90)
Reasons for Drop Out (n2) No transportation
(n1) Work Commitments (n1)
Reasons for Drop Out (n5) Died (n2) Sx
complications
Post-Surgery Tests Completed N13 (13/18 72)
Jones et al. Cancer 2007
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Pre-Op StudyParticipant Characteristics (n20)
Jones et al. Cancer 2007
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Pre-Op StudyResults VO2peak -ITT
2.4mL.kg.min (? 15) (p.002)
Jones et al. Cancer 2007
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Pre-Op StudyResults VO2peak (adherence)
80 adherence 3.3mL.kg.min (? 20)
(p.006) lt80 adherence 0.8mL.kg.min (? 5)
(p.129)
Jones et al. Cancer 2007
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Pre-Op StudyResults VO2peak (n13)
? 18
? 18
0
Jones et al. Cancer 2007
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Current Clinical Trials
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Duke Infrastructure
Exercise Training
Exercise Testing
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NSCLC Post-Op Study
Jones LW, Crawford J, Garst J, Kraus WE, Peterson
B

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

• 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
• N20 patients recruited 19 completed 1 on study

Funded by the Lance Armstrong Foundation
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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

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Breast Neoadjuvant Study
Jones LW, Marcom PK, Dewhirst, M, Blackwell K,
Allen J, Douglas PD, Kraus WE, Peterson, B

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

• Aims
• Effects of exercise on exercise capacity
• Examine effects of exercise on tumor physiology,
  tx response, QoL, cardiac function, blood
  markers
• Cycle ergometry (3x/wk, 30-45mins, 60-100
  VO2peak for 12 weeks)
• 6 patients completed 4 on study

Sponsored by US DOD Breast Cancer Research Program
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Glioma Profiling Study
Jones LW, Reardon D, Friedman HS, Friedman A,
Major N, Kraus WE, Peterson B

• To prospectively assess changes in exercise
  capacity and skeletal muscle function across
  primary brain tumor therapy (n25 HGG n10 LG)
• Baseline (pre chemo/XRT 6 weeks 6 months)

• Aims
• Examine feasibility of exercise capacity
  skeletal muscle function assessments
• Assess changes in these outcomes QOL
• Disease progression overall survival

Funded by NCI R03
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Assessments

• Exercise Capacity

• Skeletal Muscle Function
• Muscle size
• Muscle strength

• Body Composition

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Preliminary Results

• 105 screened 50 (48) eligible 24 (48)
  recruited
• 16 HGG 8 LG
• N24 completed baseline n20 completed 6 week
  assessment n7 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

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Forthcoming Studies
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Pre-Clinical Investigations
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Exercise/Chemotherapy InteractionPurpose

• Determine the effects of exercise training on
  antitumor efficacy of doxorubicin (DOX) in
  MDA-MB-231 breast cancer xenografts
• Funded by US Dept of Defense BCRP - Concept Award

Jones LW, Eves ND, Courneya KS, Baracos VE,
Hanson J, Mackey JR
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Method
Athymic Female HSD Mice (3-4wks) N 84
Acclimatization for 10 Days
All Mice S.C. Implanted MDA-MB-231 (5x106)
Tumor Establishment for 14 Days
R
Doxorubicin Only (n21)
Exercise Only (n21)
Exercise Doxorubicin (n21)
No Intervention Control (n21)
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Exercise Intervention

• Forced running on Treadmill (6 chambers)
• 2nd treadmill sham exercise training
• 18m/min _at_ 0 grade for 45 mins, 5d.wk, 8 wks
• 70-75 VO2max

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Results
Log Rank P0.015
Surviving
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20
16
Days
Control N21 Events14 Median Growth
Delay25
Ex Only N21 Events16 Median Growth
Delay25
Ex CT N21 Events16 Median Growth
Delay36 (gtC0 p0.029 Ex Only p0.080)
CT Only N21 Events13 Median Growth
Delay42 (gtC0 p0.0084 Ex Only p0.029)
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Discussion

• Moderate intensity TM running does not
  significantly influence DOX-induced tumor growth
  delay in MDA-MB-231 xenografts
• Trend for longer survival in DOX only suggests
  that TM running may partially inhibit the
  efficacy of DOX therapy
• Clinical trial underway (DOD funded study)

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Summary
Growing interest in role of exercise for cancer
survivors
Preliminary evidence safe, feasible,
beneficial supportive intervention
Current/forthcoming research addressing
fundamental questions
Integral part of comprehensive cancer care