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

2. Presentation Outline Brief Overview of Cancer-Related Pain (CRP) Brief Overview of Cancer-Related Pain (CRP) Management of CRP Management of CRP Role of Physical-Based Approaches for CRP Role of Physical-Based Approaches for CRP Future Directions Future Directions Brief Overview of Cancer-Related Pain (CRP) Brief Overview of Cancer-Related Pain (CRP) Management of CRP Management of CRP Role of Physical-Based Approaches for CRP Role of Physical-Based Approaches for CRP Future Directions Future Directions

3. Brief Overview of CRP

4. Overview of CRP 30% to 50% undergoing therapy 30% to 50% undergoing therapy 70% to 90% advanced disease 70% to 90% advanced disease Bone pain most common (>75% related to neoplastic invasion) Bone pain most common (>75% related to neoplastic invasion) CRP Syndromes CRP Syndromes Nociception - damage to pain receptors Nociception - damage to pain receptors Neuropathic - nerve damage (peripheral neuropathy) Neuropathic - nerve damage (peripheral neuropathy) Treatment-related pain – damage to receptors by Sx, RT, CT, & ET Treatment-related pain – damage to receptors by Sx, RT, CT, & ET 30% to 50% undergoing therapy 30% to 50% undergoing therapy 70% to 90% advanced disease 70% to 90% advanced disease Bone pain most common (>75% related to neoplastic invasion) Bone pain most common (>75% related to neoplastic invasion) CRP Syndromes CRP Syndromes Nociception - damage to pain receptors Nociception - damage to pain receptors Neuropathic - nerve damage (peripheral neuropathy) Neuropathic - nerve damage (peripheral neuropathy) Treatment-related pain – damage to receptors by Sx, RT, CT, & ET Treatment-related pain – damage to receptors by Sx, RT, CT, & ET

5. The Symptom Cluster PAIN FATIGUE DISTRESS FUNCTIONDECLINE QOL QOL

6. Management of CRP

7. Pharmacologic Approaches Opoids / Analgesics / NSAIDs Opoids / Analgesics / NSAIDs Bisphosphonates / new approaches Bisphosphonates / new approaches Inadequate pain relief Inadequate pain relief Not benign (GI toxicity / cog dysfunction) Not benign (GI toxicity / cog dysfunction) Pharmacologic Approaches Opoids / Analgesics / NSAIDs Opoids / Analgesics / NSAIDs Bisphosphonates / new approaches Bisphosphonates / new approaches Inadequate pain relief Inadequate pain relief Not benign (GI toxicity / cog dysfunction) Not benign (GI toxicity / cog dysfunction) Non-Pharmacologic Approaches Surgery / psychological (grp psychotherapy / stress management, etc.) Surgery / psychological (grp psychotherapy / stress management, etc.) Address physical dimensions?? Address physical dimensions?? Non-Pharmacologic Approaches Surgery / psychological (grp psychotherapy / stress management, etc.) Surgery / psychological (grp psychotherapy / stress management, etc.) Address physical dimensions?? Address physical dimensions??

8. Role of Physical-Based Approaches for CRP

9. Types of Physical-Based Approaches Yoga Yoga mediation, gentle postures, breathing exercises mediation, gentle postures, breathing exercises Tai Chi Tai Chi Meditative form of exercise & postures Meditative form of exercise & postures Structured Exercise Training Structured Exercise Training Bodily activity aim of improving fitness & health Bodily activity aim of improving fitness & health Physical / Rehabilitation Therapy Physical / Rehabilitation Therapy Prevention, management, & tx of movement disorders Prevention, management, & tx of movement disorders Yoga Yoga mediation, gentle postures, breathing exercises mediation, gentle postures, breathing exercises Tai Chi Tai Chi Meditative form of exercise & postures Meditative form of exercise & postures Structured Exercise Training Structured Exercise Training Bodily activity aim of improving fitness & health Bodily activity aim of improving fitness & health Physical / Rehabilitation Therapy Physical / Rehabilitation Therapy Prevention, management, & tx of movement disorders Prevention, management, & tx of movement disorders

19. Review of Literature >50% of exercise studies conducted in early- stage breast cancer patients >50% of exercise studies conducted in early- stage breast cancer patients >50% completed during treatment >50% completed during treatment Majority tested aerobic-based interventions Majority tested aerobic-based interventions Cycle ergometry/treadmill walking Cycle ergometry/treadmill walking 3d.wk for 6-24 weeks, moderate intensity 3d.wk for 6-24 weeks, moderate intensity >50% of exercise studies conducted in early- stage breast cancer patients >50% of exercise studies conducted in early- stage breast cancer patients >50% completed during treatment >50% completed during treatment Majority tested aerobic-based interventions Majority tested aerobic-based interventions Cycle ergometry/treadmill walking Cycle ergometry/treadmill walking 3d.wk for 6-24 weeks, moderate intensity 3d.wk for 6-24 weeks, moderate intensity Adherence levels (if reported) > 70% Adherence levels (if reported) > 70% Jones & Demark-Wahnefried. Lancet Oncol 2007

20. Review of Literature All reported significant benefits No adverse events Multiple Biopsychosocial Outcomes 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

21. Prior Work Examined potential role of exercise in the following: Examined potential role of exercise in the following: DescriptiveIntervention Early-Stage Breast Cancer Metastatic Breast Non-Hodgkins LymphomaInoperable NSCLC Multiple MyelomaPreoperative NSCLC Primary Brain CancerNeoadjuvant Breast EndometrialAdjuvant NSCLC ColorectalAnemic Cancer Pts ProstateNHL Examined potential role of exercise in the following: Examined potential role of exercise in the following: DescriptiveIntervention Early-Stage Breast Cancer Metastatic Breast Non-Hodgkins LymphomaInoperable NSCLC Multiple MyelomaPreoperative NSCLC Primary Brain CancerNeoadjuvant Breast EndometrialAdjuvant NSCLC ColorectalAnemic Cancer Pts ProstateNHL

22. Prior Clinical Trials

23. REHAB Trial Examined the effects of endurance training on exercise capacity, QOL, & biologic outcomes in PM breast cancer survivors Courneya, Jones et al. JCO 2003 Aims Effects on QOL (FACT-B) and exercise capacity (VO 2peak ) Effects on metabolic hormones (insulin, IGF-1, IGFBPs), & CV risk factors (BP, CRP, etc.) Aims Effects on QOL (FACT-B) and exercise capacity (VO 2peak ) Effects on metabolic hormones (insulin, IGF-1, IGFBPs), & CV risk factors (BP, CRP, etc.)

24. REHAB Trial Method 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 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

25. REHAB Trial Patient Characteristics All Cases n=53 Exercise n=24 Control n=28 Mean / % Mean Age (yrs)59 58 BMI (kg/m 2 )29 Stage I40%42%39% Chemotherapy40%42%39% Radiotherapy71%67%75% Endocrine46% Courneya, Jones et al. JCO 2003

26. REHAB Trial Results – Exercise Capacity - ITT 2.7 mL.kg.min within group ( 17.4%) (p<.001) 3.4 mL.kg.min between groups Courneya, Jones et al. JCO 2003

27. REHAB Trial Results – QOL +9.1 points within group (clinically meaningful) (p<.001) +8.8 between groups Courneya, Jones et al. JCO 2003

28. REHAB Trial Results – Fatigue -9.3 points within group (clinically meaningful) (p<.006) -7.3 between groups EG fatigue (adjusted analyses) Courneya, Jones et al. JCO 2003

29. REHAB Trial Other 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 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) 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)

30. 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 (VO 2peak ) Effects on Hb response & dosing requirement Aims Effects on QOL (FACT-An), fatigue, exercise capacity (VO 2peak ) Effects on Hb response & dosing requirement

31. EXTRA Trial Method 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 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

32. EXTRA Trial Participant Characteristics All Cases n=55 DA Alone n=29 DA+EX n=26 Mean / % Mean Age (yrs)565458 Breast Cancer Dx60%62%58% Stage IV47%38%57% Chemotherapy92%90%96% Prior transfusion20%24%15% Heart Disease16%17%14%

33. EXTRA Trial Results – Exercise Capacity - ITT 3.5 mL.kg.min within group ( 22%) (p<.001) 3.0 mL.kg.min between groups Courneya, Jones et al. JCO Submitted

34. EXTRA Trial Results – QOL +13.4 points within group (clinically meaningful) (p=.637) -6.9 between groups Courneya, Jones et al. JCO Submitted

35. EXTRA Trial Results – Hb Outcomes

36. 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 Aims Determine feasibility of exercise training Determine the effects of exercise training on exercise capacity, QoL, & biologic outcomes Jones et al. Cancer 2007

37. Pre-Op Study Methods Patients and Eligibility Suspected stage I-IIIa NSCLC with or without preoperative histologic confirmation Surgery for curative intent No contraindications to CPET Patients and Eligibility Suspected stage I-IIIa NSCLC with or without preoperative histologic confirmation Surgery for curative intent No contraindications to CPET

38. Pre-Op Patient Flow Number of Patients Screened N=43 Number of Patients Eligible N=35 (35/43 = 81%) Baseline Tests Completed N=25 (25/35 = 71%) Patients Becoming Ineligible N=5 (5/25 = 20%) Pre-Surgery Tests Completed N=18 (18/20 = 90%) Post-Surgery Tests Completed N=13 (13/18 = 72%) Reasons for Non-Eligibility (n=8) Geographical Location (n=6) Reasons for Non-Consent (n=10) Not Interested (n=6) Reasons for Drop Out (n=2) No transportation (n=1) Work Commitments (n=1) Reasons for Drop Out (n=5) Died (n=2) Sx complications Reasons for Non-Eligibility (n=5) Became inoperable (n=4) Jones et al. Cancer 2007

39. Pre-Op Study Participant Characteristics (n=20) No.% Age, mean - yrs65±10 Male, %630 BMI, mean27±4 NSCLC Diagnosis1365 Lobectomy1575 FEV 1, Liters 1.9±0.6 (73%) VO 2peak, mL.kg.min -1 15.7±3.6 (70%) 6MWD, meters427±89 (68%)

40. Pre-Op Study Results – VO 2peak -ITT 2.4mL.kg.min ( 15%) (p=.002) Jones et al. Cancer 2007

41. Pre-Op Study Results – VO 2peak (adherence) 80% adherence: 3.3mL.kg.min ( 20%) (p=.006) <80% adherence: 0.8mL.kg.min ( 5%) (p=.129) Jones et al. Cancer 2007

42. Pre-Op Study Results – VO 2peak (n=13) Jones et al. Cancer 2007 18% ~0%

43. Current Clinical Trials

44. Duke Infrastructure Exercise Training Exercise Testing

45. 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% VO 2peak ) for 14 weeks N=20 patients recruited; 19 completed; 1 on study 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% VO 2peak ) 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

46. 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 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

47. Effects of exercise training on tumor response to chemotherapy among 20 breast cancer patients undergoing neoadjuvant chemotherapy Effects of exercise training on tumor response to chemotherapy among 20 breast cancer patients undergoing neoadjuvant chemotherapy Sponsored by US DOD Breast Cancer Research Program Aims Effects of exercise on exercise capacity Effects of exercise on exercise capacity Examine effects of exercise on tumor physiology, tx response, QoL, cardiac function, & blood markers Examine effects of exercise on tumor physiology, tx response, QoL, cardiac function, & blood markers Cycle ergometry (3x/wk, 30-45mins, 60-100% VO 2peak for 12 weeks) Cycle ergometry (3x/wk, 30-45mins, 60-100% VO 2peak for 12 weeks) 6 patients completed; 4 on study 6 patients completed; 4 on studyAims Effects of exercise on exercise capacity Effects of exercise on exercise capacity Examine effects of exercise on tumor physiology, tx response, QoL, cardiac function, & blood markers Examine effects of exercise on tumor physiology, tx response, QoL, cardiac function, & blood markers Cycle ergometry (3x/wk, 30-45mins, 60-100% VO 2peak for 12 weeks) Cycle ergometry (3x/wk, 30-45mins, 60-100% VO 2peak for 12 weeks) 6 patients completed; 4 on study 6 patients completed; 4 on study Jones LW, Marcom PK, Dewhirst, M, Blackwell K, Allen J, Douglas PD, Kraus WE, Peterson, B Breast Neoadjuvant Study

48. To prospectively assess changes in exercise capacity and skeletal muscle function across primary brain tumor therapy (n=25 HGG; n=10 LG) To prospectively assess changes in exercise capacity and skeletal muscle function across primary brain tumor therapy (n=25 HGG; n=10 LG) Baseline (pre chemo/XRT; 6 weeks; 6 months) Baseline (pre chemo/XRT; 6 weeks; 6 months) To prospectively assess changes in exercise capacity and skeletal muscle function across primary brain tumor therapy (n=25 HGG; n=10 LG) To prospectively assess changes in exercise capacity and skeletal muscle function across primary brain 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 Aims Examine feasibility of exercise capacity & skeletal muscle function assessments Examine feasibility of exercise capacity & skeletal muscle function assessments Assess changes in these outcomes & QOL Assess changes in these outcomes & QOL Disease progression & overall survival Disease progression & overall survivalAims Examine feasibility of exercise capacity & skeletal muscle function assessments Examine feasibility of exercise capacity & skeletal muscle function assessments Assess changes in these outcomes & QOL Assess changes in these outcomes & QOL Disease progression & overall survival Disease progression & overall survival Jones LW, Reardon D, Friedman HS, Friedman A, Major N, Kraus WE, Peterson B Glioma Profiling Study

49. Assessments Exercise Capacity Exercise Capacity Skeletal Muscle Function Skeletal Muscle Function Muscle size Muscle size Muscle strength Muscle strength Skeletal Muscle Function Skeletal Muscle Function Muscle size Muscle size Muscle strength Muscle strength Body Composition Body Composition

50. 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 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

51. Forthcoming Studies

52. Pre-Clinical Investigations

53. Determine the effects of exercise training on antitumor efficacy of doxorubicin (DOX) in MDA- MB-231 breast cancer xenografts 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 Funded by US Dept of Defense BCRP - Concept Award Determine the effects of exercise training on antitumor efficacy of doxorubicin (DOX) in MDA- MB-231 breast cancer xenografts 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 Funded by US Dept of Defense BCRP - Concept Award Exercise/Chemotherapy Interaction Purpose Jones LW, Eves ND, Courneya KS, Baracos VE, Hanson J, & Mackey JR

54. Method Athymic Female HSD Mice (3-4wks) N = 84 All Mice S.C. Implanted MDA- MB-231 (5x10 6 ) Acclimatization for 10 Days Doxorubicin Only (n=21) R Exercise Only (n=21) Exercise + Doxorubicin (n=21) No Intervention Control (n=21) Tumor Establishment for 14 Days

55. Exercise 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 wks 18m/min @ 0% grade for 45 mins, 5d.wk, 8 wks 70-75% VO 2max 70-75% VO 2max 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 wks 18m/min @ 0% grade for 45 mins, 5d.wk, 8 wks 70-75% VO 2max 70-75% VO 2max

56. Results % Surviving Days Control N=21Events=14 Median Growth Delay=25 Ex Only N=21Events=16 Median Growth Delay=25 Ex + CTN=21Events=16 Median Growth Delay=36 (>C0 p=0.029; Ex Only p=0.080) CT Only N=21Events=13 Median Growth Delay=42 (>C0 p=0.0084; Ex Only p=0.029) Log Rank P=0.015 35% 20% 16%

57. Discussion Moderate intensity TM running does not significantly influence DOX-induced tumor growth delay in MDA- MB-231 xenografts 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 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) Clinical trial underway (DOD funded study) Moderate intensity TM running does not significantly influence DOX-induced tumor growth delay in MDA- MB-231 xenografts 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 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) Clinical trial underway (DOD funded study)

58. 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