Daniel A. Galvão, PhD Co-Director, Exercise Medicine Research Institute Cancer Council Western Australia Research Fellow

Transcription

1 Exercise in the setting of androgen deprivation therapy and bone metastatic disease Daniel A. Galvão, PhD Co-Director, Exercise Medicine Research Institute Cancer Council Western Australia Research Fellow

2 Five-year Survival Rates Stage Distribution (%) 5-year Survival (%) Localised Distant Localised Distant All stages Jemal et al. CA Cancer J Clin 58:-96, 2008

3 Common Treatments (e.g. prostate cancer) Active surveillance Prostatectomy Radiation therapy Androgen deprivation Chemotherapy (Docetaxel) Abiraterone/Enzalutamide non treatment surgical removal external/brachytherapy LHRHa, orchiectomy, antiandrogen metastatic CRPC Herr CA Cancer J Clin 1997; Catalona et al. CA Cancer J Clin 1999; Yan et al. Cancer 2000

4 PCa Landscape

5 Hormone Treatment Androgen deprivation (ADT) Eliminates testosterone production (LHRHa) Survival benefit from RCTs (+external RT for high risk PCa) Increasingly used in the management of Prostate Cancer Significant adverse effects Bolla et al. Lancet. 2002;360: ; Denham et al. Lancet Oncol. 2005;6: ; D Amico et al. JAMA. 2008;299:

6 Spry et al. Prostate Cancer and Prostatic Diseases 2012;102: Months from BL Whole Body Fat Whole Body Lean +2.3 kg FAT -1.5 kg Muscle

7 itreat Testosterone Recovery After ADT POST 26% failed to recover at 24 months Odds of regaining eugonadal levels of testosterone reduced by 50% if 70yr Spry et al. British Journal of Urology International 2009;104(6):806-12

8 Chang D et al. J Med Imaging Radiat Oncol Apr;58(2):223-8.

9 Alibhai et Journal of Clinical Oncology 2010;28(34):

10 Impaired physical function and balance Reduced upper and lower body muscle strength Galvão et al. Prostate Cancer Prostatic Dis. 2009;12(2):

11 Fatigue Prevalence ADT Biochemically controlled PCa on long-term ADT CRF 43% prevalence (BFI) Independent associated with depression and pain No association with age, disease burden or treatment duration CRF Interferes with function BFI = Brief Fatigue Inventory score > 3 (0-10 scale) Storey D et al Annals of Oncology 23: , 2012.

12 Surveillance, Epidemiology and End Results (SEER) and Medicare database; records from 196 local and local regional Increased risk associated with Androgen Suppression Diabetes 44% Coronary heart disease 16% Myocardial infarction 11% Sudden death 16% Keating et al. Journal of Clinical Oncology 2006;24:

13 ADT Sarcopenia-Related Disorders ADT Sarcopenia-Related Disorders lean mass fat mass muscle strength cardiovascular metabolic disease fatigue quality of life Galvão et al. Prostate Cancer Prostatic Dis 2007;10(4):340-6

14 DXA BMD Regional Changes BMD 9 months change Lumbar spine -3.9%* Total Hip -1.5%* Upper limb -1.3%* Lower Limb -0.6% *p<0.001 Galvão DA et al. British Journal of Urology International 2008;102:44-47

15 Cancer Treatment-Induced Bone Loss Higano C. Nature Clinical Practice Urology 2008;5:24-34

16 Prevalence of Osteoporosis Baseline and years on ADT Percentage of patients Androgen deprivation therapy duration (years) Overall prevalence of osteoporosis, osteopenia, and normal BMD according to ADT duration. *Patients had not received ADT at time of BMD measurement. Morote et al., Urology. 2007;69:

17 Shahinian et al. New England Journal of Medicine 2005;352:154-64

18 Musculoskeletal Fitness Normal Aging ADT Treated Men Physical Reserve Capacity ADT Sarcopenia-Related Disorders Disability Condition Age, years Galvão DA et al. Prostate Cancer & Prostatic Diseases 2007;10(4):340-6

19 MUSCLE STRENGTH & FUNCTION baseline week 10 week Chest press Seated row 0 Chair rise Stair Climb 400 -m w alk 6 m backw ard w alk 6 m usual w alk 6 m fast w alk Quadriceps Muscle thickness increase by 15% p=0.050 B-Mode Ultrasound Galvão et al Med Sci Sports Exerc 2006;23:

20 Treatment Design ADT (24% Radiation) RCT Sample 57 Intervention Protocol Primary endpoint 12-week (2x) resistance & aerobic 2-4 sets 6-12RM min 60-85%MHR 10-13RPE lean mass Galvão et al. J Clinical Oncology 2010;10;28(2):340-7

21 Regional and Whole Body Composition Kilograms Adjusted group difference in mean change (95%CI) over 12 weeks ANCOVA (baseline, ADT time, antiandrogen, # medications, education) p=.047 ( ) p=.003 ( ) p=.019 ( ) p<.001 ( ) p=.964 ( ) Whole Lean ASM Upper Lean Lower Lean Whole Fat Galvão et al. J Clinical Oncology 2010;10;28(2):340-7

22 Units Quality of Life Adjusted group difference in mean change over 12 weeks ANCOVA (baseline, ADT time, antiandrogen, # medications, education) p=.154 p=.119 p=.022 p= p=.441 p=.223 p=.207 p= p=.491 p= Physical Role-P Pain G Health Vitality Social Role-E M Health PHC MHC Galvão et al. J Clinical Oncology 2010;10;28(2):340-7

23 Buffart et al. Cancer Jan 15;120(2):

24 Treatment ADT (~5 months) Design RCT (3-arm) Intervention 12 months Sample 164 Protocol Primary endpoint (1) Supervised resistance/impact vs. (2) Supervised resistance/aerobic vs. (3) Usual care Bone mass (lumbar spine & hip BMD); lean mass; VO2 Newton et al. BMC Cancer Jun 29;9:210.

25 Change over 6 months (%) Exercise and bone mass during ADT Lumbar Spine Bone Mineral Density Resistance & Impact Exercise Resistance & Aerobic Exercise Usual Care Newton et al. In Review 2017

26 Fatigue and Vitality Fatigue Baseline 6 months 12months P-value ILRT 27.9 ± ± ± B > 6, 12 ART 23.4 ± ± ± B, 6 > 12 UC/DE 25.8 ± ± ± B, 6 > 12 Vitality Baseline 6 months 12 months Fatigue ILRT 50.0 ± ± ± 8.5 < B, 6 < 12 ART.5 ± ± ± B, 6 < 12 UC/DE 50.3 ± ± ± 8.1 < B, 6 < 12 ILRT ART UC/DE Baseline 6 months 12 months Vitality ILRT ART UC/DE Taaffe DR et al. European Urology 2017

27 Sexual Dysfunction Up to 90% of men with prostate cancer will experience sexual dysfunction (Bobber et al. J Clin Oncol 2012) Bacon et al. Ann Intern Med 2003 Webber et al. Med J Aus 2013 ~50% of Australian prostate cancer survivors report unmet sexual health care needs (Smith et al. J Clin Oncol 2007) Sexual health ranked as the area with the most unmet need

28 Exercise and Sexual Health during ADT Treatment ADT (37% previous RT; 40% PT) Design RCT (2-arm) Sample 57 Intervention 3 months Protocol Supervised resistance & aerobic exercise Primary endpoint Sexual activity (QLQ-PR25) Cormie P, Newton RU, Taaffe DR, et al. Prostate Cancer Prostatic Dis. 2013;16(2):

29 SEXUAL ACTIVITY LIBIDO 17% vs. 0% p = Exercise Usual Care Exercise Usual Care Exercise maintained sexual activity during treament Driven by changes in libido Related to change in quality of life (p 0.030) Cormie P, Newton RU, Taaffe DR, et al. Prostate Cancer Prostatic Dis. 2013;16(2):

30 PSA Response to Acute and Chronic Exercise Galvão et al Med Sci Sports Exerc Segal et al J Clin Oncol Galvão et al Prostate Cancer Prostatic Dis Galvão et al J Clin Oncol Galvão et al J Urol Bourke et al Eur Urol Galvão et al Eur Urol Cormie et al BJU Int Resistance Resistance or aerobic Resistance (acute) Resistance and aerobic Resistance and aerobic Aerobic Resistance and aerobic Resistance and aerobic No Change

31 Progression of PCa: bone metastases

32 Exercise and bone metastatic disease Galvão et al. BMC Cancer 2011

33 Exercise and bone metastatic disease 103 patients with PCa bone metastatic disease were screened in WA 57 patients were randomized to exercise (n=28) or usual care (n=29) group no major adverse events or bone pain were reported in relation to the intervention Exercise improved self-reported physical function compared to controls - adjusted mean difference at 12 weeks between groups of 3.5 points (95% confidence interval; 0.70 to 6.3; p=.015) Galvão et al. BMC Cancer 2011; unpublished data

34 Zopf EM, Newton RU et al. Eur J Cancer Care (Engl) Sep 20

35 Population-based cohort of 463 prostate cancer survivors who were 10.8 months post-curative therapy were assessed for compliance with current exercise guidelines for cancer survivors (12.3%) reported sufficient exercise levels (40.2%) were insufficiently active (47.5%) were inactive Only a small proportion of Australian prostate cancer survivors met contemporary exercise oncology recommendations Galvão et al. Psycho-Oncology 2015.

36 Musculoskeletal Fitness Physical Reserve Capacity Normal Aging ADT Treated Resistance Trained ADT Treated Physical Reserve Capacity Disability Condition Galvão DA et al. Prostate Cancer & Prostatic Diseases 2007;10(4):340-6 Age, years ADT Sarcopenia-Related Disorders

37 KEY CHALLENGES Men are living longer with prostate cancer. They are not surviving well. PC survivorship research & translation under-represented & poorly co-ordinated. KNOWLEDGE GENERATION PSYCHOSOCIAL & PSYCHOSEXUAL HEALTH EXERCISE MEDICINE ECONOMIC MODELLING SOCIODEMOGRAPHIC & GEOGRAPHIC INEQUALITIES IN OUTCOMES OUTCOMES Stepped model of psychosocial care Model of psychosexual care Test models in RCT RCTs of exercise interventions Lifestyle programs Heath economics model Suite of costeffectiveness analyses National atlas of outcomes Contextual model to describe why inequalities exist Community & awareness action campaign High level evidence: Descriptive & implementation research, systematic reviews & meta-analyses. Translation: Guidelines & tool kits, community partnerships, policy & practice, clinical pathways, evidence-based survivorship guidelines. Sustainability: Training new research & translation leaders, building national & global action networks.

38 Robert Newton (ECU) Dennis Taaffe (ECU) Nigel Spry (SCGH, Genesis) Suzanne Chambers (GU) David Joseph (SCGH, ECU) Frank Gardiner (RBH, UQ, ECU) Nicolas Hart (ECU) Favil Singh (ECU) Dickon Hayne (FH, UWA) Thomas Shannon (HH) James Denham (UNew, NMH) David Lamb (UOtago) Carolyn McIntyre (ECU) Akhlil Hamid (PRH, ECU) Evan Ng (RPH, Genesis) Raphael Chee (Genesis, UWA) Jerard Ghossein (JHC) Siobhan Ng (SCGH, SJG) Yvonne Zissiadis (Genesis, ECU) Research Support

39 Thank You! Daniel A. Galvão

40 Exercise and bone metastatic disease Treatment 100% ADT, 55% Radiation, 20% PT Design RCT (2-arm) Sample 20 Intervention 3 months Protocol Supervised modular resistance exercise Primary endpoint Physical function

41 Adverse events during the exercise sessions 0 Attendance (out of 24 sessions) 20.2 ± 7.6 Compliance (% of successfully completed sessions) 93.2 ± 6.3 Perceived tolerance of the exercise sessions (0 = intolerable; 7 = highly tolerable) No between-group difference in bone pain (P=0.602) No between-group difference in number of adverse events (P=0.264) No change in use of pain medication throughout 12 weeks Cormie P, Newton RU, Spry N, et al. Prostate Cancer Prostatic Dis. 2013;16(4): ± 0.7 Perceived exercise intensity (session RPE) 13.8 ± 1.5 Severity of bone pain at the start of each session (average of all sessions; 0 = no pain; 10 = very severe pain) Incidence of bone pain negatively affecting the ability to undertake ADL between exercise sessions ADL = activities of daily living; RPE = rating of perceived exertion 0.6 ± 0.7 0

42 Favours Usual Care Percent Difference (%) Favours Exercise 25 p = p = p < Bone Pain a p = Muscle Strength p = Aerobic Fitness p = Ambulation Lean Mass Physical Acitivty Activity Level -10 Cormie P, Newton RU, Spry N, et al. Prostate Cancer Prostatic Dis. 2013;16(4):

43 Considerations Exercise improves recovery/qol after prostate cancer Exercise does not interfere with treatment response (e.g. PSA) Exercise manages symptoms during ADT (especially for symptomatic patients) Preliminary studies with bone mets showing safety Preliminary efficacy in patients with bone mets to improve physical function

44 Quartiles of Fatigue and Vitality Fatigue Vitality P < P < Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 EORTC QLQ-C30 fatigue is a 3-item subscale Vitality scale of the SF-36 a 4-item domain with scores from Taaffe DR et al. European Urology 2017

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46 Exercise After Treatment Diagnosis Design (>5 yr post diagnosis) RCT (2-arm) Sample 100 Intervention 12 months Protocol Primary endpoint Resistance & aerobic exercise (6 months supervised + 6 months home based) vs. physical activity education material Cardiorespiratory fitness Galvão DA et al. Eur Urol. 2014;65(5):

47 1-RM Chest Press kg 1-RM Leg Extension kg 400-m walk time/sec Chair rise time/sec Exercise vs Physical Activity After Treatment A (7.6) (7.6) EX PA -19s (8.4) -13s (7.3) *P=.029 **P= (8.4) (7.3) B 12.8 (0.4) 11.6 (0.4) EX -1.1s *P= (0.5) 11.7 (0.5) PA -1.1s 11.7 (0.4) **P= (0.4) 260 Baseline 6 Months 12 Months 10.5 Baseline 6 Months 12 Months C EX PA 40.4 (1.8) +6.6kg 39.5 (2.1) 38.6 (1.8) *P=.004 **P= (1.8) 38.1 (1.8) 36.1 (2.1) Baseline 6 Months 12 Months D EX PA 59.3 (3.0) 56.6 (2.8).0 (2.9) *P<.001 **P= (3.0) 49.9 (2.9) 50.2 (2.8) Baseline 6 Months 12 Months +3.0kg PA, physical activity. Galvão DA et al. Eur Urol. 2014;65(5):

48 Exercise and Sexual health