Exercise as Cancer Treatment

Transcription

1 Exercise as Cancer Treatment W. Thomas Purcell, MD, MBA Executive Medical Director, Oncology Services, University of Colorado Hospital Associate Director for Clinical Services, University of Colorado Cancer Center System Director, Oncology Services, University of Colorado Health Colorado Cancer Day, November 1, 2014 Conflict of Interest: 1. No Speaker / Consultant 2. No Advisory Boards 3. No Stock Holdings / Investments Agenda Background the why Mechanism of action Evidence Primary v. Secondary v. QoL Cancer Exercise program launch The Future? mitochondria fitness?

2 Balancing Lifestyle and Genomics Research for Disease Prevention Who exercises? Only 25% of adults meet the recommended requirements 58% adults are sedentary 43 million have used a treadmill 48 million have used free weights 150 million adults participate in some type of non work related physical activity Far side tv

3 Obesity Trends Among U.S. Adults BRFSS, 2008 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14 15% 19% 20% 24% 25% 29% 30% Cancer Arises from a variety of factors: Family history/genetics (up to 25%) Environmental causes i.e. Smoking-30% of all cancer deaths in USA Dietary factors (poor nutrition-1/3 of all cancer deaths in US) Lifestyle choices Lack of exercise, diet, exposure to toxins-cigarettes Mechanism for Cancer Reduction with Exercise! Physical activity lowers levels of biologically available sex hormones! Decreased lifetime exposure to endogenous sex hormones -> decreased risk of hormone-related cancers! Breast, endometrial, ovaries, prostate, testes

4 ! Exercise decreases endogenous insulin production! Higher levels of circulating insulin linked with several cancers! Exercise associated with decreased levels of IGF! High levels of IGF-1 a/w several cancers (colon, prostate, breast, lung) Mechanism for Cancer Reduction with Exercise! Adiposity and Cancer Risk! Increased fat associated with increased risk of cancers of colon, kidney, esophagus, endometrium, thyroid, postmenopausal breast! Physical activity decreases colon transit time! Decreases colonic exposure to carcinogens in stool! Level of physical activity inversely related to levels of C- reactive protein! NSAID use in physically active! NSAID use appears to decrease colon cancer risk Table 2 Proposed mechanisms of impaired cardiorespiratory fitness in patients with cancer Lakoski, S. G. et al. (2012) Exercise rehabilitation in patients with cancer Nat. Rev. Clin. Oncol. doi: /nrclinonc Lakoski, S. G. et al. (2012) Exercise rehabilitation in patients with cancer Nat. Rev. Clin. Oncol. doi: /nrclinonc

5 Table 3 Efficacy of exercise training to augment oxygen transport organ components in clinical populations Lakoski, S. G. et al. (2012) Exercise rehabilitation in patients with cancer Nat. Rev. Clin. Oncol. doi: /nrclinonc Energy intake, Physical activity, High Glycemic diet Pituitary GH secretion IGF-I response to GH Obesity Insulin resistance IGFBP-1 Competent beta-cell secretion C-peptide Hyperinsulinemia (Fasting or Post-Prandial) Bioactive IGF-I Direct effect? Cell survival and proliferation C-peptide Levels & Colorectal Cancer Risk in Men (PHS) P trend <0.05 RR ref Plasma C-peptide Ma, et al. J Natl Cancer Inst 2004

6 NCCN Guidelines for Survivorship

7 Evidence for Exercise Benefit in Cancer Primary Prevention Secondary Prevention QoL assessments

8 Primary Prevention J Clin Oncol 31, 2013 (suppl; abstr 1520) Cooper Institute Study--- CRF Cardiorespiratory Fitness 17,049 men enrolled in study with median age of 50 Stratified by their fitness levels Treadmill performance (METs); 5 different levels Over next 20 years, 2885 men were diagnosed with prostate, lung, or colorectal cancer and 769 died. looked at "fitness," or the ability to get on a treadmill and go as far as you can, predicted whether or not you'll develop cancer. HYPOTHESIS: people who had lower fitness, or went less time on the treadmill, were more at risk for developing cancer later in life. " Metabolic Equivalent Term What is a MET? " 1 MET = "Basal" aerobic oxygen consumption to stay alive = 3.5 ml O2 /Kg/ min = couch " Actually differs with thyroid status, post exercise, obesity, disease states " But by convention just divide ml O2/Kg/min by 3.5 Metabolic Equivalent Conversions METS for 1 hour of that activity Normal pace walking (2-2.9 mph) 3 Brisk pace walking (3-3.9 mph) 4 Very brisk pace walking (4+ mph) 4.5 Jogging (slower than 10 minutes/mile) 7 Running (faster than 10 min/mile) 12 Bicycling 7 Tennis, squash, racquetball 7 Lap swimming 7 Calisthenics, ski or stair machine, other aerobic Yoga, stretching, toning, lower intensity exercise Other vigorous activities (lawn mowing) 6 6 4

9 The most common activity is walking Survey Data METS Intensity Exercise = Physical Activity Vigorous > 6 METS Can t sustain activity for > 20 minutes Work up a sweat and your heart pounds Moderate 3 6 METS Not exhausting Sustain activity for 60 minutes Mild Bowling Fitness and Mortality in Men, ACLS Fitness Categories Age Groups (years) Fitness and Mortality in Women, ACLS Fitness Categories Age Groups (years) Table values are maximal METS attained during the exercise text

10 Myers J et al. N Engl J Med 2002;346: Relative Risks of Death from Any Cause among Subjects with Various Risk Factors Who Achieved an Exercise Capacity of Less Than 5 MET or 5 to 8 MET, as Compared with Subjects Whose Exercise Capacity Was More Than 8 MET Myers J et al. N Engl J Med 2002;346: Primary Prevention Men with HIGH CRF (>9 METs) had 68% less chance of developing lung cancer and 38% less colorectal cancer No effect on prostate cancer incidence A 1-MET increase in CRF was associated with a 14% reduction in cancer-specific mortality. Health impact cancer risk (colon, breast) reduced In primary prevention, routine physical activity is associated with a: % relative risk reduction in the incidence of colon cancer compared to inactive people % relative risk reduction in the incidence of breast cancer compared to inactive women.

11 Exercise and colon cancer: convincing evidence Consistent 30-40% lower risk, RR Independent of confounding factors, including BMI Findings replicated in different populations Dose-response evident: min/day of moderate to vigorous activity is optimal No effect on risk of rectal cancer Physical activity and breast cancer convincing evidence 55 observational studies (23 cohort, 32 casecontrol) Reasonably clear pattern of lower rates among active women median RR 0.8 (20-30% lower risk) Stronger, more consistent effect for postmenopausal women (median RR 0.7) Linear trend in two thirds of the studies that looked at dose-response Lowest risk in lean, physically active women Exercise and risk of breast cancer Overall 25-30% decreased risk Greatest in thinner women Lifetime exercise matters Modest amounts: 1-3 hours brisk walking/week WHI Observational Cohort" (n=74,171; 1780 cancers)" McTiernan, JAMA, 2003."

12 Secondary Prevention Exercise and Breast Cancer Courneya, et. al., Journal of Clinical Oncology, Oct Randomized controlled trial 82 usual care subjects 82 resistance exercise subjects 78 aerobic exercise subjects

13 Exercise and Breast Cancer Courneya, continued Aerobic exercise Improved self-esteem (P=.015), aerobic fitness (P=.066), % body fat (adjusted P=.076) Resistance exercise Improved self-esteem (P=.018), muscular strength (P<.001), lean body mass (P=.015), chemotherapy completion rate (P=.033) Changes in QOL, fatigue, depression and anxiety were higher in exercise groups but did not reach statistical significance. No lymphedema or adverse events. Meyerhardt, et. al. Journal of Clinical Oncology, 2006 Subjects compared with patients who engaged in less than 3 MET hours per week of physical activity The adjusted hazard rate for disease-free survival was 0.51 for MET-hours per week, 0.55 for 27 or more MET-hours per week. Post diagnosis activity was associated with similar improvements in recurrence-free survival (P for trend=.03) and overall survival for trend =.01) Flowchart of search process for exercise interventions in patients with prostate cancer receiving androgen-deprivation therapy (ADT). Gardner J R et al. JCO 2014;32: by American Society of Clinical Oncology

14 Segal et al. J Clin Oncol. 20;27(3):

15 Treatment-Related Side Effects and Exercise Benefits QoL Benefits in Cancer Patients For 70% of the population, there is an inability or unwillingness to meet the minimum physical activity guidelines established by the American College of Sports Medicine.

16 Monitored rehab? Personal training? Case management? Doctor s Advice / Guidance? Physical Therapy? Community Resources? Support Groups? Recreation Center Memberships?

17 Harms 25% 65% annual risk of injury while running 8.7% risk in strength training in yo. Marathon training 85% (18 mo time period) Aerobic Dancer - 25% (12 week time period) Walk 14 mi/wk - 5% (6 month time period) Recreational activities?? Mitochondrial Function is Key for Correct Metabolic Health Many Chronic Diseases are Characterized by a Mitochondrial Dysfunction Kelley DE et al. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51: , Lowell BB, Shulman GI Mitochondrial dysfunction and type 2 diabetes. Science2005;307:384-87, 2005 Petersen KF et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300: , 2003 Moreira, Paula I., et al. Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease (2010): Maruszak, A., & Żekanowski, C. (2011). Mitochondrial dysfunction and Alzheimer's disease. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 35(2), Albrekkan, F. M., & Kelly-Worden, M. (2013). Mitochondrial Dysfunction and Alzheimer s Disease. Open Journal of Endocrine and Metabolic Diseases, 3, 14. Madamanchi, N. R., & Runge, M. S. (2007). Mitochondrial dysfunction in atherosclerosis. Circulation Research, 100(4), Ballinger, S. W. (2005). Mitochondrial dysfunction in cardiovascular disease.free Radical Biology and Medicine, 38(10), Rosenberg, P. (2004). Mitochondrial dysfunction and heart disease.mitochondrion, 4(5),

18 Mitochondrial Dysfunction Also Involved in Cancer Modica-Napolitano, J. S., & Singh, K. K. (2004). Mitochondrial dysfunction in cancer. Mitochondrion, 4(5), Boland, M. L., Chourasia, A. H., & Macleod, K. F. (2013). Mitochondrial dysfunction in cancer. Frontiers in oncology, 3. SINGH, K. K. (2004). Mitochondrial dysfunction is a common phenotype in aging and cancer. Annals of the New York Academy of Sciences, 1019(1), Pelicano, H., Lu, W., Zhou, Y., Zhang, W., Chen, Z., Hu, Y., & Huang, P. (2009). Mitochondrial dysfunction and reactive oxygen species imbalance promote breast cancer cell motility through a CXCL14-mediated mechanism.cancer research, 69(6), Shapovalov, Y., Hoffman, D., Zuch, D., de Mesy Bentley, K. L., & Eliseev, R. A. (2011). Mitochondrial dysfunction in cancer cells due to aberrant mitochondrial replication. Journal of Biological Chemistry, 286(25), Warburg Effect is a form of mitochondrial dysfunction Physical Inactivity Causes Mitochondrial dysfunction Coyle et al, 1984

19 Physical Activity is the single most important stimulator of Mitochondrial Biogenesis # Elite endurance athletes have the highest mitochondrial capacity and best metabolism of any humans # The Fittest people on earth # The only population where 100% of them are free of any acquired metabolic and cardiovascular disease. Simply, It doesn t exist! Central Adapta,ons Physical ac,vity is not just about cardiovascular health but about metabolic health and Mitochondria are the Epicenter Local Adapta,ons Lactate clearance is key for athle,c performance. Lactate is cleared in the mitochondria Lactate Metabolism Between Different Popula,ons Data from Dr. Inigo San Millan s Lab at University of Colorado

20 Thank You!