International Graduate Course in Exercise & Clinical Physiology

Transcription

1 International Graduate Course in Exercise & Clinical Physiology Exercise and Cancer A view to the future through the eyes of the past Robert D. Kilgour, Ph.D., FACSM Professor & Chair Department of Exercise Science

2 Presentation Outline Therapeutic role of exercise in cancer Reluctance on the part of the oncologist Historical timelines and milestones Highlights along the cancer trajectory Exercise therapy prior to surgical resection (pre-surgery) Exercise therapy during adjuvant therapy (post-surgical) Exercise therapy following completion of adjuvant therapy (Survivorship or secondary prevention) Exercise therapy in advanced cancer (palliative care) McGill Nutrition and Performance Laboratory (MNUPAL) Assessing the advanced cancer patient Multimodal therapy (exercise / nutrition / medication)

3 Reluctance to investigate the therapeutic role of exercise Why? Prevailing dogma (belief or doctrine) Cancer associated with Poor prognosis Fatigue Muscle weakness Depression Malnutrition Immune deficiency

4 Historical timelines and milestones Meryl Winningham (Exercise relieves cancer symptoms & improves function) Winningham & MacVicar (1988) Bicycle activity chemotherapy nausea MacVicar, Winningham & Nickel (1989) bicycle activity & increased capacity Winningham et al (1989) bicycle activity & increased lean mass Roanne Segal (Segal et al (2001) Effects of aerobic training in women undergoing chemotherapy with Stage I-II breast cancer 2002 American Cancer Society Guidelines for nutrition and physical activity for cancer risk 2005-present day: Over 150 studies completed

5 Presentation Outline Therapeutic role of exercise in cancer Reluctance on the part of the oncologist Historical timelines and milestones The role and importance of exercise along the cancer trajectory Exercise therapy prior to surgical resection (pre-surgery) Exercise therapy during adjuvant therapy (post-surgical) Exercise therapy following completion of adjuvant therapy (Survivorship or secondary prevention) Exercise therapy in advanced cancer (palliative care) McGill Nutrition and Performance Laboratory (MNUPAL) Assessing the advanced cancer patient Multimodal therapy (exercise / nutrition / medication)

6 Role of exercise during the Exercise therapy prior to surgical resection (presurgery) Exercise therapy prior to surgical resection (pre-surgery) cancer trajectory Exercise therapy in advanced, incurable cancer (palliative care) Exercise therapy during the during the adjuvant therapy period (post-surgical) Exercise therapy following completion of primary adjuvant therapy (Survivorship and secondary prevention)

7 Spot Quiz 1 Name the following famous scientists What do they have in common?

8 Presentation Outline Therapeutic role of exercise in cancer Reluctance on the part of the oncologist Historical timelines and milestones The role and importance of exercise along the cancer trajectory Exercise therapy prior to surgical resection (pre-surgery) Exercise therapy during adjuvant therapy (post-surgical) Exercise therapy following completion of adjuvant therapy (Survivorship or secondary prevention) Exercise therapy in advanced cancer (palliative care) McGill Nutrition and Performance Laboratory (MNUPAL) Assessing the advanced cancer patient Multimodal therapy (exercise / nutrition / medication)

9 Pre-surgery / Prehabilitation Exercise Therapy (Why prehabilitation?) Brief period of opportunity 4-6 wks between diagnosis and surgical intervention Patient activity levels (de-conditioning) Patient nutritional levels (loss of appetite, weight loss) Patient psychology (depression, fatigue) Assess complication risk for surgery Nutrition Muscle mass / strength (conditioning) VO 2 peak (conditioning) VO 2 peak in non-small cell lung cancer (NSCLC) Increased 2.4ml/kg/min; (Jones et al 2007) Increased 2.8 ml/kg/min; (Bobbio et al 2008)

10 Pre-surgery / Prehabilitation Future Approaches (Research hypotheses) Multimodal Approach Aerobic / weight training activities / nutrition / behaviour Research outcomes Better aerobic capacity Better strength (increase muscle mass?) Better nutrition Better behaviours (less fatigue, depression) Lower perioperative and postoperative complications Out of hospital earlier Fewer hospital returns Does pre-surgical training cause any change in tumour biology?

11 Exercise therapy during the adjuvant therapy period (post-surgical) Adjuvant therapy (chemotherapy) Anticancer / cytotoxic therapies bring direct and indirect physiological injury that reduces exercise tolerance, leading to morbidity, poor psycho-social functioning VO 2 peak not increased Exercise training is well-tolerated and safe

12 Adjuvant therapy / Post-surgical Research Question: Are cancer pts equally responsive to exercise during cytotoxic therapy? Courneya et al 2007 : 17 wks aerobic training did not improve VO2 peak in women receiving anthracycline-based chemo in early breast cancer Jones et al wks aerobic training undergoing cisplatin based chemo in NSCLC Speck et al (2010) exercise affecting 60 different outcomes during cytotoxic therapy (Most common CV fitness, QoL, fatigue, and body weight/ body composition)

13 Adjuvant therapy / post-surgical Future Directions Must broaden scope of exercise to other common toxicities such as anemia, hypertension, neutropenia, peripheral neuropathy, hypogonadism Other toxicities: cardiotoxicity (anthracycline therapy-doxorubicin, epirubicin) related to decreased LVEF and ultimately CHF Research Question Does exercise modulate the cytotoxicity of chemotherapeutic agents?

14 Spot Quiz 2 Multiple Choice This automatically controlled bicycle ergometer was designed by: A) Flemming Dela B) Rob Boushel C) August Krogh D) Jørn Helge

15 Completion of adjuvant therapy / Survivorship Important goals: Identify optimal exercise prescription for cancer survivors Are you interested in symptom management, secondary prevention Program is a function of tumour location, pathogenesis, therapeutic management, and late effects Current programs to date: aerobic exercise alone, weight training alone, and a combination Use of traditional exercise guidelines: (3-5 days / wk, 50-70% of baseline VO 2 peak; weeks)

16 Completion of adjuvant therapy/ Survivorship Research questions: Do benefits extend beyond symptom control? Is there improved survival following the cancer diagnosis? Yes Regular physical activity is associated with a 15-61% reduction in the risk of death from breast and colorectal cancers. Relation between physical activity and cancer specific mortality is not uniform (varies according to volume of activity and cancer type)

17 Completion of adjuvant therapy / survivorship Breast cancer: ( 9 MET-hr/wk ; 30 min brisk walking x 5 days) Tjonna et al (2009) Breast cancer: (21 MET-hr/wk brisk walking for 75 min x 5 days) Holick et al 2008 Colorectal: 18 MET- hr/wk (60 min x 5 days/ wk) to 27 MET hr/wk (brisk walking for 90 min /day x 5 days / wk Meyerhardt et al 2006a; 2006b; 2009

18 Completion of adjuvant therapy / Survivorship Exercise and histological sub-type Exercise response may differ according to the histological sub-type (breast cancer) Holmes et al (2005): 9 MET-hr/wk RR (relative risk reduction) of 9% on estrogen receptor (ER)- negative vs 50% RR reduction in ER-positive tumours Irwin et al (2008): 0 MET hr/wk 80% reduction in ER positive vs 26% in ER negative

19 Completion of adjuvant therapy / Survivorship Histological subtype Meyerhardt et al. (2009) Ex and mortality: may depend upon p27 status (what is p27? Marker gene that slows cell division) Tumours without p27, HR (hazard ratio) for colon cancer mortality was 1.40 (95% CI ) for pts reporting 18MET hr/wk Tumours expressing p27, the HR for cancer mortality was 0.33 (95% CI )

20 Completion of adjuvant therapy / Survivorship Overall findings suggests: 1) effectiveness of exercise depends upon: tumour type molecular status exercise volume histological sub-type Must have a better understanding of the molecular underpinnings of therapeutic response

21 Identification Spot Quiz 3

22 Exercise therapy in advanced (Stage III-IV), cancer (palliative care) Median survival: heterogenous, varies dramatically, according to molecular subtype and response to therapy. Have a more broad range of toxicities, more disease related symptoms, and impaired QOL (quality of life) Exercise and outcomes of major clinical importance: treatment related morbidities, and QOL

23 Palliative Care Exercise training interventions in advanced disease: challenging Take into account metastatic form of the disease The extensive pre-treatment for prior early stage disease Receiving aggressive combination of cytotoxic and supportive care therapies (appetite stimulant, steroids, testosterone derivatives) All this may influence exercise tolerance and adherence Will likely have pre-existing co-morbid conditions (neurotoxicity, cardiotoxicity) as well as age related comorbidities such as CV disease, osteoporosis, insulin resistance) Increased probability of exercise related AE (adverse event)

24 Presentation Outline Therapeutic role of exercise in cancer Reluctance on the part of the oncologist Historical timelines and milestones The role and importance of exercise along the cancer trajectory Exercise therapy prior to surgical resection (pre-surgery) Exercise therapy during adjuvant therapy (post-surgical) Exercise therapy following completion of adjuvant therapy (Survivorship or secondary prevention) Exercise therapy in advanced cancer (palliative care) McGill Nutrition and Performance Laboratory (MNUPAL) Assessing the advanced cancer patient Multimodal therapy (exercise / nutrition / medication)

25 McGill Nutrition and PerformAnce Laboratory (MNUPAL)

26 MNUPAL Leadership Director: Antonio Vigano MD, MSc Assoc Director: José Morais MD Assoc Director: Robert Kilgour PhD

27 MNUPAL Screening Assessments General Symptom and Nutritional Assessment Questionnaire Forearm muscle strength as measured by a dynamometer. Routine blood analysis (e.g., CRP, albumin) Specialized blood analysis (e.g., gene polymorphism, pro-inflammatory factors)

28 MNUPAL Interdisciplinary evaluation Patient history and physical examination Fatigue and Quality of Life Profiles Nutritional intake Body weight and height Percentage of fat and lean body mass Muscle strength Exercise capacity Basal metabolism

29 On-going studies at MNUPAL Characterizing frailty and cancer cachexia in elderly patients: A pilot study (B. Trutschnigg, MSc graduate) The effect of hypogonadism on functional status, nutritional status, body composition, symptoms and quality of life in advanced cancer patients: A review (M. Piccioni, MSc candidate) Visceral adipose tissue (VAT) measurement in the perioperative period as a predictor of post-operative morbidity following major hepatectomy. (L. Balaszi, BSc candidate)

30 Future research at MNUPAL Investigating the link between markers of nutrition and performance with surgical outcomes in patients with liver and pancreatic cancer: A pilot study (Molla, Chaudhury, Vigano, Metrakos, Hassasain, Morais & Kilgour) Pathophysiology of mitochondrial respiration in cancer cachexia: interdisciplinary and translational perspectives (Bergdahl-Scheede, Vigano, Kilgour, et al) Comparison of different methodological treatments for breast cancer related lymphedema (A. Newman, MSc candidate) Effects of a brief prehabilitation program on muscle mass, strength, and EMG in cancer (E. Chadnova, MSc candidate)

31 Future Research Influence of aerobic training & nutritional supplementation on functional capacity and survival

32 Monotherapy or Multimodal Therapies? Possible Multimodal Therapies Aerobic exercise training + ω-3 fatty acids + Progressive resistance training + nandrolone (steroid) +. Progressive resistance training + protein +

33 Impact of progressive resistance training and nutritional supplementation on body composition and functional performance in advanced cancer patients +

34 Progressive Resistance Training (PRT) programs Possible effects and outcomes Slows progression of muscle wasting (affects cytokine activity? Ubiquitin-proteasome pathway) Increase LBM? (increased protein synthesis and IGF) Increase muscle hypertrophy? (DEXA / CT scans) Pain (??) Add testosterone / steroids Decrease mrna of proteolytic markers (e.g., CRP, IL-6)

35 More for the Future Prehabilitation programming Pre-surgical exercise training Pre-surgical nutritional intervention

36 Anticipated Clinical Outcome Measures with Prehabilitation Toxicity to treatment Survival and Quality of Life Symptoms Response to chemotherapy and radiation therapy Peri-operative complications Length of stay in hospital following surgery Hospitalizations

37 Laboratory and Student Funding CIHR CFI MUHC Concordia

38 Acknowledgements Colleagues, Associates, and Students of the McGill Nutrition and PerformAnce Laboratory (MNUPAL) Antonio Vigano, MD, MSc José A. Morais, MD, FRCP Mazen Hassanain, MBBS, FRCS(C) Prosanto Chaudhury, MD, FRCS(C) Heather Watt, PhD (Post-doctoral fellow) Anne Newman, (MSc candidate) Eva Chadnova, (MSc candidate) Melissa Piccioni, (MSc candidate) Celena Scheede-Bergdahl, PhD (Researcher)

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