CANCER CACHEXIA Barry J A Laird Clinician Scientist in Palliative Medicine, University of Edinburgh & European Palliative Care Research Centre Consultant in Palliative Medicine BWoSCC and Edinburgh Cancer Centre, UK www.igmm.ac.uk
Acknowledgements University of Edinburgh Prof Ken Fearon, Prof Marie Fallon NTNU Prof P Klepstad, Prof S Kaasa, Prof P Fayers, Prof M Hjermstad University of Glasgow Prof D McMillan
Current standard of care in cancer cachexia? What are the licensed treatments for cancer cachexia? Dexamethasone Megesterol
A well designed study to evaluate the benefit of nutritional support in patients with weight loss receiving chemotherapy is needed PJ Ross et al 2004
The relationship between clinic-pathological factors and survival in patients with metastatic lung cancer (n=390) Parameter n % Univariate Multivariate Sex (M/F) 341/ 49 87.4/12.6 0.60 (0.41-0.88) 0.009 Age ( 65/ 65-74/ 74years) 154 /150/86 39.5/38.5/22.1 1.28 (1.08 1.50) 0.004 HR (95% CI) p-value HR (95% CI) p-value Tumour type (NSCLC vs SCLC) 288/102 73.8/26.2 1.39 (1.10-1.77) 0.007 Weight loss (%) Category in past 3 months (1/2) a Performance Status (ECOG) (0-1/2/3/4) 195/195 50.0/50.0 1.49 (1.18-1.88) 0.001 271/75/31/13 69.5/19.2/7.9/ 3.3 1.90 (1.65-2.18) <0.001 1.74 (1.50-2.02) <0.001 mgps (0/ 1/ 2) 103/183/104 26.4/46.9/26.7 1.84 (1.54-2.19) <0.001 1.67 (1.40-2.00) <0.001
Pathophysiology There have been great advances in the knowledge of cachexia pathophysiology This has lead to an increased understanding that cachexia is a distinct entity and must be treated as such
ANABOLIC BLOCKADE Systemic Inflammatory Response Cachexia Anorexia Physical Inactivity
Pro-inflammatory NORMAL Anti-inflammatory CANCER CACHEXIA Anti-inflammatory Pro-inflammatory
Inflammation & Cancer Inflammation predisposes to certain tumour types Inflammation implicated in oncogenic mutations & experimental animal models of tumour development 1 Inflammation can be a result of cancer. Targeting inflammation can reduce cancer risk and cancer spread. 7 th hallmark of cancer
Why has research in cachexia been slow? Unimodal therapy trials Prerequisite of oncology trials Late phase You are not eligible if you are taking part in another trial fastidious vs pragmatic trials gatekeeping Limited pharmaceutical funding Lack of a consensus definition
Volume 12, Issue 5, May 2011, P489-495 A multifactorial syndrome characterised by an on-going muscle loss (with or without fat loss) that cannot be fully reversed by nutritional support and leads to progressive functional impairment. The pathophysiology is characterized by a negative protein and energy balance driven by a variable combination of reduced nutritional intake and abnormal metabolism
Pre-cachexia Cachexia Refractory-cachexia Death Weight loss <5% Anorexia & metabolic change Weight loss>5% or BMI<20 and weight loss >2% or sarcopenia and weight loss >2% Variable degree of cachexia. Cancer disease both procatabolic and not responsive to anti-cancer treatment. Low PS, survival <3 months
Multimodal Therapy: High protein nutrition Anti-inflammatory agents to down regulate the APPR Routine mobilisation programmes to prevent deconditioning and encourage physical activity-induced stimulation of post prandial anabolism. Mantovani G, Maccio A, Madeddu C, et al. Randomized phase III clinical trial of five different arms of treatment in 332 patients with cancer cachexia. Oncologist 2010;15:200-11
Multimodal Intervention Critical pre-cachexic phase Combined with anti-cancer therapy
premenac Study A multicentre, open, randomized phase II study comparing a multimodal intervention (oral nutritional supplements, celecoxib and physical exercise) for cachexia versus standard cancer care. (EudraCT number: 2010-022897-14) Funding EU FP6 framework
Identification Consent Treatment Arm (Multimodal intervention + Standard cancer care) Control Arm (Standard cancer care) Week 0 Week 6 Participants are offered same treatment as treatment arm (Multimodal intervention) Week 12
Multimodal Intervention (1) - Nutrition Aim: promote energy balance & ensure optimal protein intake Dietician led interview targets set. Information on dietary intake assessed. Advice given to modify diet to achieve targets Oral nutritional supplements 2 cartons (2x 220mls) per day of ProSURE. Contains 1.1g of EPA per carton. Energy and protein dense. Balstad, T.R., et al., Dietary treatment of weight loss in patients with advanced cancer and cachexia: A systematic literature review. Crit Rev Oncol Hematol, 2014. Baldwin, C., et al., Oral nutritional interventions in malnourished patients with cancer: a systematic review and meta-analysis. J Natl Cancer Inst, 2012. 104(5): p. 371-85. Cerchietti, L.C., A.H. Navigante, and M.A. Castro, Effects of eicosapentaenoic and docosahexaenoic n-3 fatty acids from fish oil and preferential Cox-2 inhibition on systemic syndromes in patients with advanced lung cancer. Nutr Cancer, 2007. 59(1): p. 14-20.
Multimodal Intervention (2) - Exercise Aim: to stabilize muscle mass, strength and improve physical performance Physiotherapist initial instruction and assessment Aerobic minimum 2 x 30 minute sessions per week (Borg scale 12-14) Resistance tailored 0.5-5kg weights. 3x20 minute sessions per week. Increasing weight over period of study Stene GB, Helbostad JL, Balstad TR, Riphagen, II, Kaasa S, Oldervoll LM. Effect of physical exercise on muscle mass and strength in cancer patients during treatment--a systematic review. Crit Rev Oncol Hematol
Multimodal Intervention (3) - COXII Aim: to target overproduction of inflammatory cytokines Celecoxib most studied, may have beneficial effects in cachexia Dose 300mg per day. Cerchietti, L.C., A.H. Navigante, and M.A. Castro, Effects of eicosapentaenoic and docosahexaenoic n-3 fatty acids from fish oil and preferential Cox-2 inhibition on systemic syndromes in patients with advanced lung cancer. Nutr Cancer, 2007. 59(1): p. 14-20. Maccio A, Madeddu C, Gramignano G, et al. A randomized phase III clinical trial of a combined treatment for cachexia in patients with gynecological cancers: evaluating the impact on metabolic and inflammatory profiles and quality of life. Gynecol Oncol 2012;124:417-25. Solheim, T.S., et al., Non-steroidal anti-inflammatory treatment in cancer cachexia: A systematic literature review. Acta Oncol, 2012.
Endpoints Primary Feasibility, recruitment, retention Secondary LBM, weight, activity, nutritional, toxicity, anti-cancer therapy
Antiinflammatories Systemic Inflammatory Response Nutritional Intake Cachexia Exercise Anorexia Immunomodulation! Physical Inactivity
Cachexia treatment hierarchy 1. Anti-neoplastic therapy 2. Target inflammation 3. Target factors affecting food and activity 4. Optimise nutritional intake 5. Promote activity
barry.laird@ed.ac.uk www.igmm.ac.uk