Cancer cachexia syndrome

1. Cancer cachexia syndrome นพ.บูรพา ปุสธรรม นพ.มณฑล ว่องวัณดี 2/3/50

2. Scope • Introduction • Pathogenesis • Conventional management • Novel therapy

3. Introduction • Cachexia : Greek word • Kakos : bad • Hexis : condition • Characteristics • Weight loss • Lipolysis • Muscle wasting • Anorexia • Chronic nausea • Asthenia • Anemia • Electrolyte and water abnormalities • Psychological distress

4. Introduction • Diagnostic criteria for cachexia • Unintentional weight loss (≥ 5%) • BMI • < 20 in those aged < 65 yrs • < 22 in those aged ≥ 65 yrs • Albumin < 3.5 g/dl • Low fat-free mass (lowest 10%) • Evidence of cytokine excess (eg, elevated C-reactive protein)

5. Introduction

6. Introduction • Cancer cachexia • 80 % of advance disease • Unclear underlying pathophysiologic mechanism • Poor prognostic factor • Differ from other condition • Starvation • Dehydration • Sarcopenia

7. Introduction • Cachexia VS anorexia (starvation) • Body composition • Cachexia : loss of fat and skeletal muscle prior decrease food intake, reserve non-muscle protein • Anorexia : loss of fat but small amount of muscle, after decrease food intake • Weight loss • Cachexia : complex metabolic events • Anorexia : simple nutritional deficiency • Treatment • Cachexia : multiple aspect • Anorexia : treatable by protein-calorie supplementation

8. Introduction

9. Introduction • Factors contributing for cancer cachexia • Host-related • Humeral factors • Treatment factors • Chemotherapy : mucositis, nausea, vomitting, diarrhea, taste alteration • Radiotherapy : enteritis, diarrhea, decrease saliva • Surgery : malabsortion due to gactrectomy, short bowel syndrome, pancreatic resection • Tumour-related • Tumour mediator • Mechanical problem • GI tract malignancy

10. Pathogenesis • Humeral factor • TNF-α • Suppress lipoprotein lipase activity • Proteolytic activity • Apoptotis of skeletal muscle • Increase level of CRH and leptin • Interleukin-1 • Blocking neuropeptide Y • Increase level of CRH and leptin

11. Pathogenesis • Humeral factor • Interleukin-6 • Activation of ubiquitin ligase-dependent preteosome pathway • Leukemia inhibitor factor (LIF) • Increase leptin • Ciliary neurotropic factor • Compose from IL-6 and LIF • Potent cachectic effect • Acute-phase protein response

12. Pathogenesis • Humeral factor • Interferon-γ (IFN-γ) • Biologic activity overlap with TNF • Monoclonal Ab against IFN-γ could reverse wasting syndrome • Anti-cachetic mediator • Interleukin-4, interleukin-10, interleukin-13 • Soluble receptor for TNF and IL-6

13. Pathogenesis • Tumour mediator • Lipid mobilizing factor(LMF) • Induce lipolysis • Correlate with weight loss • Proteolysis inducing factor(PIF) • Induce protein degradation • Decrease protein systhesis • May increase cytokines and acute phase protein

14. Pathogenesis • Tumour mediator • Anemia inducing substance(AIS) • Decrease osmotic resistance and deformability • Increase fragile • Alter energy metabolism • Tumour product? • Induce uncoupling protein(UPC) • UPC 3 : brown adipose tissue and skeletal muscle • Decrease ATP production • Increase heat production

15. Pathogenesis

16. Pathogenesis

18. Pathogenesis • Glucose homeostasis • Increase gluconeogenesis • Muscle and fat breakdown • Increase glycolysis from muscle and tumour • Increase lactate production • Elevation of cori cycle activity • 300 kcal/day of energy loss • Glucose intolerance • Insulin resistance • Increase counter regulatory hormone • Decrease muscle glucose uptake

19. Pathogenesis

20. Pathogenesis • Protein metabolism • Increase muscle catabolism • Decrease muscle protein synthesis • Muscle wasting : asthenia • Increase tumour protein synthesis • Increase liver protein synthesis • Acute phase protein

21. Pathogenesis • Lipid metabolism • Increase lipolysis • Decrease lipogenesis • Profound loss of adipose tissue • Decrease lipoprotein lipase • Decrease clearance of triglyceride • Hypertriglyceridemia • Low LDL, HDL

22. Pathogenesis