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 Characteristics 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 Interleukin-1
Suppress lipoprotein lipase activity
Proteolytic activity
Apoptotis of skeletal muscle
Increase level of CRH and leptin
Interleukin-1
Blocking neuropeptide Y

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