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

Scope Introduction Pathogenesis Conventional management Novel therapy

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

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)

Introduction

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

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

Introduction

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

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

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

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

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

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

Pathogenesis

Pathogenesis

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

Pathogenesis

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

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

Pathogenesis