Cancer cachexia Cancer cachexia syndromesyndrome

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Scope

Introduction Pathogenesis Conventional management Novel therapy

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

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 factorTNF-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

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 mediatorLipid 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 catabolismDecrease muscle protein synthesis

Muscle wasting : asthenia

Increase tumour protein synthesis Increase liver protein synthesis

Acute phase protein

Pathogenesis

Lipid metabolism Increase lipolysisDecrease lipogenesis

Profound loss of adipose tissue

Decrease lipoprotein lipase Decrease clearance of triglyceride Hypertriglyceridemia Low LDL, HDL

Pathogenesis