Abstract
Patients with peritoneal metastasis (PM) of gastrointestinal and gynecological origin present with a nutritional deficit characterized by increased resting energy expenditure (REE), loss of muscle mass, and protein catabolism. Progression of peritoneal metastasis, as with other advanced malignancies, is associated with cancer cachexia anorexia syndrome (CAS), involving poor appetite (anorexia), involuntary weight loss, and chronic inflammation. Eventual causes of mortality include dysfunctional metabolism and energy store exhaustion. Etiology of CAS in PM patients is multifactorial including tumor growth, host response, cytokine release, systemic inflammation, proteolysis, lipolysis, malignant small bowel obstruction, ascites, and gastrointestinal side effects of drug therapy (chemotherapy, opioids). Metabolic changes of CAS in PM relate more to a systemic inflammatory response than an adaptation to starvation. Metabolic reprogramming is required for cancer cells shed into the peritoneal cavity to resist anoikis (i.e., programmed cell death). Profound changes in hexokinase metabolism are needed to compensate ineffective oxidative phosphorylation in mitochondria. During the development of PM, hypoxia inducible factor-1α (HIF-1α) plays a key role in activating both aerobic and anaerobic glycolysis, increasing the uptake of glucose, lipid, and glutamine into cancer cells. HIF-1α upregulates hexokinase II, phosphoglycerate kinase 1 (PGK1), pyruvate dehydrogenase kinase (PDK), pyruvate kinase muscle isoenzyme 2 (PKM2), lactate dehydrogenase (LDH) and glucose transporters (GLUT) and promotes cytoplasmic glycolysis. HIF-1α also stimulates the utilization of glutamine and fatty acids as alternative energy substrates. Cancer cells in the peritoneal cavity interact with cancer-associated fibroblasts and adipocytes to meet metabolic demands and incorporate autophagy products for growth. Therapy of CAS in PM is challenging. Optimal nutritional intake alone including total parenteral nutrition is unable to reverse CAS. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) stabilized nutritional status in a significant proportion of PM patients. Agents targeting the mechanisms of CAS are under development.
Highlights
Cachexia anorexia syndrome (CAS), defined by an ongoing loss of skeletal muscle mass, is a common feature of advanced malignancy and some palliative medical conditions
Mean visceral fat level, skeletal muscle mass, albumin and protein levels were below normal limits and diagnostic criteria of Cachexia Anorexia Syndrome (CAS) were met in 23% of patients [22]
hypoxia inducible factor-1α (HIF-1α) can stimulate the utilization of glutamine and fatty acids as alternative substrates to glucose for mitochondrial energy production [24]
Summary
Cachexia anorexia syndrome (CAS), defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass), is a common feature of advanced malignancy and some palliative medical conditions. Anorexia is caused by ghrelin resistance, cytokine release, and a decreased hypothalamic drive to eat, and by pain, weakness, dry mouth, difficulty chewing or swallowing, dysphagia, constipation, chemosensory disturbances (e.g., taste and smell), early satiety, and nausea. These can all contribute to reduced caloric intake [2,4,5,6]. Optimal compensated nutritional intake including total parenteral nutrition (TPN) is unable to curb the progression of cachexia and protein loss in cancer patients, as compared to simple starvation [12,13]
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