Cancer cachexia is a syndrome involving multiple organ systems throughout the body that commonly exists in patients with malignant tumors, which affects the implementation of treatment plans, reduces the sensitivity of chemotherapy, increases the difficulty of treatment and the occurrence of related treatment complications, seriously affects the quality of life of cancer patients, shortens the survival period, and is the main cause of death of cancer patients. To date, despite the progressive understanding of the mechanisms of carcinomatous cachexia, clinical treatments for carcinomatous cachexia are still very limited. The definition of diagnostic and staging criteria for cancerous cachexia will help standardize the diagnosis of cachexia, improve the understanding of the degree of cachexia in different stages of malignant tumors, and better guide clinical treatment. And the reasonable treatment of malignant disease will further improve the quality of life of tumor patients and prolong their survival time. Lu Yanda, Department of Radiotherapy, Affiliated Hospital of Hainan Medical College 1 Diagnosis The understanding of cachexia has been gradually deepened in the past decade, but there is still a lack of accurate definition and diagnostic and grading criteria for it in both clinical trials and clinical practice. Cancer cachexia is a multifactorial syndrome rather than a simple weight loss. Clarifying the diagnostic and staging criteria of carcinomatous cachexia will facilitate the early treatment of carcinomatous cachexia and thus improve the prognosis of patients with malignancy and cachexia. An international consensus on the criteria for the diagnosis and staging of cancer cachexia was recently published in Lancet Oncol by experts from eight countries. Cancer cachexia is defined as a multifactorial syndrome characterized by clinical features that are not completely reversible by conventional nutritional support therapy, partial or no sensitivity to nutritional support, with progressive development of reduced skeletal muscle mass (with or without reduced fat mass) and consequent functional impairment, and a pathophysiology characterized by negative nitrogen balance and negative energy balance due to reduced food intake and abnormal hypermetabolism The pathophysiology is characterized by negative nitrogen balance and negative energy balance due to reduced food intake and abnormally high metabolism. The Congress proposed to define a 5% weight loss or a body mass index (BMI) < 20 kg/m2 or a 2% weight loss in those who have already experienced a reduction in skeletal muscle mass as diagnostic criteria for carcinomatous cachexia. It also proposed that the classification criteria and clinical treatment of cancer cachexia should include anorexia or reduced food intake, enhanced catabolism, reduced muscle mass and consequent functional and psychosocial impairment. This time, experts from 8 countries jointly launched an international consensus, which divided cachexia into 3 stages: pre-cachexia, cachexia and refractory cachexia. The specific staging criteria are as follows: weight loss <5%, accompanied by anorexia and metabolic changes is to enter the pre-malignant stage; weight loss >5% or BMI < 20 kg/m2 within 6 months appears >2%, or the skeletal muscle index of the extremities and oligomyositis matches (male <7. 26 kg/m2, female <5.45 kg/m2) appears >2%, as the beginning of the Advanced cancer patients with active catabolism, unresponsive to anticancer therapy, low WHO physical status score (3 or 4) and survival of less than 3 months are considered to have entered the refractory cachexia stage. Referring to this international consensus, the development of experimental research and clinical diagnosis and treatment of cachexia due to cancer will be advanced. The definition of cancer cachexia introduced this time takes weight loss as its prominent clinical feature, about half of cancer patients have different degrees of weight loss, and about 86% of cancer patients have weight loss in the last 2 weeks of life. Weight loss >2.75% per month has been used as an important indicator to judge the prognosis of cancer patients, and it is proposed that weight loss in the hormonal state is completely different from that caused by chronic starvation and common anorexia nervosa. Cachexia can occur in cancer, AIDS, surgery, severe trauma, malnutrition and sepsis. Cancer cachexia is different from the weight loss of starvation. The brain and red blood cells are depleted of liver glycogen and muscle glycogen at the early stage of starvation, accelerating sugar isogenesis and quickly turning to the use of fat, and free fatty acids are transformed into ketone bodies to be used by peripheral tissues and even for brain tissues, so that muscle is preserved. In anorexia nervosa, 3/4 of the weight loss is due to fat loss and only a small percentage is due to muscle loss. However, weight loss in carcinomatous cachexia is dominated by a loss of skeletal muscle mass with or without a loss of fat mass. Therefore, when weight loss is the same, cancerous cachexia loses more muscle than anorexia nervosa. Although patients with cancerous cachexia are often associated with loss of appetite (15%-40%), it is not the main cause of cancerous cachexia. The degree of reduced intake in malnourished cancer patients does not correspond to the degree of malnutrition, even if muscle and fat loss occurs before the decline in eating. Additional caloric provision does not reverse the changes in body composition of cancerous cachexia, nor does it reverse the onset of cancerous cachexia. Parenteral nutrition can temporarily maintain fat reserves, but it cannot maintain fat-free body weight and prolong the average survival time and long-term survival time of cancerous cachexia. Therefore, the mechanism of cancerous cachexia is more complicated than starvation alone. 2 Treatment 2.1 Traditional treatment methods: nutritional support therapy can improve the metabolic status of patients with cancerous cachexia, enhance the immunity of the body and improve the quality of life of patients, and also effectively restore and maintain the physiological functions of the organs of the body, which is conducive to the improvement of the bioavailability of chemotherapy and other drugs. At present, immunonutritional preparations containing special substrates such as arginine, glutamine and various branched-chain amino acids have been put into clinical application for the treatment of patients with advanced cancer and cancerous cachexia. However, studies have shown that simple nutritional support therapy cannot reverse the cachexia state, and anorexia is a major symptom of cachexia. Traditional treatment is mostly carried out in the late stage of cachexia with nutritional support along with the following treatment methods. 2.1.1 Appetite stimulants to assist in eating: Medroxyprogesterone is a synthetic progestin derivative, which can affect metabolism through direct and indirect pathways and can improve appetite and increase caloric intake through the production of cytokines with anabolic effects. Although the appetite and body weight of patients increased after medroxyprogesterone administration, marker molecules of bone and visceral proteins did not increase significantly. Its main adverse effects include thromboembolism at high doses, headache, transient adrenocortical insufficiency, anemia, coma, and insomnia. In addition, progesterone decreases the muscle ratio and increases the fat ratio, and these adverse effects affect the use of megestrol as a routine treatment for cachexia. 2.1.2 Antidepressants to relieve anxiety: Mirtazapine is a tetracyclic antidepressant, mainly used for the treatment of depression, to improve appetite and maintain body weight by improving patients’ mood, but like other appetite-promoting drugs, although it can make patients’ anorexia improve and body weight increase, the marker protein molecules of skeletal muscle and viscera do not increase, and it has no obvious effect on cachexia. 2.1.3 Antiemetics to prevent vomiting: Dronabinol is an antiemetic derived from Indian cannabis that increases appetite and mood. Although its appetite enhancing effect in patients with AIDS-related weight loss is positive, its pharmacokinetics have not been studied in depth. In addition, the lack of control in terms of dose control and adverse effects such as hallucinations and depression limits its use in cancerous malignancies and is more suitable as an adjunctive treatment in patients in palliative care. 2.2 New treatments 2.2.1 Eicosapentaenoic acid: eicosapentae-noic acid (EPA) is an n-3 fatty acid that cannot be synthesized in mammals and can only be obtained through diet. These polyunsaturated fats are found in fish oil from cod liver, sardines and salmon. epa inhibits the interleukin (IL)-6 gene promoter, reduces IL-6 production, inhibits IL-6 production and reduces acute response protein production by hepatocytes in pancreatic cancer patients, and stabilizes body weight. Laboratory and clinical studies have shown that EPA has antitumor and cachexia effects. Preliminary studies using animal models have shown that nuclear factor-κB (NF-κB) is upregulated in cachectic patients in parallel with increased protein hydrolysis and myotubular apoptosis. In contrast, EPA can prevent protein catabolism by inhibiting NF-κB accumulation in the nucleus. n-3 fatty acids and EPA capsules have been shown to be important in maintaining body weight in patients with advanced pancreatic cancer and improving quality of life in those with reduced body weight. Studies have shown that n-3 fatty acids prevent the destruction of integrated fibroblast proteins by downregulating NF-κB and modulating the inflammatory response, resulting in elevated serum proteins and increased lean body mass and improved function. 2.2.2 Growth hormone releasing peptide: Growth hormone releasing peptide is a natural ligand of growth hormone, mainly produced by the stomach, and is the only circulating hormone that can promote appetite, on the one hand it is an anabolic hormone that can store protein in the case of fat consumption. Growth hormone-releasing peptide promotes the secretion of growth hormone, which is several times stronger than growth hormone-releasing hormone in the same environment, and growth hormone promotes lipolysis, lipid synthesis, myogenic cell cell differentiation and muscle growth. The FDA has approved recombinant growth hormone for patients with wasting AIDS, short bowel syndrome dependent on parenteral nutrition, pediatric chronic kidney disease, and growth hormone deficiency with adverse effects such as arthralgia, carpal tunnel syndrome, insulin resistance, sodium retention, and peripheral edema. Stimulation of growth hormone secretion by growth hormone releasing peptide rarely causes these adverse reactions. On the other hand growth hormone releasing peptide can inhibit the production of anorexia pre-inflammatory factors. It inhibits the production of pro-inflammatory cytokines such as 11-1 B, IL-6, tumor necrosis factor-α only in vivo and in vitro. In clinical trials, application of growth hormone-releasing peptide significantly reduced pro-inflammatory factors and sputum neutrophil levels in patients with respiratory diseases, and conversely, it induced the production of the anti-inflammatory factor IL-10. In patients with cachexia NF-κB causes protein degradation through gene, proteasome pathway, and its activation may regulate skeletal muscle proteasome expression and protein degradation by upregulating two muscle-specific gene ligases ubiquitin ligase MAFbx and muscle ring finger protein 1 (MuRF1) during catabolism, while growth hormone releasing peptide was able to inhibit NF-κB activation. In addition, growth hormone releasing peptide can promote the synthesis of insulin-like growth factor (IGF)-1, which can inhibit the expression of MuRF1 and MAFbx by activating the phosphatidylinositol 3-kinase-protein kinase B pathway and suppressing the forkhead box transcription factor 0. Thus growth hormone-releasing peptide is very effective in attenuating the inflammatory response in cachectic patients via NF-κB and IGF-1. Several studies have evaluated the role of growth hormone-releasing peptides in the treatment of cachexia caused by a variety of diseases, including congestive heart failure, chronic obstructive pulmonary disease, cancer, and end-stage renal disease. These studies will be useful in guiding new clinical applications of growth hormone-releasing peptides. In experiments with growth releasing peptide application in rats and humans, repeated application of growth releasing peptide resulted in significant weight gain in rats and patients with chronic obstructive pulmonary disease, with an increased rate of obesity in rats and a decreased rate of obesity in humans, and this difference may be related to the dose and frequency of growth releasing peptide application, with long-term injections of low doses of growth releasing peptide twice weekly resulting in a significant reduction in adiposity in adult rats. 2.2.3 Alamorelin: Alamorelin is a growth hormone-releasing peptide receptor agonist, and the application showed elevated IGF-1, which is much better than the application of growth hormone-releasing peptide alone. 12 weeks of application of alamorelin resulted in a significant increase in food intake, and IGF-1 was 36.5 ng/ml and 5.95 ng/ml in the experimental and control groups, respectively, after treatment on healthy volunteers After 6 days of treatment, IGF-1 in the experimental group reached 60 ng/ml, while in the control group it was 0. IGF-1 is the main factor in maintaining the energy balance of the body. 3 Conclusion Traditional treatments (including nutritional support, appetite stimulation, anti-inflammatory and other treatments) are often started for patients in the late stage of cachexia, and the treatment effect is based on the change of patients’ body weight, which often cannot improve the changes of cytokines in patients’ bodies and therefore cannot really alleviate the cachectic state of patients. With the in-depth research on molecular level, it was found that the combination of EPA and growth hormone-releasing peptide with traditional therapies in the early stage of cachexia, and the detection of changes in NF-κB and other molecules in the body, could really bring about significant remission of cachexia and thus improve the quality of life and survival rate of patients. 2013-01-05 06:28 Source: International Journal of Oncology Author：Liu Zifeng et al.