Cancer cachexia

Cancer cachexia is a severe debilitating disorder for which there are currently few therapeutic options. It is driven by the release of pro-inflammatory cytokines and cachectic factors by both host and tumour. Over the past few years, basic science advances have begun to reveal the breadth and complexity of the immunological mechanisms involved, and in the process have uncovered some novel potential therapeutic targets. The effectiveness of thalidomide and eicosapentaenoic acid at attenuating weight loss in clinical trials also provides a further rationale for modulating the immune response. We are now entering an exciting period in cachexia research, and it is likely that the next few years will see effective new biological therapies reach clinical practice.     

Eicosapentaenoic Acid

Cancer cachexia affects about half of all cancer patients and is associated with negative effects on functional status and quality of life. This condition is also a major contributor to the morbidity and mortality of patients with advanced malignancy. Although current strategies to improve appetite and lean body mass by administering appetite stimulants, increasing physical activity and using nutritional supplementation have a scientific rationale, randomised studies have continued to demonstrate that a reduction in the loss of lean body mass is difficult to achieve unless the underlying metabolic abnormalities in cancer cachexia are corrected. Initial studies using animal models have demonstrated that nuclear factor-κ B (NF-κB) is upregulated in cancer cachexia, increasing proteolysis and breakdown of myofibrillar proteins, which results in sarcopenia. Laboratory studies have shown that eicosapentaenoic acid (EPA), an n-3 fatty acid, has anticachectic effects and may attenuate protein degradation by preventing NF-κB accumulation in the nucleus. EPA is associated with weight stabilisation, gain in lean body mass, and improvement in quality-of-life markers in weight-losing patients with advanced pancreatic cancer. Although animal studies have demonstrated the molecular basis of the effects of EPA, this has never been validated in human clinical trials. On the basis of the promising results of the laboratory and clinical studies, we hypothesise that selective targeting of proteasome activity by EPA (a polyunsaturated fatty acid) administered to cancer patients, including elderly patients, with cancer cachexia will alter metabolic abnormalities by downregulating NF-κB, modulating immune and inflammatory response and thus preventing the breakdown of myofibrillar proteins. This will result in promotion of anabolism, reduction of weight loss and increase in lean body mass and physical function, thus establishing a case for future, prospective clinical trials.     

The 'cancer cachectic factor'

The object of this study was to summarize information on catabolic factors produced by tumours which lead to tissue catabolism in cancer cachexia and to use this information for the development of effective therapy. The study population was made up of patients with cancer cachexia and weight loss greater than 1 kg month(-1). They had a varied range of carcinomas, particularly pancreatic, but also of the breast, ovary, lung, colon and rectum. Cachectic factors were isolated by standard biochemical methods, and the mechanism of tissue catabolism was evaluated in vitro and in vivo. We isolated a 24-kDa sulphated glycoprotein produced by cachexia-inducing murine and human tumours, which induces catabolism of myofibrillar proteins in skeletal muscle and for this reason has been named proteolysis-inducing factor (PIF). PIF was shown to be present in a diverse range of carcinomas in patients whose rate of weight loss exceeded 1.0 kg month(-1). Administration of PIF to normal mice produced a rapid decrease in body weight, which arose primarily from a loss of skeletal muscle, accompanied by increased mRNA levels for ubiquitin, the ubiquitin-carrier protein (E2(14k)), and proteasome subunits. This suggests that PIF induces protein catabolism through an increased expression of the key components of the ATP-ubiquitin-dependent proteolytic pathway. The action of PIF was attenuated both in vitro and in vivo by eicosapentaenoic acid (EPA). Oral EPA has been found to stabilize the body weight of patients with advanced pancreatic cancer and, when combined with an energy- and protein-rich nutritional supplement, to produce weight gain arising solely from an increase in lean body mass. Nutritional supplementation alone is unable to reverse the process of muscle wasting in cancer patients, since this arises from activation of the ubiquitin proteasome pathway by PIF, which is independent of nutrient intake. EPA is able to down-regulate the increased expression of this pathway and prevents muscle wasting in cancer patients.     

Management of cancer cachexia

The diagnosis of cancer has traditionally been associated with malnutrition and wasting. Oncology patients are at risk for nutrition-related problems because of the cancer itself, as well as the treatment prescribed. Clinical manifestations of cachexia include anorexia, weight loss, muscle wasting, and fatigue, resulting in poor performance status. Control of symptoms, such as anorexia, nausea and vomiting, and mucositis is imperative in the management of cancer cachexia. Current pharmacologic therapies, as well as complementary and alternative methods, are presented. The nurse plays a key role in ensuring that the nutritional needs of oncology patients are met.     

Conjugated linoleic acid preserves gastrocnemius muscle mass in mice bearing the colon-26 adenocarcinoma

Cancer cachexia is a syndrome of weight loss, muscle wasting, fatigue, and anorexia that occurs in patients with advanced or recurrent solid tumor disease. Tumor necrosis factor-alpha (TNFalpha) and prostaglandin E2 (PGE2) have been implicated in the biology of cachexia and serve as possible targets for treatment of this condition. Conjugated linoleic acid (CLA) is a polyunsaturated fatty acid that alters the synthesis of PGE2 and reduces the negative effects of TNF on body weight of healthy mice. We hypothesized that a diet supplemented with .5% CLA might reduce muscle wasting in mice bearing the colon-26 adenocarcinoma, an animal model of cancer cachexia. CLA preserved gastrocnemius muscle mass and reduced TNF receptors in muscle of tumor-bearing mice. These data suggest that CLA may preserve muscle mass by reducing the catabolic effects of TNF on skeletal muscle.     

The starving patient: supportive care for people with cancer

Unintentional weight loss in people with cancer is associated with decreased quality of life and increased mortality. Addressing risk factors that lead to weight loss may improve quality of life and prevent cachexia. Specific, individualized counseling is the most beneficial and economic intervention for nutritional health. Appetite stimulants promote oral intake, and oral supplements help to meet the increased need for calories and protein during the course of the disease and its treatment. Utilizing the gut for digestion and absorption of food maintains the critical functions of the bowel lumen. Tube feeding and parenteral nutrition may be indicated for prevention of malnutrition in some disease conditions and during certain types of cancer treatment.     

Nutritional support in multimodal therapy for cancer cachexia

Introduction Malnutrition has since long been known to be associated with adverse outcomes in cancer patients. The wasting in cancer cachexia involves loss of muscle and fat and reflects a catabolic metabolism induced by an abnormal host response to tumour presence and/or tumour factors. Patients with cancer cachexia frequently develop a chronic negative energy and protein balance driven by a combination of reduced food intake and metabolic change. Thus, alterations in both energy intake and components of energy expenditure may contribute to progressive weight loss. Increased resting energy expenditure related to the systemic inflammatory response is common and a sustained hypermetabolism over a long period of disease progression can make a large contribution to negative energy balance and wasting if not compensated for by an increase in energy intake. Hypermetabolism and diminished energy intake due to anorexia may thus constitute a vicious circle in the development of cancer cachexia. Discussion Though nutritional support alone can improve energy intake to a variable extent and for a variable period of time, it will not address the underlying catabolic metabolism and is thus likely to be of limited efficacy if attempts to attenuate the tumour-induced catabolic response are not carried out at the same time. Concomitant drug treatments for cancer cachexia may slow down the wasting process by reducing anorexia, attenuating the systemic inflammation, the skeletal muscle catabolism or stimulating the muscle protein anabolism. Thus, improved management of cancer cachexia may require a multimodal approach by a multi-disciplinary team and is best commenced earlier rather than later. Early start of therapy also facilitates the use of oral nutritional supplementation, which is preferable to parenteral nutrition in the majority of cases. Once a patient is severely wasted it may be neither practical nor ethical to intervene with anything else than supportive care. Conclusion An improvement in the condition of all patients with cachexia may not be possible, however, the goal must be to stabilise cachexia and prevent or delay further decline. There is currently no single or combined treatment strategy which is successful in all patients. However, strategies to counteract both hypermetabolism and reduced dietary intake have been demonstrated to be of importance for the survival, function and quality of life of cancer patients and should be further explored in interventional studies. Presented as invited lecture at the MASCC/ISOO 20th Anniversary International Symposium Supportive Care in Cancer in St. Gallen, June 2007.     

胃癌患者围手术期营养支持的研究进展

肿瘤性恶病质是上消化道癌患者常见的临床表现。大多胃癌患者伴有肿瘤厌食-恶液质综合征，因长期禁食出现体重减轻、食欲下降、疲乏虚弱是影响患者预后的重要因素。虽然有文献报道围手术期的营养支持可明显降低术后并发症的发生率和患者死亡率，但有关胃癌患者围手术期系统的营养支持方案并不成熟。本文对胃癌患者营养评估工具、风险筛查、干预方案进行综述，为临床提供参考。     

The biochemical basis of metabolism in cancer cachexia.

Cancer cachexia is a syndrome of progressive body wasting characterized by loss of adipose tissue and skeletal muscle mass. It is the most common side effect of malignancy occurring in approximately one-half of untreated cancer patients. The pathophysiology of cancer cachexia is not fully understood; however, studies have shown that cytokines are important in the alteration of carbohydrate, lipid, and protein metabolism. This leads to a shorter survival time and a decreased response to therapy. Cachexia is often found before any signs or symptoms of the cancer. An uncertainty with cachexia is whether nutritional support is feeding the patient or the tumor. Often, cachexia is not responsive to simple nutritional interventions. Furthermore, appetite stimulants, cytokine inhibitors, and Cori cycle inhibitors have been used to treat cancer cachexia.     

Nursing management of nutrition in cancer and palliative care

Malnutrition is prevalent in patients with cancer. This can have deleterious effects including reduced response to treatment, diminished quality of life, increased length of hospital stay and decreased survival. It is, therefore, imperative that thorough nutritional screening is carried out by nurses on patients' admission and during their hospital stay to detect those who are malnourished or at risk of malnutrition in order to plan their nutritional care effectively. Cancer cachexia is the progressive weight loss and emaciation seen in cancer patients, particularly in advanced disease, which can have a devastating effect on the physical, psychological, social and spiritual aspects of the patient's life. Therefore, the aims of nutritional care are identified depending on the stage of the patient's illness and recommendations made for nursing, pharmacological and nutritional intervention. These include nursing comfort strategies, the use of recommended pharmacological agents and dietary interventions such as experimenting with different foods, textures, portion sizes and nutritional supplements. The use of fish oil-enhanced nutritional supplements and artificial nutritional support is also discussed. Consideration is also given to the legal and ethical aspects of providing nutrition and nutritional support.     

A descriptive review of the factors contributing to nutritional compromise in patients with head and neck cancer

Introduction

Malnutrition has been known to be associated with adverse outcomes in cancer patients. Patients who have been and/or are being treated for head and neck cancer have a compromised nutritional status. Nutritional deficits have a significant impact on mortality, morbidity, and quality of life.

Discussion

The wasting in cancer cachexia involves loss of muscle and fat and reflects a catabolic metabolism induced by an abnormal host response to tumor presence and/or tumor factors. Disturbances of various physiological functions like taste, smell, dysphagia, xerostomia apart from cachexia can contribute to long-term nutritional complications and outcome.

Conclusion

Improved management of patients in posttreatment for head and neck cancer may require a multimodal approach by a multidisciplinary team and is best commenced earlier in the trajectory of the disease.     

Nutrition support. Making the difficult decisions

Weight loss and cachexia are common characteristics associated with the cancer patient. Although the wasted appearance seems the same in each person, the causes are varied. Studying a patient's history and identifying surgical causes to weight loss or weight loss as a result of treatment complications assists in the consideration of nutritional support. Nutritional parameters combined with the oncology nurse's knowledge of the patient, disease process, and treatment side effects place the nurse in the position to help identify options for nutritional support. The oncology nurse's expertise assists in the decision making process, since it is often not appropriate to institute nutritional support in the inpatient setting nor extend it to the home situation. Objective assessment parameters for home parenteral nutrition assist the nurse in making some of these decisions. The conflicts that arise within the decision making process are usually not clearcut nor easily resolvable. Home parenteral nutrition brings to the forefront requirements and variables that are often not consciously addressed when hyperalimentation is instituted in the inpatient setting.     

Nutrition in cancer: an overview

OBJECTIVES: To provide a review of weight loss, cachexia (both primary and secondary), and weight gain in cancer patients. DATA SOURCES: Research reports, review articles, textbooks, and personal communications. CONCLUSIONS: Alterations in nutritional status have the potential to affect mortality, morbidity, and quality of life outcomes. The detection and treatment of malnutrition is important to success of therapy. IMPLICATIONS FOR NURSING PRACTICE: Nursing interventions to help maintain optimal nutritional status in patients with cancer include careful assessment, identification of patients at risk, and management of problems before the initiation of therapy.     

Preeclampsia and reproductive performance in a community of vegans

Studies at "the Farm," a community of spiritually gathered young people in Summertown, Tenn, have shown that it is possible to sustain a normal pregnancy on a vegan diet. The source of dietary protein (ie, animal or vegetable) does not seem to affect birth weight, as long as vegans are health conscious, receive continuous prenatal care, supplement their diets with prenatal vitamins, calcium, and iron, and apply protein-complementing nutritional principles. Preeclampsia may be caused by a relative prostacyclin deficiency in the face of excessive production of thromboxane A2. A vegan diet (one low in arachidonic acid) might provide protection against this condition, especially if the conversion of linoleic acid to arachidonic acid is inhibited by decreased activity of the enzyme delta-6-desaturase. We examined the maternity care records of 775 vegan mothers for symptoms of preeclampsia, and only one case met the clinical criteria. Since preeclampsia in our culture is frequently associated with unrestrained consumption of "fast foods" (foods having high levels of saturated fat) and rapid weight gain, it is possible that a vegan diet could alleviate most, if not all, of the signs and symptoms of preeclampsia.     

Modulation of the liver export protein synthetic response to feeding by an n-3 fatty-acid-enriched nutritional supplement is associated with anabolism in cachectic cancer patients

The acute-phase protein response is associated with accelerated weight loss and shortened survival in cancer. This may be due to hepatic protein synthesis increasing demand for amino acids. An n -3 fatty-acid-enriched nutritional supplement will moderate aspects of cachexia in cancer patients. The present study examined the effect of such a supplement on hepatic synthesis of albumin and fibrinogen. Albumin and fibrinogen synthesis were measured in the fed and fasting state in eight weight-losing patients with pancreatic cancer by an intravenous flooding dose technique. Tracer incorporation into proteins was measured by GC/MS. Patients were restudied after 3 weeks of oral supplement enriched with fish oil (providing 2510 kJ/day and 2 g of eicosapentaenoic acid/day). At baseline, all patients were losing weight (median, 2.4 kg/month). After 3 weeks of consumption of the fish-oil-enriched nutritional supplement, patients' weight stabilized (median change, +1 kg; P = 0.01). At baseline, albumin and fibrinogen synthesis rates were stimulated in the fed compared with the fasting state [14.2 compared with 11.3 g/day (29% rise; P = 0.01) and 4.5 compared with 3.3 g/day (38% rise; P = 0.01) respectively]. After 3 weeks of the supplement, this stimulation in the fed state was no longer observed for albumin and was reduced for fibrinogen [11.2 compared with 10.5 g/day (3% rise; P = 0.21) and 3.7 compared with 2.9 g/day (17% rise; P = 0.01) respectively]. After 3 weeks, the combined albumin plus fibrinogen synthetic rate tended to fall in the fasting state (14.7 compared with 12.3 g/day; P = 0.09) and was significantly reduced in the fed state (18.7 compared with 14.6 g/day; P = 0.01). Modulation of hepatic export protein synthesis with feeding may have contributed to the net whole-body anabolism observed with administration of the n -3 fatty-acid-enriched oral supplement.     

癌性恶病质诊断、评估及治疗进展

癌性恶病质是一类复杂的代谢综合征,包括肌肉消耗、脂肪消耗、非计划的体质量下降、厌食和免疫功能破坏等。恶病质可显著降低肿瘤患者的抗肿瘤治疗疗效,增加治疗毒副反应,加重患者的症状负担,影响患者的生活质量,并最终缩短患者的生存时间。本文将对癌性恶病质的诊断、临床评估以及治疗的研究进展进行综述。     

Anorexia–Cachexia syndrome in cancer: implications of the ubiquitin–proteasome pathway

Introduction Malnutrition is a common problem in cancer patients. Its incidence varies according to disease stage (between 15 and 90%) and is considered a possible prognostic factor for therapeutic response and survival. It is also one of the causes contributing to the increase in morbidity and mortality in patients. Tumor cachexia is defined as a nutritional defect caused by tumor growth in the patient and presents as a significant weight loss. This weight loss is mainly caused by a degradation of skeletal muscle proteins.Conclusion The ubiquitin–proteasome system is the most important pathway of protein degradation. As a regulatory system governing protein half-life, it is involved in the regulation of the cell cycle, signal transmission, immune system response, apoptosis, and oncogenesis. Knowledge of the molecular pathways involved in the induction of cancer-associated cachexia will favor a more rational approach to its treatment as well as possible quality of life and survival benefit for the patient.     

Nutrition in the care of patients with cancer cachexia

Cancer cachexia, a progressive wasting syndrome experienced by approximately 80% of patients, is characterized by loss of adipose tissue and lean body mass. This complex metabolic process reflects both reduced nutrient availability and increased nutritional demand. Though cachexia is most commonly associated with particular tumours, no patient or tumour are excluded. This article provides an overview of cachexia and its pathophysiology and the factors contributing to its development before considering its impact on individuals. Emphasis is placed on the nutritional aspects of its management.     

Parenteral versus enteral nutrition in cancer patients: indications and practice

 Prospective randomly controlled trials have failed to demonstrate the clinical efficacy of providing nutritional support to most cancer patients in terms of morbidity, mortality, and duration of hospitalization. Serious shortcomings in study design have limited the possibility of drawing definitive conclusions from the data. Thus, nutritional intervention needs to be seen as a method of support, with the aim of maintaining nutritional and functional status during the stress of the oncology treatment to prevent or attenuate cachexia. There is no disease during which the patient benefits from prolonged wasting. Pretreatment weight loss is quoted as a major indicator of poor survival and response to therapy of cancer patients. As a consequence, an early and serial assessment of nutritional status, perhaps followed by an immediate intervention with nutritional support is strongly recommended. There are other specific reasons for using the gut rather than the intravenous route for nutrient administration besides the often reported disadvantage of significant cost. Local intestinal stimulation prevents the mucosal atrophy and bacterial translocation that can be triggered by several precipitating factors, as frequently seen in oncologic patients. These include endotoxin, radiation therapy, cytotoxic and immunosuppressive drugs, cytokines, bowel and biliary obstruction, broad-spectrum antibiotics, and the tumour itself, as well as parenteral nutrition (PN). As the enteral route of nutritional support has been found to be as good as or preferable to PN in terms of maintenance of nutritional status or immune function, prevention of bacterial translocation, maintenance of normal gut flora, transit and histology, and prevention of hypercatabolic responses to stressful events, it is always preferable in terms of physiological response, local and systemic competence, quality of life and cost, and should be the method of choice for the nutritional support of cancer patients. Although retrospective studies of PN suggest a benefit for patients with cancer who are undergoing surgery, radiation, or chemotherapy, carefully designed, prospective studies report less conclusive findings. The failure of conventional PN to improve clinical outcomes in patients with cancer may be related to the fact that standard formulations do not address or reverse abnormalities of intermediate metabolism that result in cancer cachexia. Supplemental substances have been proposed in an attempt to improve the efficacy of PN, including insulin, growth hormone and branched chain amino acids. The difficult task is to identify those patients who are at risk for malnutrition and at the same time identify the subset of patients who will benefit clinically from parenteral nutritional repletion. Severe malnutrition in patients requiring surgery, bone marrow transplantation in patients unable to tolerate enteral supplementation and postoperative complications necessitating nutritional support are specific indications. Routine use of PN should be discouraged.