Rethinking nutritional support for persons with cancer cachexia

Cancer cachexia is a poorly understood syndrome of anorexia, weight loss, and muscle wasting that negatively impacts quality of life and survival in cancer patients. Research has clearly implicated pro-inflammatory cytokines in the biology of cancer cachexia. More recent research implicates products of arachidonic acid and suggests that cachexia may be a chronic inflammatory condition rather than a nutritional aberration. To date, nutritional support to slow weight loss has focused primarily on increasing calorie intake. Alternatively, many foods contain factors that can modulate the synthesis or activity of pro-inflammatory mediators, especially the synthesis of prostaglandin E2 from arachidonic acid. These factors and foods are sometimes called nutraceuticals, and research is needed to evaluate their efficacy in combating cancer cachexia.     

Cancer-induced fatigue and skeletal muscle wasting: the role of exercise

Fatigue is the most frequently reported symptom by cancer patients. Many of these patients perceive fatigue as the most distressing symptom associated with their illness because it imposes limitations on their physical activity level. Skeletal muscle wasting, which occurs as part of cancer cachexia, is one of the mechanisms that contribute to fatigue. Cancer-induced skeletal muscle wasting may occur despite normal food intake and is not prevented by nutritional supplementation. Evidence suggests that endurance exercise ameliorates cancer-related fatigue. There is no compelling evidence to support that exercise-induced reduction in fatigue is related to preservation of muscle mass. Resistance exercise attenuates muscle wasting associated with a variety of catabolic conditions. However, its effects on cancer-induced muscle wasting have not been adequately studied. This article describes the physiological mechanisms implicated in the induction of cancer-related muscle wasting, summarizes findings from endurance and resistance exercise studies in relation to fatigue and muscle wasting during cancer and selected clinical conditions, and proposes directions for future research.     

Interleukin 1, tumour necrosis factor-alpha (cachectin) and the pathogenesis of cancer cachexia

Summary. Soluble proteins synthesized and released by phagocytic cells may be responsible for the protein and energy wasting frequently observed during catabolic states, including cancer cachexia. This hypothesis is based upon the observation that many of the hosts's metabolic responses to infection, inflammation, accidental trauma and some forms of cancer are remarkably similar. Anorexia and degradation of skeletal and connective tissue protein, as well as increases in hepatic protein synthesis and energy expenditure, can all be reproduced by the administration of activated macrophage products. During inflammatory states, including active tumour growth, increased production of some cytokines, including interleukin 1 and tumour necrosis factor-alpha (cachectin), have been observed. If these monokines serve as metabolic inducers, then efforts to block therapeutically the actions of macrophage-secreted substances may play a role in slowing the progression of tissue-wasting associated with catabolic states, particularly due to malignant tumours.     

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.     

Understanding cachexia and excessive weight loss in cancer

Cachexia, a wasting condition often seen in advanced cancer, is often confused with anorexia but they are two separate conditions. It is evident that cachexia frequently leads to anorexia but anorexia alone cannot cause cachexia. The cachexia syndrome is weight loss with a specific cause--the action of cytokines, chemical messengers that are produced both by the body in response to the tumour and by the tumour to ensure its growth and spread. Treatment of cachexia is very difficult. Drugs to improve appetite have little effect, however, supplementing the diet with fish oils and vitamin E seems to be beneficial. Increasing a patient's level of exercise, even if bed-bound, does seem to have a positive effect and helps to synthesize skeletal muscle protein and delay the ravages of cachexia. Increasing exercise also has a positive effect on fatigue levels, a side-effect of cachexia.     

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.     

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.     

Malnutrition,anorexia and cachexia in cancer patients: A mini-review on pathogenesis and treatment

Malnutrition, anorexia and cachexia are a common finding in cancer patients. They become more evident with tumor growth and spread. However, the mechanisms by which they are sustained often arise early in the history of cancer. For malnutrition, these mechanisms can involve primary tumor or damage by specific treatment such as anticancer therapies (surgery, chemotherapy, radiotherapy) also in cancers that usually are not directly responsible for nutritional and metabolic status alterations (i.e. bone tumors). For anorexia, meal-related neural or hormonal signals and humoral signals related to body fat or energy storage and the interaction of these signals with the hypothalamus or the hypothalamic inappropriate response play a pathogenetic role. Some cytokines are probably involved in these mechanisms. For cachexia, the production of proinflammatory cytokines by tumour cells is the initial mechanism; the main biochemical mechanisms involved include the ubiquitine proteasome-dependent proteolysis and heat shock proteins. Treatment includes pharmaceutical and nutritional interventions.     

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.     

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 and cachexia in advanced cancer.

During the last days of life, patients experience a myriad of symptomatology. While the exact percentage of patients with cancer affected by anorexia may be subject to debate, there is a clear indication that a significant portion of patients with cancer will at some point in the course of his or her illness suffer the ravages of anorexia and the related progressive weight loss that accompanies it. Anorexia is often related to the tissue wasting process of cachexia, a more severely debilitating condition that may be a contributing factor, or even the primary cause of death, in approximately 20% of cancer patients. Clinicians involved in oncology and hospice/palliative care should have a clear understanding of this process and appropriate interventions for patients experiencing anorexia/cachexia.     

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.     

Inhibitors of COX activity preserve muscle mass in mice bearing the Lewis lung carcinoma, but not the B16 melanoma

Tumor-induced skeletal muscle wasting (SMW) contributes to the fatigue and weakness experienced by persons with cancer cachexia. Tumor necrosis factor-alpha (TNFa) and cyclooxygenase (COX) activity have been implicated in SMW in some animal models of cancer cachexia. We report that indomethacin, a nonspecific inhibitor of COX, and NS398, a specific inhibitor of COX2, preserved muscle mass and reduced type 1 TNF receptors in muscles of mice bearing the Lewis lung carcinoma, but not in mice bearing the B16 melanoma. These data suggest that tumor-induced SMW can occur via a COX2-independent pathway. The COX2-dependent pathway may involve reducing the catabolic effects of TNFa in muscle. Further study is needed to understand the relationship between COX and SMW, and whether patients with cancer cachexia might benefit from COX inhibitors.     

Restoring nitrogen balance after burn injury

The metabolic response to burn injury is characterized by weight loss and marked protein wasting. This phenomenon is mediated hormonally, resulting in hypermetabolism. Energy expenditure increases linearly with the extent of burn injury, reaching a plateau of twice resting energy expenditure when 50% of the total body surface area is involved. It is therefore essential to minimize other factors that may further augment postburn catabolism. Occlusive dressings, a warm ambient environment, analgesics, and timely closure of the burn wound are all important therapeutic measures in this regard. Furthermore, it is imperative to institute early nutritional support in order to offset the negative metabolic effects of severe burn injury.     

Changes in taste sensation and feeding behaviour in cancer patients: a review.

Recent studies suggest the importance of alterations in taste sensation as a determinant of anorexia in cancer patients. These studies collectively support the conclusions that the likelihood of developing abnormalities in taste increases with increasing body burden of tumour, that taste abnormality is reversible on response of the underlying tumour to therapy, and that the abnormalities in taste can be correlated with decreased intake of energy. It is suggested that these studies, and studies currently in progress, may aid our understanding of food choices in cancer patients and may guide the use of food supplements to assist the cancer patient in maintaining adequate energy intake.     

Pathophysiology of cancer cachexia

Patients with advanced cancer and cachexia typically demonstrate modestly increased rates of energy expenditure in the presence of diminished food intake due to anorexia and to gastrointestinal disturbances. Rates of glucose production by the liver, gluconeogenesis and glycolysis to lactate (Cori cycle) are increased, fat mobilisation and oxidation are accelerated. There is a redistribution of body proteins away from muscle towards visceral proteins, resulting in marked muscle protein loss. Cancer cachexia differs from simple starvation and demonstrates metabolic similarities to sepsis or polytrauma. The metabolic response in the patient with cancer is largely due to mediators released by the tumour or by the host; recently the role of cytokines such as tumour necrosis factor (TNF), interleukin-1 (IL-1) and-6 (IL-6) and interferon (INF) has been emphasized. Catabolic hormones such as glucocorticoids and adrenaline have also been implicated. Cytokines have the potential to reproduce experimentally the clinical syndrome of cancer cachexia. There is evidence of increased production of several of them in certain types of cancer. There are overlapping activities of the cytokines TNF, IL-1, IFN and IL-6. The contribution of each of them to cancer cachexia remains unclear. Inhibition of cytokine activity using specific antibodies in cancer-bearing experimental animals demonstrated partial prevention of cachexia. A positive feedback between macrophage-derived IL-1 and tumour-derived IL-6 has been demonstrated recently in experimental cancer cachexia. Cytokines may support tumour growth by acting as growth factors.Presented as an invited lecture at the 4th International Symposium: Supportive Care in Cancer, St. Gallen, Switzerland, 24–27 February 1993     

Is the pharmacological treatment of cancer cachexia possible?

Cancer cachexia is highly prevalent in patients with advanced cancer. Its main clinical manifestation is profound anorexia. Progestational drugs have shown meaningful effects on appetite, food intake, and nutritional status in patients with advanced cancer and AIDS, and could be useful in managing anorexia. Corticosteroids also seem to produce increased appetite, but these effects are short-lived. Cyproheptadine, hydrazine sulfate, and cannabinoids also are being studied in the management of cancer-induced anorexia, but their role has not yet been clearly established. Future research should evaluate how the different drugs affect specific symptoms associated with cachexia.Presented as an invited lecture at the 4th International Symposium: Supportive Care in Cancer, St. Gallen, Switzerland, 24–27 February 1993     

Influence of parenteral nutrition on rates of net substrate oxidation in severe trauma patients

Optimal nutritional support should use a patient's energy expenditure as a guide for administering sufficient but not excessive caloric intake. Eight patients requiring parenteral nutrition were evaluated, using indirect calorimetry measurements, to determine the nutritional influence on the rates of substrate utilization in the critical period of catabolic illness due to accidental trauma. Five days of total parenteral nutrition, providing calories to match the measured basal resting energy expenditure and N to replace the initial urinary losses a) shifted the RQ from 0.74 +/- 0.03 to 0.81 +/- 0.03, b) improved but could not reverse negative N balance, c) decreased net fat oxidation, d) increased carbohydrate and protein oxidation, e) elevated daily norepinephrine and epinephrine excretion rates, and f) attained positive energy balance. The results suggest that positive energy balance could be achieved in trauma patients by providing total energy intake matching their basal measured energy expenditure plus 7% to 10% for activity energy expenditure. To prevent further loss of lean body mass, an N intake of 350 mg/kg.day was needed in these catabolic ICU patients.     

Cachexia in patients with advanced cancer

Cancer cachexia generally is considered to be the end stage in the progression of nutritional deterioration and wasting of malignancy (Ottery, 1995). In patients with advanced cancer, this condition is very common and decreases quality of life, as well as survival (Fearon et al., 2001; Ottery; Smith & Souba, 2001; Whitman, 2000). However, if early diagnosis and intervention can control cachexia, the potential exists to greatly improve a patient's quality of life and prolong survival. Because metabolic alterations inhibit the effective use of conventional nutritional support, anti-inflammatory agents or fish oil are possible options. Orexigenic agents may be prescribed if patients wish to improve oral intake. Steroids and progestational agents may be used to attempt to improve mood and appetite. Nutrition affects symptoms that need to be managed effectively. Nurses should work aggressively to correct factors that contribute to decreased food intake (e.g., nausea, pain) and correct factors that worsen debility (e.g., anemia). Information must be presented so that informed choices can be made and realistic eating goals set. An interdisciplinary approach that involves the nurse, physician, dietician, and possibly social worker or case manager, as well as the patient and family, is necessary to identify nutritional alterations, assess specific needs, and plan individual interventions. Whitman (2000) stated that counseling is the most effective and least expensive intervention. It may be conducted by any member of the healthcare team and should be combined with other interventions. Palliation of cachexia in patients with advanced cancer is a challenge for nurses. Hopefully, early and judicious use of these interventions may decrease the significant morbidity and mortality that result from cancer cachexia.     

The biological mechanisms of cancer-related skeletal muscle wasting: the role of progressive resistance exercise

Cancer results in perturbations in skeletal muscle protein metabolism leading to muscle wasting. Although severe wasting is seen primarily in persons with advanced malignancies, a number of cancer patients show some degree of wasting at presentation. Although cancer-related skeletal muscle wasting is attributable, in part, to decreased muscle protein synthesis, its primary cause appears to be increased muscle protein degradation. Although several proteolytic systems may be involved, compelling evidence suggests that the major system responsible for skeletal muscle protein degradation in cancer is the ATP-dependent ubiquitin- proteasome system. Other contributing factors include proinflammatory cytokines and the tumor-released proteolysis-inducing factor. Decreased physical activity and decreased nutritional intake may also play a role. Cancer-related skeletal muscle wasting is clinically significant because of its profound effects on functional outcomes and quality of life. Nevertheless, no specific interventions have proved to be effective in preventing or reversing the problem. Interventions such as nutritional supplementation and appetite stimulants are only partially helpful. A nonpharmacologic intervention that may attenuate cancer-related skeletal muscle wasting is progressive resistance exercise training (PRT). PRT is a potent stimulus of growth in muscle mass and strength. PRT may attenuate cancer-related skeletal muscle wasting by downregulating the activity of proinflammatory cytokines and by increasing the phosphorylation of intramuscular amino acid-signaling molecules. This article discusses several cancer-related skeletal muscle wasting mechanisms and proposes how PRT might attenuate muscle wasting by counteracting some of these mechanisms.