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.     

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。     

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.     

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.     

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.     

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.     

Animal models of the cancer anorexia�Ccachexia syndrome

Background and aims  

Cancer cachexia, a complex wasting syndrome, is common in palliative medicine. Animal models expand our understanding of its mechanisms. A review of cancer cachexia and anorexia animal models will help investigators make an informed choice of the study model.     

Management of common symptoms in terminally ill patients: Part I. Fatigue, anorexia, cachexia, nausea and vomiting

Physical symptoms other than pain often contribute to suffering near the end of life. In addition to pain, the most common symptoms in the terminal stages of an illness such as cancer or acquired immunodeficiency syndrome are fatigue, anorexia, cachexia, nausea, vomiting, constipation, delirium and dyspnea. Management involves a diagnostic evaluation for the cause of each symptom when possible, treatment of the identified cause when reasonable, and concomitant treatment of the symptom using nonpharmacologic and adjunctive pharmacologic measures. Part I of this two-part article discusses fatigue, anorexia, cachexia, nausea and vomiting. Fatigue is the most common symptom at the end of life, but little is known about its pathophysiology and specific treatment. Education of the patient and family is the foundation of treatment with the possible use of adjunctive psychostimulants. Anorexia and cachexia caused by wasting syndromes are best managed with patient and family education, as well as a possible trial of appetite stimulants such as megestrol or dexamethasone. For appropriate pharmacologic treatment, it is helpful to identify the pathophysiologic origin of nausea in each patient.     

Cachexia and anorexia: cancer's covert killer

 Cachexia and anorexia are often not observed at the time of diagnosis of cancer. While the initial medical intervention for cancer patients includes antitumor therapy and pain management, the consequences of cachexia and anorexia may be ignored, to the detriment of the patient's quality of life and his or her potential response to chemotherapy. The importance of a well-defined therapeutic strategy to treat cachexia is in order if the patient's overall wellbeing is to improve. Presented is a review of the pharmacological management of anorexia and cachexia, including a four-step ladder approach to medical management. Published online: 13 March 2000     

Cancer cachexia: a therapeutic approach

Cancer cachexia is a complex syndrome which occurs in more than two-thirds of patients who die with advanced cancer. The main components of this pathological state are anorexia and metabolic abnormalities such as glucose intolerance, fat depletion, and muscle protein catabolism among others. The aim of the present study is to review the different therapeutic approaches that have been designed to fight and counteract cancer cachexia.     

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     

Cannabinoide in der Palliativtherapie des Anorexie-Kachexie-Syndroms

Loss of appetite and cachexia are frequent symptoms in palliative care patients. However, therapeutic regimens often prove ineffective, and the quality of life of many patients is significantly impaired by these symptoms. Causes and pathophysiology of anorexia and cachexia are complex and must be identified and treated. Symptomatic pharmacological therapy aims at metabolic, neuroendocrinological and catabolic changes. Prokinetic drugs, corticosteroids and gestagenes are used for symptomatic therapy. Recently, the use of cannabinoids for treatment of loss of appetite and cachexia has become the focus of interest. In cancer patients, cannabinoids proved more effective than placebo but less than gestagenes. Compared to placebo, higher efficacy of cannabinoids could be demonstrated in patients with AIDS as well as in patients with Morbus Alzheimer. However, side effects, such as dizziness, tiredness and daze led to discontinuation of the cannabinoid therapy in some patients.     

Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation

Cachexia is a potentially lethal syndrome of unknown etiology characterized by anorexia, weight loss, and protein wasting that frequently complicates the treatment of chronic inflammation and cancer. Cachectin/TNF was isolated during the search for a humoral mediator of cachexia and found to stimulate the breakdown of energy stores from adipocytes and myocytes in vitro, but the chronic effects of the monokine in vivo are not known. Sublethal doses of recombinant human cachectin administered twice daily for 7-10 d caused cachexia in rats, as evidenced by reduced food intake, weight loss, and depletion of whole-body lipid and protein stores. Significant anemia is also observed and found to be the result of decreased red blood cell mass, not expanded plasma volume. Leukocytosis and histopathological evidence of tissue injury and inflammation are observed in several organs, including omentum, liver, spleen, and heart. These data suggests that the exposure of the normal host to cachectin is capable of inducing a pathophysiological syndrome of cachexia, anemia, and inflammation similar to that observed during inflammatory states or malignancy.     

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.     

Anti-cytokine strategies for the treatment of cancer-related anorexia and cachexia

Importance of the field: Cachexia is a syndrome characterized by body weight loss and metabolic abnormalities. It is a frequent feature of patients affected by chronic pathologies, including cancer. Neoplastic patients with cachexia show increased morbidity and mortality rates, benefit less from antineoplastic therapies, and have a poorer quality of life. Among the general mechanisms proposed to account for cachexia, anorexia and altered homeostasis of hormones and cytokines appear to play a major role.

Areas covered in this review: The present review will focus on anti-inflammatory drugs useful for the treatment of cancer-related anorexia and cachexia.

What the reader will gain: Molecules able to block cytokine production or biological activity are currently under evaluation. At present, none of them has been authorized for the clinical treatment of cancer-related anorexia and cachexia, since the few published clinical trials lead to contrasting results, and others are still pending.

Take home message: Considering the multifactorial pathogenesis of cancer-related anorexia and cachexia, combination protocols are probably the better choice. In this regard, anti-cytokine strategies should be pursued and included in the treatment of neoplastic patients, although cytokines modulate a number of processes.     

Rapid progression of advanced "hormone-resistant" prostate cancer during palliative treatment with progestins for cancer cachexia

We report three patients with advanced "hormone-resistant" prostate cancer, each of whom had rapid progression of the disease during treatment with megestrol acetate for cancer cachexia. All patients had been previously treated with total androgenic deprivation. With progression of the disease, megestrol acetate was given to palliate the cancer-related wasting syndrome. No other antineoplastic drugs were contemporaneously given, and no concomitant condition that could favor the progression of the disease was present. The worsening observed while receiving megestrol acetate, and the atypical withdrawal syndrome occurring after the treatment was stopped, seem to suggest a promoting role of megestrol acetate in advanced "hormone-resistant" prostate cancer. The risk of rapid disease progression overwhelming the anti-cachectic palliative effect should be kept in mind when progestins are administered as a palliative treatment of cancer cachexia in patients with advanced "hormone-resistant" prostate cancer.     

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.     

Suramin interferes with interleukin-6 receptor binding in vitro and inhibits colon-26-mediated experimental cancer cachexia in vivo.

Neoplastic diseases are frequently associated with metabolic changes collectively known as cancer cachexia. The presence of cachexia complicates therapeutic intervention and is an important cause of death in cancer patients. At present there is no effective treatment for cachexia. Recently, the involvement of interleukin-6 (IL-6) in the wasting of colon-26 adenocarcinoma-bearing mice was demonstrated. The research presented here establishes an anticachectic role for the experimental drug suramin, since it partially blocks (up to 60%) the catabolic effects associated with the growth of this tumor in vivo. Suramin prevents the binding of IL-6 to its cell surface receptor subunits, as demonstrated by radioreceptor binding assay and affinity crosslinking experiments. Furthermore, the uptake of radioactive IL-6 by the liver is significantly reduced in suramin-treated mice. On the other hand, the drug is approximately 10-fold less potent in inhibiting the binding of tumor necrosis factor-alpha to indicator cell line in vitro and fails to block liver uptake of this cytokine in vivo. Collectively, these results suggest that suramin inhibits cancer-associated wasting, in part by interfering with the binding of IL-6 to its receptor. Whether suramin inhibits the action of other factors/cytokines that may also participate in colon-26-mediated cachexia is not yet known.     

Management of cancer anorexia/cachexia

Cancer anorexia/cachexia is a common clinical problem that substantially impacts upon the quality of life and survival of affected patients. Extensive investigations have not supported the use of either enteral or paternal hyperalimentation for such patients. Despite positive pilot trial reports, large randomized studies have been unable to demonstrate a clinically defensible role for either pentoxifylline, cyproheptadine, or hydrazine sulfate for patients with anorexia. Multiple placebo-controlled, randomized, double-blind, clinical trials have demonstrated that corticosteroids do have appetite-enhancing properties in patients suffering from cancer anorexia/cachexia, but none of these studies has demonstrated weight gain. In comparison, multiple studies have demonstrated that the progestational agent, megestrol acetate, has both appetite-enhancing and weight-promoting properties.Presented as an invited lecture at the 6th International Symposium: Supportive Care in Cancer, New Orleans, La., USA, 2–5 March 1994