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     

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     

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。     

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.     

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.     

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.     

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 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.     

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.     

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.     

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.     

Objective physical activity and self-reported quality of life in patients receiving palliative chemotherapy

There is little objective data on how cancer and its therapy affect physical activity. The main aims of this pilot study were 1) to compare physical activity in patients receiving palliative chemotherapy and healthy controls, and 2) to explore the relationship between patients' activity, quality of life (QoL), and clinical performance status. A miniaturized electronic meter objectively recorded activity for one week in 20 patients with upper gastrointestinal cancer receiving palliative chemotherapy and in 13 age-matched healthy controls. Patients also completed the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F; fatigue), and Functional Assessment of Anorexia and Cachexia Therapy (FAACT; anorexia/cachexia) quality-of-life questionnaires. The patients' median estimated total energy expenditure was 8% lower (P = 0.0003), median time spent upright was approximately two hours/day less (P = 0.0002), and median steps taken/day was 43% lower (P = 0.002) than that of the control group. Neither estimated energy expenditure nor average steps taken/day correlated significantly with EORTC QLQ-C30 physical functioning, fatigue, or global health status/QoL. There was no correlation with the FAACT “Trial Outcome Index” (TOI), but the FACIT-F TOI and both estimated energy expenditure and the average steps taken/day correlated significantly (r = 0.59, P = 0.009 and r = 0.59, P = 0.008). It is concluded that patients receiving palliative chemotherapy were less active than healthy controls; however, the relationship between physical activity and QoL requires further characterization.     

Biomarkers for cancer cachexia: is there also a genetic component to cachexia?

Introduction Cancer cachexia is a severe debilitating disorder, which causes significant morbidity and mortality. In clinical practice, cachexia is often not treated until a late stage, when therapeutic options are limited. Objective It is therefore of great interest to analyse early biomarkers of this syndrome. Conclusion In this review article, we summarise recent biomarkers found in various body compartments. We also explore the likelihood of a genetic predisposition to cachexia and focus on the potential role of single nucleotide polymorphisms in genes coding for pro- and anti-inflammatory cytokines, and ‘atrogenes’ associated with wasting in skeletal muscle. An erratum to this article can be found at     

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.     

Nutritional deficiencies in patients receiving cancer chemotherapy

Cancer often causes malnutrition and specific vitamin and protein deficiencies. Chemotherapy also causes deficiencies by promoting anorexia, stomatitis, and alimentary tract disturbances. Antimetabolite drugs in particular inhibit synthesis of essential vitamins, purines, and pyrimidines. Because vitamin levels in the blood are often nondiagnostic, nutritional deficiency is identified almost exclusively on the basis of clinical signs and symptoms and the patient's response to therapy. Signs and symptoms of cachexia and hypoalbuminemia are common in patients with advanced cancer. Deficiencies of vitamins B1, B2, and K and of niacin, folic acid, and thymine also may result from chemotherapy. Nutritional deficiencies are chemically correctable; however, the tumor must be eradicated to relieve cachexia.     

The Growth Hormone Response to Insulin Induced Hypoglycemia in Anorexia Nervosa and Control Underweight or Normal Subjects

Summary. Hypoglycaemic stimulation of growth hormone (GH) secretion has been measured in 12 anorexia nervosa patients, 11 adolescents approximately matched for weight and age, 14 underweight adults with no history of anorexia nervosa and 27 normal patients. The results showed a high proportion of blunted growth hormone responses among the anorexia nervosa patients as compared to normal subjects, underweight adolescents or adults. In the group of underweight adults, diminished growth hormone responses were most frequently seen in patients with depressive illness. The complex pathogenesis of the diminished growth hormone response in anorexia nervosa involves many factors; undernutrition itself, possible hypothalamic insufficiency related to the psychopathological background and other endocrine abnormalities like hypogonadism, relative hypercorticism and hypothyroidism. The interference of the nutritional, psychological and endocrine factors could not be dissociated in our investigation or from the review of the literature on this subject. It is suggested that hypothalamic insufficiency plays a prominent role in the growth hormone hyporesponsiveness in anorexia nervosa. Although diminished, the stimulated growth hormone response remains higher in anorexia nervosa than in true hypopituitarism. This phenomenon coupled to a preserved or even increased suprarenal function enables one to differentiate cachexia resulting from anorexia nervosa and hypopituitarism leading eventually to cachexia.     

The growth hormone response to insulin induced hypoglycaemia in anorexia nervosa and control underweight or normal subjects.

Hypoglycaemic stimulation of growth hormone (GH) secretion has been measured in 12 anorexia nervosa patients, 11 adolescents approximately matched for weight and age, 14 underweight adults with no history of anorexia nervosa and 27 normal patients. The results showed a high proportion of blunted growth hormone responses among the anorexia nervosa patients as compared to normal subjects, underweight adolescents or adults. In the group of underweight adults, diminshed growth hormone responses were most frequently seen in patients with depressive illness. The complex pathogenesis of the diminshed growth hormone response in anorexia nervosa involves many factors; undernutrition itself, possible hypothalamic insufficiency related to the psychopathological background and other endocrine abnormalities like hypogonadism, relative hypercorticism and hypothyroidism. The interference of the nutritional, psychological and endocrine factors could not be dissociated in our investigation or from the review of the literature on this subject. It is suggested that hypothalamic insufficiency plays a prominent role in the growth hormone hyporesponsiveness in anorexia nervosa. Although diminished, the stimulated growth hormone response remains higher in anorexia nervosa than in true hypopituitarism. This phenomenon coupled to a preserved or even increased suprarenal function enables one to differentiate cachexia resulting from anorexia nervosa and hypopituitarism leading eventually to cachexia.     

The experience of cancer cachexia: A qualitative study of advanced cancer patients and their family members

Background

Cachexia in advanced malignancy is a debilitating syndrome which contributes to approximately two million deaths worldwide annually. In spite of advances in understanding the biomedical aspects of cancer cachexia, little attention has been paid to exploring its holistic impact on patients and those who care for them.

Objective

The aim of this paper is to describe the lived experience of cachexia from the perspective of patients with cancer and their family members.

Design

An interpretative phenomenological approach was employed.

Setting and participants

A purposive sampling strategy recruited 15 patients and 12 family members from the Regional Cancer Centre in Northern Ireland.

Method

Each participant was interviewed during 2004/2005 using an unstructured interview. All interviews were recorded and transcribed verbatim. Analysis combined a two stage approach using thematic and interpretative phenomenological analysis.

Results

Analysis generated six superordinate themes that reflected the complex dynamics of the cachexia experience. Themes were: physiological changes in appetite; visuality of cachexia; weight loss interpreted as a bad sign; response from health care professionals; conflict over food; and coping responses.

Conclusions

Findings confirmed that cancer cachexia has far reaching implications for patients and their families, extending beyond physical problems into psychological, social and emotional issues. This insight is a critical first step in the development of more responsive care for these clients.     

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     

Decreased taste sensitivity in cancer patients under chemotherapy

Goals of work The aim of the study was to measure taste thresholds among cancer patients under chemotherapy compared to controls.Patients and methods The study was performed with 110 cancer patients and 170 healthy subjects of similar age distribution were included in the study. The electrogustometric detection threshold was evaluated as the lowest current intensity perceived by the subject in three tongue sites independently with a constant current generator.Main results Taste thresholds for all cancer patients demonstrated significantly higher values compared to controls.Conclusions Cancer patients treated by chemotherapy demonstrated a temporary taste sensitivity deficit. Associated with the illness due to the treatment, this deficit explains the patients complaining of abnormal or bad tastes, which results in food aversion and has a negative impact on nutritional status and quality of life. In order to prevent the risk of anorexia and the enhanced morbidity related to this deficit, treatment should include relevant information to the subject for anticipating objective taste modifications and a psychological follow-up during the actual change of taste quality perceptions in everyday life.