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sunnuntai 5. kesäkuuta 2016
Cancer cachexia, mechanism and treatment - Kakeksian hoito, tulehdusreaktio
It is estimated that half of all patients with cancer eventually develop a syndrome of cachexia, with anorexia and a progressive loss of adipose tissue and skeletal muscle mass. Cancer cachexia is characterized by systemic inflammation, negative protein and energy balance, and an involuntary loss of lean body mass. It is an insidious syndrome that not only has a dramatic impact on patient quality of life, but also is associated with poor responses to chemotherapy and decreased survival. Cachexia is still largely an underestimated and untreated condition, despite the fact that multiple mechanisms are reported to be involved in its development, with a number of cytokines postulated to play a role in the etiology of the persistent catabolic state. Existing therapies for cachexia, including orexigenic appetite stimulants, focus on palliation of symptoms and reduction of the distress of patients and families rather than prolongation of life. Recent therapies for the cachectic syndrome involve a multidisciplinary approach. Combination therapy with diet modification and/or exercise has been added to novel pharmaceutical agents, such as Megestrol acetate, medroxyprogesterone, ghrelin, omega-3-fatty acid among others. These agents are reported to have improved survival rates as well as quality of life. In this review, we will discuss the emerging understanding of the mechanisms of cancer cachexia, the current treatment options including multidisciplinary combination therapies, as well an update on new and ongoing clinical trials.
Keywords: Physical exercise, Pharmacological treatment, Cancer cachexia
Core tip: This review aims to present the clinical presentation, the mechanisms, and current treatment options, such as pharmacological treatment and physical exercise for cancer cachexia.
Although there is no single universally agreed upon definition of cachexia, a recent consensus statement states that cachexia is a complex metabolic syndrome associated with underlying illness, and is characterized by the loss of muscle with or without loss of fat mass. Cachexia is seen in many medical conditions, including cancer, acquired immunodeficiency syndrome (AIDS), chronic obstructive pulmonary disease, multiple sclerosis, chronic heart failure, tuberculosis, familial amyloid polyneuropathy, mercury poisoning (acrodynia) and hormonal deficiency[1,2]. Cancer cachexia is characterized by systemic inflammation, negative protein and energy balance, and an involuntary loss of lean body mass, with or without wasting of adipose tissue. Clinically, cachexia is represented by significant weight loss in adults and failure to thrive in children, accompanied by alterations in body composition and a disturbed balance of biological systems[5-7]. Whilst the loss of skeletal muscle mass is the most obvious symptom of cancer cachexia, cardiac muscle is also depleted, though muscle of other visceral organs tend to be preserved. Though cachexia is seen in several disease states, the loss of muscle mass has been shown to occur most rapidly in cancer patients.
Cancer cachexia is an insidious syndrome that not only has a dramatic impact on patient quality of life, but is also associated with poor responses to chemotherapy and survival[9-11]. Indeed, cachexia occurs in the majority of terminal cancer patients and, according to Warren, is responsible for the death of 22% of cancer patients[12,13].
Current therapies focus on palliation of symptoms and the reduction of distress of patients and families rather than cure. In many cases, cachexia remains a largely underestimated and untreated condition[4,15]. Approximately half of all patients with cancer experience cachexia[16,17], with the prevalence rising as high as 86% in the last 1-2 wk of life[18,19], and with 45% of patients lose more than 10% of their original body weight over the course of their disease progression. Death usually occurs when there is 30% weight loss.
The best management strategy of cancer cachexia is to treat the underlying cancer as this will completely reverse the cachexia syndrome. Unfortunately, this remains an infrequent achievement with advanced cancers. A second option could be to counteract weight loss by increasing nutritional intake, but since in the majority of cachectic patients anorexia is only a part of the problem, nutrition as a unimodal therapy has not been able to completely reverse the wasting associated with cachexia.
In this review, we discuss the presentation, mechanisms, and current treatment options for cancer cachexia, including diet and exercise therapy to improve quality of life as well as prognosis for affected patients.
Multiple mechanisms are involved in the development of cachexia, including anorexia, decreased physical activity, decreased secretion of host anabolic hormones, and an altered host metabolic response with abnormalities in protein, lipid, and carbohydrate metabolism. Due to the complex clinical findings, guidelines for the diagnosis of cachexia have just recently started to appear. Even so, there is great variation in definitions, which presents problems when comparing studies and informing clinical diagnoses[21,22] (Table (Table11).
One proposed mechanism of cancer cachexia is that it is an integrated physiological response of substrate mobilization driven by inflammation. There is an increase in pro-inflammatory cytokine activity during cancer progression[24,25], and systemic inflammation is a hallmark of cancer cachexia, indicated by the production of acute-phase response (APR) proteins such as C-reactive protein (CRP) and fibrinogen[26,27]. CRP is considered to be an accurate measure of the pro-inflammatory cytokine activity that has been implicated in muscle wasting. The APR is related to the inflammation and weight loss seen in cachexia[30,31] and the reduced quality of life and shortened survival of cachexia patients[10,32-35]. These phenomena increase muscle catabolism and transfer amino acids from muscle anabolism toward the amino acid pool required for APR protein anabolism[36,37]. It has been suggested that eicosanoids also mediate inflammation in cancer cachexia[38-40].
There is considerable evidence that signaling through cytokines and myostatin/activin pathways has a role in cancer cachexia and anorexia[41-43] (Figure (Figure1).1). Numerous cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), IL-6, and interferon-gamma (IFN-γ), have been postulated to play a role in the etiology of cancer cachexia[44-52]. The cytokines are transported across the blood-brain barrier where they interact with the luminal surface of brain endothelial cells causing release of substances that affect appetite. Receptors of TNF-α and IL-1 are found in the hypothalamic areas of the brain, which regulates food intake. Anorexia induced by both TNF-α and IL-6 can be blocked by inhibitors of cyclooxygenase, suggesting that a prostaglandin, such as PGE2, may be the direct mediator of appetite suppression.
Role of tumor-induced systemic inflammation with metabolic pathways in organs affected by cancer cachexia. IL: Interleukin; TNF: Tumor necrosis factor; IFN: Interferon; STAT3: Signal transducers and activators of transcription 3.
The role of TNF-α in mediating cancer cachexia is supported by evidence that intraperitoneal injection of a soluble recombinant human TNF-receptor antagonist improved food take and weight gain in tumor-bearing rats. TNF-α increases gluconeogenesis, lipolysis and proteolysis, decreases the synthesis of proteins, lipids and glycogen, induces the formation of IL-1, and stimulates the expression of Uncoupling proteins (UCP) 2 and UCP3 in cachectic skeletal muscle. Despite the fact that TNF-α induces the symptoms of cachexia, its inhibition has not been shown to stop or to reverse cancer cachexia. This indicates that though TNF-α may be involved in the development of cachexia, it is not solely responsible for the effects seen in cachectic patients.
IL-1 concentrations increase in the cachectic state and have been known to cause similar effects to TNF-α. IL-1 induces anorexia in cachectic patients as it causes an increase in plasma concentrations of tryptophan, which in turn increases serotonin levels, causing early satiety and suppressing hunger. Increased tryptophan leading to associated increased serotonin production from the hypothalamus has been linked to anorexia[57,58]. A conflicting study showed that IL-1 did not affect food intake or weight loss, suggesting that IL-1 has a local effect on a particular tissue or the exogenous doses of IL-1 must be larger in order to see characteristics of cachectic state.
IL-6 is an important mediator in the defense mechanism of humans through its regulation of immune responses. Concentration levels of IL-6 increase transferrin in cancer patients. Levels of IL-6 were observed to be higher in patients with cachexia than weight-stable patients. Although IL-6 may have an important role in the development of cachexia, it is not considered to be solely responsible, working through indirect action, indicated by the failure of IL-6 administration to reproduce cachexia in animal model. As such, it is likely that a complex interplay of these factors is responsible for cachexia, rather than each working in isolation. However, since there is limited variation in levels of circulating cytokines, and circulating cytokines are produced by isolated peripheral mononuclear cells, it is speculated that local production in affected tissues is more important and relevant to cachexia than systemic circulation of these factor.
Signal transducers and activators of transcription 3 (STAT3) is a member of the STAT family of proteins. STAT3 function as essential signal transducing effector proteins of cytokine-induced pathways that control the development, proliferation, differentiation, homeostasis of many cell types. STAT3 activation is a common feature of muscle wasting. STAT3 is activated in muscle by IL-6 and by different types of cancer and sterile sepsis. It is not certain whether the cytokine production is primarily from tumor or host inflammatory cells. It has been hypothesized that either tumor cell production of pro-inflammatory cytokines or the host inflammatory cell response to tumor cells is the source of the APR protein seen in many malignancies and in cachexia.
A number of factors in cancer patients are known to increase the catabolic response, leading to unsustainable levels of fat and muscle mobilization and levels of muscle depletion that cause significant morbidity and mortality.
The metabolic changes found in cachexia resemble those of infection rather than starvation and are multifactorial and complex. Although the weight loss brought on by starvation is mainly from adipose tissue stores, the weight loss of cancer cachexia is caused by loss of both skeletal muscle and adipose tissue mass. In patients with cachexia there is an increase in muscle protein catabolism leading to a net loss of muscle mass. This imbalance of protein synthesis and degradation is one of the most obvious aspects of metabolism disruption in cancer cachexia. It has been widely observed that the rate of muscle protein catabolism increases in cachexia, whilst anabolism of new proteins decreases, resulting in net protein breakdown[8,69-71].
Increased energy expenditure may also contribute to the wasting process. Resting energy expenditure (REE) is increased in the cachectic state, with futile metabolic cycling accounting for much of this increase. About 70% of the total energy expenditure in sedentary people arises from the REE. The REE in cancer patients is strongly determined by the type of tumor. For example, patients with pancreatic and lung cancer had increased REE compared with healthy subjects[73,74]. Patients with gastric and colorectal cancer were reported to have no elevation of REE, though it seems that these results reflect how close the patients were to death at the time of measurement. In malnourished patients near death there is an increase in REE and in protein catabolism which could relate to the utilization of the last skeletal muscle mass.
Although skeletal muscle is the most important site for thermogenesis in the adult human, brown adipose tissue (BAT) is also to have an important role in cachexia. Non-shivering thermogenesis takes place in BAT, and in a single study using autopsy samples of peri-adrenal tissue examined by light microscopy, BAT was observed in 20 of the cachectic cancer patients (80%) compared to 2 of the age-matched subjects (13%).
UCPs, related to the regulation of mitochondrial proton gradients and the production of reactive oxygen species in skeletal muscle and adipose tissue, may also play a role in the increased REE observed in cachexia. There are three UCPs: UCP1 found only in BAT, UCP2 found in most tissues, and UCP3 found only in BAT and skeletal muscle. In particular, the expression of UCP2 and UCP3, associated with energy expenditure and metabolism in skeletal muscle, is upregulated in the cachectic state, indicating involvement of these mechanisms. Expression levels of mRNA of UCP1 in BAT were significantly elevated over controls in mice bearing cachexia inducing tumors, while expression levels of UCP2 and -3 did not change in BAT, but were significantly increased in skeletal muscle. This may also be applicable to cancer patients, since UCP-3 mRNA levels are increased in muscle only when weight loss is associated with cancer. UCP-2 mRNA levels in muscle seems unaffected by cancer either with or without weight loss. The increase in UCP3 mRNA might enhance energy expenditure and contribute to tissue catabolism.
Megestrol acetate (MEGACE) and medroxyprogesterone (MPA) are synthetic, orally active derivatives of the naturally occurring hormone, progesterone.
MEGACE was first synthesized in England in 1963. Developed as an oral contraceptive, the agent was first tested in the treatment of breast cancer in 1967 and, was later tested for the treatment of endometrial cancer. MEGACE is currently used to improve appetite and to increase weight in cancer-associated anorexia. From September 1993, MEGACE was approved by the Food and Drug Administration in the United States for the treatment of anorexia, cachexia or unexplained weight loss in patients with AIDS. MEGACE has been found to improve appetite, caloric intake and nutritional status in several clinical trials[80-90]. Recently a meta-analysis of 35 trials, comprising 3963 patients, for the effectiveness of MEGACE was conducted, demonstrating a beneﬁt of MEGACE compared with placebo, particularly with regard to appetite improvement and weight gain in cancer. Higher doses were more related to weight improvement than lower doses. Quality of life improvement in patients was seen only when comparing MEGACE vs placebo. The mechanism for the associated weight gain is mostly unknown, although MEGACE may stimulate the synthesis, transport, and release of neuropeptide γ, known to produce appetite-stimulating effects in rats.
MPA has similarly been shown to increase appetite and food intake with a stabilization of body weight. There is evidence that high-dose synthetic progestins have effects on both appetite and body weight, the two clinical hallmarks most widely identified in patients with cancer anorexia and cachexia. MPA has been shown to reduce the in vitro production of serotonin and cytokines (IL-1, IL-6 and TNF-α) by peripheral blood mononuclear cells of cancer patients[92,93,95,96]. These findings have also been replicated in the clinical setting, with IL-1, IL-6, and TNF-α levels in serum reported to be decreased in cancer patients after MEGACE or MPA treatment.
Ghrelin, a 28-amino-acid gastric peptide hormone, was first identified in the rat stomach in 1999 as an endogenous ligand for the growth hormone secretagogue receptor. The functions of ghrelin include food intake regulation, gastrointestinal (GI) motility, and acid secretion in the GI tract. Many GI disorders involving infection, inflammation, and malignancy are correlated with altered ghrelin production and secretion. Circulating levels of ghrelin are noted to be increased when human melanoma cells are implanted in nude mice. In a similar manner, circulating levels of both acyl and des-acyl ghrelin are elevated in cachectic cancer patients with gastric cancer[100,101] and lung cancer[102,103]. The levels of acyl-ghrelin are reported to be 50% higher in cancer patients with cachexia. These elevated levels of ghrelin could represent a counter regulatory mechanism to fight anorexia associated with tumor growth, representing an endocrine response to the so-called “ghrelin resistance” found in cancer patients. This is the rationale behind the clinical studies of high dose ghrelin as a treatment to counteract anorexia in cancer.
An experimental study showed that repeated administration of ghrelin improves cardiac structure and function and attenuates the development of cardiac cachexia in chronic heart failure, with ghrelin thought to regulate energy metabolism through growth hormone dependent and growth hormone independent mechanisms. For cancer cachexia, a phase II randomized, placebo-controlled, double-blind study, using an oral ghrelin mimetic was conducted. This study demonstrated an improvement in lean body mass, total body mass and hand grip strength in cachectic cancer patients.
Cannabinoids, which are present in marijuana, are a class of diverse chemical compounds that activate cannabinoid receptors on cells that repress neurotransmitter release in the brain. Cannabinoids have a definite effect on weight gain and, bearing this in mind, have been used to increase food intake in cancer patients. The main effective constituent of cannabis is delta-9-tetrahydrocannabinol[106,107], but the mechanism by which cannabinoids exert their effects has yet to be clarified. It has been postulated that they may act viaendorphin receptors, through inhibition of prostaglandin synthesis, or by inhibiting IL-1 secretion. Despite high expectations for cannabinoids to be effective against cancer-related anorexia/cachexia syndrome, both of the two separate randomized clinical trials carried out by Jatoi et al and Strasser et al have failed to show benefit as compared to MEGACE or placebo, respectively.
The melanocortin-4 (MC4) receptor subtype plays a pivotal role in body weight regulation. Acute and chronic stimulation of MC4 receptors produces anorexia, weight loss, and an increase in metabolic rate, the cardinal features of disease-associated cachexia. Knock-out or antagonism of MC4 receptors in animal models of cachexia protects from anorexia and the loss of both lean and fat body mass, and it is suggested that an MC4 antagonist may be beneficial in wasting diseases, which are poorly treated by available therapies. The MC4 receptor is involved in the anorexigenic cascade leading to a decrease in neuropeptide γ and, therefore, a decrease in food intake. The use of MC4 antagonists has been proven to be effective in preventing anorexia associated with cachexia, loss of lean body mass and basal energy in animal models[112,113]; however, there is no clinical data at this time. Future clinical trials are needed to prove the efficacy of this antagonist in the treatment of human cachexia.
Thalidomide and etanercept
TNF-α, IL-6, and IFN-c have all been implicated in the pathogenesis of cachexia, and in cachectic tumor bearing murine models treatment with anti-TNF-α, anti-IL-6, and anti-IFN-c antibodies can attenuate the disease process, although it cannot stop or reverse cancer cachexia[49,114-120]. There is also some evidence that cytokines play a role in the pathogenesis of cachexia. It has been suggested that by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin by persistent stimulation of anorexigenic peptides, or by inhibition of the neuropeptide Y pathway, cytokines could induce anorexia. Thus modulating cytokine expression in cancer patients may also affect cancer associated anorexia. Therapeutic strategies have been based on either blocking cytokine synthesis or their action.
Thalidomide (a-N-phthalimidoglutaramide) has complex immune-modulatory and anti-inflammatory properties. It has been shown to down-regulate the production of TNF-α and other pro-inflammatory cytokines in monocytes, to inhibit the transcription factor nuclear factor kappa B (NFκB), down-regulate cyclooxygenase 2, and to inhibit angiogenesis[124,125]. One randomized placebo-controlled trial in patients with cancer cachexia showed that the drug was well-tolerated and effective at attenuating loss of weight and lean body mass in patients with advanced pancreatic cancer.
Etanercept, a soluble p75 tumor necrosis factor receptor: FC (TNFR: FC) fusion protein for plasma cytokines, has been used over the last decade for the treatment of immune-mediated rheumatic diseases. In a clinical pilot study, patients with several advanced malignancies treated with etanercept combined with docetaxel had less fatigue and improved tolerability to anti-tumor treatment, although etanercept alone did not show effects.
Eicosapentaenoic acid (EPA) is one of several omega-3 polyunsaturated fatty acids found abundantly in fish oil. Polyunsaturated fatty acids have been proposed to reduce cachexia-associated tissue wasting as well as tumor growth[129,130]. EPA down-regulates the production of pro-inflammatory cytokines in both healthy individuals and patients with cancer. Furthermore, the effects of proteolysis inducing factor, a cachectic factor produced by cancer, are also inhibited by EPA.
Three systematic reviews have been published regarding n-3-FA. Only one of these formulated a weak recommendation of n-3-FA for patients with advanced cancer and weight loss, stating that there was a fair evidence to recommend its use (recommendation grade B). The other two reviews found no clear advantages from treatment with n-3-FA. A meta-analysis by Colomer et al contained 17 trials[61,132-146], and attempted to evaluate the effectiveness and safety of n-3-FA in relieving symptoms associated with the cancer cachexia syndrome. They reported that EPA improved various clinical, biochemical, and quality of life parameters after 8 wk of treatment. Dewey et al showed that data were insufficient to determine whether oral EPA is better than placebo in their analysis of 5 trials[130,137,140,148,149]. Comparison of EPA vs MEGACE as an appetite stimulant provided no evidence that EPA improved cachexia-related symptoms. Mazzotta et al systematically reviewed several databases including publications until 2006 in order to identify the clinical efficacy of EPA and DHA for the management of cachexia in cancer patients. They analyzed 10 studies and 7 RCTs[133,137,140-142,151,152] and found no clear advantage of either EPA or DHA on weight, lean muscle mass, symptoms, quality of life, or survival. Studies that reported statistically significant differences were found to have only a small clinical difference, not enough to justify the use of EPA or DHA alone as a treatment option. However, it does seem clear that multidimensional treatments represent the most useful approach for cachexia in advanced cancer.
Altogether, there is not enough evidence to support a net benefit from n-3-FA in treating cachexia from advanced cancer. On the other hand, adverse effects were infrequent and not severe. More research is needed not only on drugs such as eicosapentaenoic acid or other n-3-FA, but also on multimodal approaches combining drugs and non-drug interventions.
Herbal medicine (kampo)
Kampo is the Japanese herbal medical practice, which is an adaptation of traditional Chinese medicine that came to Japan between the 7th and 9th centuries. Kampo has been shown to have significant clinical benefits for cachexia. Fujitsuka et al reported that Rikkunshito, a Kampo formula, improved anorexia, gastrointestinal dysmotility, muscle wasting, and anxiety-related behavior. Rikkunshito improved anorexia-cachexia and prolonged survival of tumor-bearing rats in this study. Moreover, Rikkunshito significantly prolonged median survival of pancreatic cancer patients with ascites who were treated with gemcitabine. These studies suggest that Rikkunshito may be useful in clinical practice for cachectic cancer patients. Although the mechanisms of how the herbs demonstrate these effects are unclear and remain to be elucidated, they deserve further studies as new potential therapy agents for cancer treatment.
Corticosteroids are one of the most widely used appetite stimulants. In randomized controlled studies, they have been shown to improve appetite and quality of life compared with placebo. MEGACE and corticosteroids seem equally effective, although for long-term use, corticosteroids result in more serious adverse effects such as protein breakdown, insulin resistance, water retention, and adrenal suppression. Therefore, corticosteroids are not suitable for long-term use and should be used in a limited fashion, such as during the pre-terminal phase of cachexia.
There are four studies investigating the relationship between non-steroidal anti-inflammatory drugs (NSAIDs) and cancer cachexia[158-161]. These studies demonstrated improved quality of life, performance status, inflammatory markers, weight gain and survival. Notably these reviews show that side effects of NSAIDs use were not remarkable in these reports that were evaluated.
However, two reports concluded data were insufficient for interpreting their widespread use of NSAIDs in practice[162,163]. This reflection comes up from the view of the large studies heterogeneity in terms of study design, number of patients, type of cancer, clinical parameters, definition of effect criteria, and the weakness of the many individual studies.
β2-adrenergic agonists are potent muscle growth promoters in many animal species resulting in skeletal muscle hypertrophy[164-167], and reduction of the body fat content[168,169]. The wide variety of physiologic functions controlled by β-adrenergic receptors suggest that the mechanisms underlying effects on carcass composition may be extremely complex.
Formoterol is a long-acting β2 agonist approved for the management of asthma and chronic obstructive pulmonary disease. Formoterol exerts a selective, powerful protective action on heart and skeletal muscle by antagonizing the enhanced protein degradation, which is a characteristic of cancer cachexia. β2-agonists are also proposed to have a protective action against the apoptosis of skeletal muscle. Formoterol may be potential therapeutic tool in pathologic states.
Other drugs that are investigated to be used for cancer cachexia include Erythropoetin[171-173], ACE inhibitors, and β-blockers.
At the present time, cancer cachexia cannot be cured. However, several recent randomized trials using combinations of newer chemotherapy agents have shown promising results. Combination chemotherapy was initially assessed with low-efficacy regimens designed for symptomatic management in the palliative setting until effective regimens were discovered that were found improve survival in the adjuvant setting. Regimens combining multiple drugs are expected to be successful. In a phase II study, the combined administration of anti-oxidants, pharmaco-nutritional support, progestagen and anti-cyclooxygenase-2 drugs, was shown to be safe and effective for cancer cachexia. Based on those results, an ongoing randomized phase III study began recruiting patients in 2005, with the aim of including more than 300 cachectic cancer patients. Findings to date reinforce the use of multi-modal therapies in the treatment of the cachexia-anorexia syndrome in cancer. Usually the response to therapy is better with early intervention during active adjuvant or palliative cancer therapy, compared to treatment when the patient has progressed to become refractory to anti-cachexia treatment. One of the challenges to undertaking “upfront” randomized trials for cachexia is that the systemic chemotherapy for cancer treatment itself can aggravate weight loss, and for anti-cachexia therapy to show benefit it has to “compete” with chemotherapy.
Since cancer cachexia differs from starvation, at the present time no single modality therapies using traditionally applied nutritional regimens has succeeded in demonstrate any efﬁcacy in improving weight gain, including gain in lean body mass, in patients diagnosed with cancer cachexia. The average calorie deficit in weight-losing patient is reported to be approximately 200 kcal per day in the setting of advanced cancer and 250-400 kcals/d in those patients with cancer cachexia. An average supplementation of 1 calorie/mL has not been shown to improve the nutritional status of patients receiving chemotherapy[140,179].
The average protein intake in patients with cancer cachexia is about 0.7-1.0 g/kg per day. Food energy intake needs to increase by 300-400 kcal per day and protein intake to increase by up to 50% to have an effect on anabolic resistance (recommended intake 1.0-1.5 g/kg per day). The analysis of a randomized trial found that in addition to oral nutritional support, the use of parenteral nutrition resulted in a short (6-8 wk) but significant (P < 0.001), prolongation of survival when nutritional goals were achieved. A meta-analysis of oral nutritional interventions in malnourished patients with cancer suggests that oral nutritional interventions have no effect on survival and that the effect on body weight and energy intake is inconsistent, though statistically significant improvements in some aspects of QOL may be achieved. In this study, nutritional intervention was associated with a significant increase in energy intake (430 kcal per day) and a weight gain of 1.9 kg. There was a beneficial effect on appetite and global quality of life.
Physical exercise has been suggested as a promising countermeasure for preventing cachexia. Unfortunately, only a few studies, in both clinical and experimental settings, have been performed to define the effectiveness of exercise against cachexia.
The rationale for the use of exercise is relies on the known are dramatic reduction of muscle strength and endurance during cachexia[183-186]. Since it is also reported that exercise increases insulin sensitivity, protein synthesis rate, and anti-oxidative enzyme activity it may lead to a suppression of the inflammatory response and enhancement of immune function. There is significant evidence that endurance exercise (e.g., a high number of repetitions performed over extended time periods against relatively low resistance) ameliorates cancer-related fatigue. A randomized trial has also reported that, in patients with advanced-stage cancer, exercise is feasible and that although fatigue is not reduced, physical performance is improved significantly. Combination of resistance and aerobic muscle training has been suggested to be incorporated into cachexia treatment programs. Exercise training is able to increase both strength and endurance in healthy conditions, depending on the type of exercise, and moreover, it has been proven to act as an excellent anabolic drive for skeletal muscle in combination with anabolic steroids or other muscle anabolic drugs.
Additional directions for study in the field of cancer cachexia may come from the results of Bossola et al who showed hyper-expression of mRNA for ubiquitin and increased proteolytic activity of proteasomes prior to weight loss in cancer patients. This finding could open a new research area in the field of early intervention and of prevention of cancer induced weight loss. Further research is also needed into cancer anorexia, due to the frequent finding of reduced food intake in cancer patients, and the lack of any current powerful therapies to improve appetite and daily caloric intake.
Cancer cachexia has been regarded as a non-curable disease, and has been estimated to be responsible for the death of over 20% of cancer patients. The management of cancer cachexia has improved dramatically in the past decade, as the mechanisms involved in the development and progression of the condition continue to be elucidated. Currently all treatments for cancer cachexia are considered palliative, but new agents have improved patient survival as well as their quality of life. Regular anti-neoplastic agents have ability to treat cancer, but in many cases worsen cachexia. Future progress in the field will be realized through development of treatment agents with ability to affect cancer progression as well as improve patient quality of life.
P- Reviewer: Chai J, Kralj M, Toth EA S- Editor: Qi Y L- Editor: A E- Editor: Lu YJ
Supported by NIH, No. R01CA160688 and No. T32CA085159-10.
Conflict-of-interest: No potential conflicts of interest relevant to this article were reported.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
1. Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev. 2009;89:381–410. [PubMed]
2. Fearon K, Arends J, Baracos V. Understanding the mechanisms and treatment options in cancer cachexia.Nat Rev Clin Oncol. 2013;10:90–99. [PubMed]
3. Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, Jatoi A, Loprinzi C, MacDonald N, Mantovani G, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12:489–495. [PubMed]
4. Evans WJ, Morley JE, Argilés J, Bales C, Baracos V, Guttridge D, Jatoi A, Kalantar-Zadeh K, Lochs H, Mantovani G, et al. Cachexia: a new definition. Clin Nutr. 2008;27:793–799. [PubMed]
5. Tisdale MJ. Cachexia in cancer patients. Nat Rev Cancer. 2002;2:862–871. [PubMed]
6. Congleton J. The pulmonary cachexia syndrome: aspects of energy balance. Proc Nutr Soc. 1999;58:321–328. [PubMed]
7. von Haehling S, Lainscak M, Springer J, Anker SD. Cardiac cachexia: a systematic overview. Pharmacol Ther. 2009;121:227–252. [PubMed]
8. Giordano A, Calvani M, Petillo O, Carteni’ M, Melone MR, Peluso G. Skeletal muscle metabolism in physiology and in cancer disease. J Cell Biochem. 2003;90:170–186. [PubMed]
9. Dewys WD, Begg C, Lavin PT, Band PR, Bennett JM, Bertino JR, Cohen MH, Douglass HO, Engstrom PF, Ezdinli EZ, et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J Med. 1980;69:491–497. [PubMed]
10. Deans C, Wigmore SJ. Systemic inflammation, cachexia and prognosis in patients with cancer. Curr Opin Clin Nutr Metab Care. 2005;8:265–269. [PubMed]
11. Tan BH, Fearon KC. Cachexia: prevalence and impact in medicine. Curr Opin Clin Nutr Metab Care.2008;11:400–407. [PubMed]
12. Warren S. The immediate cause of death in cancer. Am J Med Sci. 1932;184:610–613.
13. Skipworth RJ, Stewart GD, Dejong CH, Preston T, Fearon KC. Pathophysiology of cancer cachexia: much more than host-tumour interaction? Clin Nutr. 2007;26:667–676. [PubMed]
14. Hopkinson JB, Wright DN, McDonald JW, Corner JL. The prevalence of concern about weight loss and change in eating habits in people with advanced cancer. J Pain Symptom Manage. 2006;32:322–331.[PubMed]
15. von Haehling S, Anker SD. Cachexia as a major underestimated and unmet medical need: facts and numbers. J Cachexia Sarcopenia Muscle. 2010;1:1–5. [PMC free article][PubMed]
16. Diffee GM, Kalfas K, Al-Majid S, McCarthy DO. Altered expression of skeletal muscle myosin isoforms in cancer cachexia. Am J Physiol-Cell Ph. 2002;283:C1376–C1382. [PubMed]
17. Tijerina AJ. The biochemical basis of metabolism in cancer cachexia. Dimens Crit Care Nurs.2004;23:237–243. [PubMed]
18. Teunissen SC, Wesker W, Kruitwagen C, de Haes HC, Voest EE, de Graeff A. Symptom prevalence in patients with incurable cancer: a systematic review. J Pain Symptom Manage. 2007;34:94–104. [PubMed]
20. Mantovani G, Madeddu C. Cancer cachexia: medical management. Support Care Cancer. 2010;18:1–9.[PubMed]
21. Springer J, von Haehling S, Anker SD. The need for a standardized definition for cachexia in chronic illness. Nat Clin Pract Endoc. 2006;2:416–417. [PubMed]
22. Lainscak M, Filippatos GS, Gheorghiade M, Fonarow GC, Anker SD. Cachexia: Common, deadly, with an urgent need for precise definition and new therapies. Am J Cardiol. 2008;101:8E–10E. [PubMed]
23. Straub RH, Cutolo M, Buttgereit F, Pongratz G. Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. J Intern Med. 2010;267:543–560. [PubMed]
24. Argilés JM, Busquets S, Toledo M, López-Soriano FJ. The role of cytokines in cancer cachexia. Curr Opin Support Palliat Care. 2009;3:263–268. [PubMed]
25. MacDonald N, Easson AM, Mazurak VC, Dunn GP, Baracos VE. Understanding and managing cancer cachexia. J Am Coll Surg. 2003;197:143–161. [PubMed]
26. Blum D, Omlin A, Baracos VE, Solheim TS, Tan BH, Stone P, Kaasa S, Fearon K, Strasser F. Cancer cachexia: a systematic literature review of items and domains associated with involuntary weight loss in cancer. Crit Rev Oncol Hematol. 2011;80:114–144. [PubMed]
27. Deans DA, Tan BH, Wigmore SJ, Ross JA, de Beaux AC, Paterson-Brown S, Fearon KC. The influence of systemic inflammation, dietary intake and stage of disease on rate of weight loss in patients with gastro-oesophageal cancer. Br J Cancer. 2009;100:63–69. [PMC free article][PubMed]
28. Fearon KC, Barber MD, Falconer JS, McMillan DC, Ross JA, Preston T. Pancreatic cancer as a model: inflammatory mediators, acute-phase response, and cancer cachexia. World J Surg. 1999;23:584–588.[PubMed]
29. Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC, Bellotti V, Hawkins PN, Myers RM, Smith MD, Polara A, et al. Targeting C-reactive protein for the treatment of cardiovascular disease.Nature. 2006;440:1217–1221. [PubMed]
30. Staal-van den Brekel AJ, Dentener MA, Schols AM, Buurman WA, Wouters EF. Increased resting energy expenditure and weight loss are related to a systemic inflammatory response in lung cancer patients. J Clin Oncol. 1995;13:2600–2605. [PubMed]
31. Scott HR, McMillan DC, Crilly A, McArdle CS, Milroy R. The relationship between weight loss and interleukin 6 in non-small-cell lung cancer. Br J Cancer. 1996;73:1560–1562. [PMC free article][PubMed]
32. Blay JY, Negrier S, Combaret V, Attali S, Goillot E, Merrouche Y, Mercatello A, Ravault A, Tourani JM, Moskovtchenko JF. Serum level of interleukin 6 as a prognosis factor in metastatic renal cell carcinoma.Cancer Res. 1992;52:3317–3322. [PubMed]
33. Falconer JS, Fearon KC, Ross JA, Elton R, Wigmore SJ, Garden OJ, Carter DC. Acute-phase protein response and survival duration of patients with pancreatic cancer. Cancer. 1995;75:2077–2082. [PubMed]
34. O'Gorman P, McMillan DC, McArdle CS. Impact of weight loss, appetite, and the inflammatory response on quality of life in gastrointestinal cancer patients. Nutr Cancer. 1998;32:76–80. [PubMed]
35. Barber MD, Ross JA, Fearon KC. Changes in nutritional, functional, and inflammatory markers in advanced pancreatic cancer. Nutr Cancer. 1999;35:106–110. [PubMed]
36. Reeds PJ, Fjeld CR, Jahoor F. Do the differences between the amino acid compositions of acute-phase and muscle proteins have a bearing on nitrogen loss in traumatic states? J Nutr. 1994;124:906–910. [PubMed]
37. Barber MD, Fearon KC, McMillan DC, Slater C, Ross JA, Preston T. Liver export protein synthetic rates are increased by oral meal feeding in weight-losing cancer patients. Am J Physiol Endocrinol Metab.2000;279:E707–E714. [PubMed]
38. Ross JA, Fearon KC. Eicosanoid-dependent cancer cachexia and wasting. Curr Opin Clin Nutr Metab Care. 2002;5:241–248. [PubMed]
39. Tisdale MJ. The ‘cancer cachectic factor’ Support Care Cancer. 2003;11:73–78. [PubMed]
40. Baracos VE, Mazurak VC, Ma DW. n-3 Polyunsaturated fatty acids throughout the cancer trajectory: influence on disease incidence, progression, response to therapy and cancer-associated cachexia. Nutr Res Rev. 2004;17:177–192. [PubMed]
41. Zhou X, Wang JL, Lu J, Song Y, Kwak KS, Jiao Q, Rosenfeld R, Chen Q, Boone T, Simonet WS, et al. Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell.2010;142:531–543. [PubMed]
42. Benny Klimek ME, Aydogdu T, Link MJ, Pons M, Koniaris LG, Zimmers TA. Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia. Biochem Biophys Res Commun. 2010;391:1548–1554. [PubMed]
43. Murphy KT, Chee A, Gleeson BG, Naim T, Swiderski K, Koopman R, Lynch GS. Antibody-directed myostatin inhibition enhances muscle mass and function in tumor-bearing mice. Am J Physiol Regul Integr Comp Physiol. 2011;301:R716–R726. [PubMed]
44. Fearon KC, Glass DJ, Guttridge DC. Cancer cachexia: mediators, signaling, and metabolic pathways.Cell Metab. 2012;16:153–166. [PubMed]
45. Dodson S, Baracos VE, Jatoi A, Evans WJ, Cella D, Dalton JT, Steiner MS. Muscle wasting in cancer cachexia: clinical implications, diagnosis, and emerging treatment strategies. Annu Rev Med. 2011;62:265–279. [PubMed]
46. Carson JA, Baltgalvis KA. Interleukin 6 as a key regulator of muscle mass during cachexia. Exerc Sport Sci Rev. 2010;38:168–176. [PMC free article][PubMed]
47. Haslett PA. Anticytokine approaches to the treatment of anorexia and cachexia. Semin Oncol.1998;25:53–57. [PubMed]
48. Mantovani G, Macciò A, Lai P, Massa E, Ghiani M, Santona MC. Cytokine activity in cancer-related anorexia/cachexia: role of megestrol acetate and medroxyprogesterone acetate. Semin Oncol. 1998;25:45–52.[PubMed]
49. Tisdale MJ. Biology of cachexia. J Natl Cancer Inst. 1997;89:1763–1773. [PubMed]
50. Plata-Salamán CR. Immunoregulators in the nervous system. Neurosci Biobehav Rev. 1991;15:185–215.[PubMed]
51. Plata-Salamán CR. Anorexia during acute and chronic disease. Nutrition. 1996;12:69–78. [PubMed]
52. Moldawer LL, Copeland EM. Proinflammatory cytokines, nutritional support, and the cachexia syndrome: interactions and therapeutic options. Cancer. 1997;79:1828–1839. [PubMed]
53. Banks WA. Anorectic effects of circulating cytokines: role of the vascular blood-brain barrier. Nutrition.2001;17:434–437. [PubMed]
54. Hellerstein MK, Meydani SN, Meydani M, Wu K, Dinarello CA. Interleukin-1-induced anorexia in the rat. Influence of prostaglandins. J Clin Invest. 1989;84:228–235. [PMC free article][PubMed]
55. Torelli GF, Meguid MM, Moldawer LL, Edwards CK, Kim HJ, Carter JL, Laviano A, Rossi Fanelli F. Use of recombinant human soluble TNF receptor in anorectic tumor-bearing rats. Am J Physiol.1999;277:R850–R855. [PubMed]
56. Yeh SS, Schuster MW. Geriatric cachexia: the role of cytokines. Am J Clin Nutr. 1999;70:183–197.[PubMed]
57. Laviano A, Meguid MM, Yang ZJ, Gleason JR, Cangiano C, Rossi Fanelli F. Cracking the riddle of cancer anorexia. Nutrition. 1996;12:706–710. [PubMed]
58. Picton SV. Aspects of altered metabolism in children with cancer. Int J Cancer Suppl. 1998;11:62–64.[PubMed]
59. Albrecht JT, Canada TW. Cachexia and anorexia in malignancy. Hematol Oncol Clin North Am.1996;10:791–800. [PubMed]
60. Mihara M, Hashizume M, Yoshida H, Suzuki M, Shiina M. IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clin Sci (Lond) 2012;122:143–159. [PubMed]
61. Barber MD, Fearon KC, Tisdale MJ, McMillan DC, Ross JA. Effect of a fish oil-enriched nutritional supplement on metabolic mediators in patients with pancreatic cancer cachexia. Nutr Cancer. 2001;40:118–124. [PubMed]
62. Socher SH, Martinez D, Craig JB, Kuhn JG, Oliff A. Tumor necrosis factor not detectable in patients with clinical cancer cachexia. J Natl Cancer Inst. 1988;80:595–598. [PubMed]
63. Falconer JS, Ross JA, Fearon KC, Hawkins RA, O’Riordain MG, Carter DC. Effect of eicosapentaenoic acid and other fatty acids on the growth in vitro of human pancreatic cancer cell lines. Br J Cancer.1994;69:826–832. [PMC free article][PubMed]
64. Spitzner M, Ebner R, Wolff HA, Ghadimi BM, Wienands J, Grade M. STAT3: A Novel Molecular Mediator of Resistance to Chemoradiotherapy. Cancers (Basel) 2014;6:1986–2011. [PMC free article][PubMed]
65. Bonetto A, Aydogdu T, Jin X, Zhang Z, Zhan R, Puzis L, Koniaris LG, Zimmers TA. JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia.Am J Physiol Endocrinol Metab. 2012;303:E410–E421. [PMC free article][PubMed]
66. Donohoe CL, Ryan AM, Reynolds JV. Cancer cachexia: mechanisms and clinical implications.Gastroenterol Res Pract. 2011;2011:601434. [PMC free article][PubMed]
67. Argilés JM, Moore-Carrasco R, Fuster G, Busquets S, López-Soriano FJ. Cancer cachexia: the molecular mechanisms. Int J Biochem Cell Biol. 2003;35:405–409. [PubMed]
68. Moley JF, Aamodt R, Rumble W, Kaye W, Norton JA. Body cell mass in cancer-bearing and anorexic patients. JPEN J Parenter Enteral Nutr. 1987;11:219–222. [PubMed]
69. Dworzak F, Ferrari P, Gavazzi C, Maiorana C, Bozzetti F. Effects of cachexia due to cancer on whole body and skeletal muscle protein turnover. Cancer. 1998;82:42–48. [PubMed]
70. Tisdale MJ. Loss of skeletal muscle in cancer: biochemical mechanisms. Front Biosci. 2001;6:D164–D174. [PubMed]
71. Acharyya S, Ladner KJ, Nelsen LL, Damrauer J, Reiser PJ, Swoap S, Guttridge DC. Cancer cachexia is regulated by selective targeting of skeletal muscle gene products. J Clin Invest. 2004;114:370–378.[PMC free article][PubMed]
72. Vaughan VC, Martin P, Lewandowski PA. Cancer cachexia: impact, mechanisms and emerging treatments. J Cachexia Sarcopenia Muscle. 2013;4:95–109. [PMC free article][PubMed]
73. Fredrix EW, Soeters PB, Wouters EF, Deerenberg IM, von Meyenfeldt MF, Saris WH. Effect of different tumor types on resting energy expenditure. Cancer Res. 1991;51:6138–6141. [PubMed]
74. Falconer JS, Fearon KC, Plester CE, Ross JA, Carter DC. Cytokines, the acute-phase response, and resting energy expenditure in cachectic patients with pancreatic cancer. Ann Surg. 1994;219:325–331.[PMC free article][PubMed]
75. Rigaud D, Hassid J, Meulemans A, Poupard AT, Boulier A. A paradoxical increase in resting energy expenditure in malnourished patients near death: the king penguin syndrome. Am J Clin Nutr. 2000;72:355–360. [PubMed]
76. Shellock FG, Riedinger MS, Fishbein MC. Brown adipose tissue in cancer patients: possible cause of cancer-induced cachexia. J Cancer Res Clin Oncol. 1986;111:82–85. [PubMed]
77. Qualliotine-Mann D, Agwu DE, Ellenburg MD, McCall CE, McPhail LC. Phosphatidic acid and diacylglycerol synergize in a cell-free system for activation of NADPH oxidase from human neutrophils. J Biol Chem. 1993;268:23843–23849. [PubMed]
78. Bing C, Brown M, King P, Collins P, Tisdale MJ, Williams G. Increased gene expression of brown fat uncoupling protein (UCP)1 and skeletal muscle UCP2 and UCP3 in MAC16-induced cancer cachexia.Cancer Res. 2000;60:2405–2410. [PubMed]
79. Collins P, Bing C, McCulloch P, Williams G. Muscle UCP-3 mRNA levels are elevated in weight loss associated with gastrointestinal adenocarcinoma in humans. Br J Cancer. 2002;86:372–375. [PMC free article][PubMed]
80. Loprinzi CL, Michalak JC, Schaid DJ, Mailliard JA, Athmann LM, Goldberg RM, Tschetter LK, Hatfield AK, Morton RF. Phase III evaluation of four doses of megestrol acetate as therapy for patients with cancer anorexia and/or cachexia. J Clin Oncol. 1993;11:762–767. [PubMed]
81. Bruera E, Macmillan K, Kuehn N, Hanson J, MacDonald RN. A controlled trial of megestrol acetate on appetite, caloric intake, nutritional status, and other symptoms in patients with advanced cancer. Cancer.1990;66:1279–1282. [PubMed]
82. Neri B, Garosi VL, Intini C. Effect of medroxyprogesterone acetate on the quality of life of the oncologic patient: a multicentric cooperative study. Anticancer Drugs. 1997;8:459–465. [PubMed]
83. Nelson KA. The cancer anorexia-cachexia syndrome. Semin Oncol. 2000;27:64–68. [PubMed]
84. Gagnon B, Bruera E. A review of the drug treatment of cachexia associated with cancer. Drugs.1998;55:675–688. [PubMed]
85. Argilés JM, Meijsing SH, Pallarés-Trujillo J, Guirao X, López-Soriano FJ. Cancer cachexia: a therapeutic approach. Med Res Rev. 2001;21:83–101. [PubMed]
86. Feliu J, González-Barón M, Berrocal A, Ordóñez A, Barón-Saura JM. Treatment of cancer anorexia with megestrol acetate: which is the optimal dose? J Natl Cancer Inst. 1991;83:449–450. [PubMed]
87. Loprinzi CL, Ellison NM, Schaid DJ, Krook JE, Athmann LM, Dose AM, Mailliard JA, Johnson PS, Ebbert LP, Geeraerts LH. Controlled trial of megestrol acetate for the treatment of cancer anorexia and cachexia. J Natl Cancer Inst. 1990;82:1127–1132. [PubMed]
88. Tchekmedyian NS, Hickman M, Siau J, Greco FA, Keller J, Browder H, Aisner J. Megestrol acetate in cancer anorexia and weight loss. Cancer. 1992;69:1268–1274. [PubMed]
89. Loprinzi CL, Schaid DJ, Dose AM, Burnham NL, Jensen MD. Body-composition changes in patients who gain weight while receiving megestrol acetate. J Clin Oncol. 1993;11:152–154. [PubMed]
90. Rowland KM, Loprinzi CL, Shaw EG, Maksymiuk AW, Kuross SA, Jung SH, Kugler JW, Tschetter LK, Ghosh C, Schaefer PL, et al. Randomized double-blind placebo-controlled trial of cisplatin and etoposide plus megestrol acetate/placebo in extensive-stage small-cell lung cancer: a North Central Cancer Treatment Group study. J Clin Oncol. 1996;14:135–141. [PubMed]
91. Ruiz Garcia V, López-Briz E, Carbonell Sanchis R, Gonzalvez Perales JL, Bort-Marti S. Megestrol acetate for treatment of anorexia-cachexia syndrome. Cochrane Database Syst Rev. 2013;3:CD004310.[PubMed]
92. McCarthy HD, Crowder RE, Dryden S, Williams G. Megestrol acetate stimulates food and water intake in the rat: effects on regional hypothalamic neuropeptide Y concentrations. Eur J Pharmacol. 1994;265:99–102. [PubMed]
93. Mantovani G, Macciò A, Massa E, Madeddu C. Managing cancer-related anorexia/cachexia. Drugs.2001;61:499–514. [PubMed]
94. Maltoni M, Nanni O, Scarpi E, Rossi D, Serra P, Amadori D. High-dose progestins for the treatment of cancer anorexia-cachexia syndrome: a systematic review of randomised clinical trials. Ann Oncol.2001;12:289–300. [PubMed]
95. Mantovani G, Macciò A, Esu S, Lai P, Santona MC, Massa E, Dessì D, Melis GB, Del Giacco GS. Medroxyprogesterone acetate reduces the in vitro production of cytokines and serotonin involved in anorexia/cachexia and emesis by peripheral blood mononuclear cells of cancer patients. Eur J Cancer.1997;33:602–607. [PubMed]
96. Costa AM, Spence KT, Plata-Salamán CR, ffrench-Mullen JM. Residual Ca2+ channel current modulation by megestrol acetate via a G-protein alpha s-subunit in rat hypothalamic neurones. J Physiol.1995;487(Pt 2):291–303. [PMC free article][PubMed]
97. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402:656–660. [PubMed]
98. Cheung CK, Wu JC. Role of ghrelin in the pathophysiology of gastrointestinal disease. Gut Liver.2013;7:505–512. [PMC free article][PubMed]
99. Hanada T, Toshinai K, Date Y, Kajimura N, Tsukada T, Hayashi Y, Kangawa K, Nakazato M. Upregulation of ghrelin expression in cachectic nude mice bearing human melanoma cells. Metabolism.2004;53:84–88. [PubMed]
100. Kerem M, Ferahkose Z, Yilmaz UT, Pasaoglu H, Ofluoglu E, Bedirli A, Salman B, Sahin TT, Akin M. Adipokines and ghrelin in gastric cancer cachexia. World J Gastroenterol. 2008;14:3633–3641.[PMC free article][PubMed]
101. Takahashi M, Terashima M, Takagane A, Oyama K, Fujiwara H, Wakabayashi G. Ghrelin and leptin levels in cachectic patients with cancer of the digestive organs. Int J Clin Oncol. 2009;14:315–320. [PubMed]
102. Shimizu Y, Nagaya N, Isobe T, Imazu M, Okumura H, Hosoda H, Kojima M, Kangawa K, Kohno N. Increased plasma ghrelin level in lung cancer cachexia. Clin Cancer Res. 2003;9:774–778. [PubMed]
103. Karapanagiotou EM, Polyzos A, Dilana KD, Gratsias I, Boura P, Gkiozos I, Syrigos KN. Increased serum levels of ghrelin at diagnosis mediate body weight loss in non-small cell lung cancer (NSCLC) patients. Lung Cancer. 2009;66:393–398. [PubMed]
104. Garcia JM, Garcia-Touza M, Hijazi RA, Taffet G, Epner D, Mann D, Smith RG, Cunningham GR, Marcelli M. Active ghrelin levels and active to total ghrelin ratio in cancer-induced cachexia. J Clin Endocrinol Metab. 2005;90:2920–2926. [PubMed]
105. Nagaya N, Kojima M, Kangawa K. Ghrelin, a novel growth hormone-releasing peptide, in the treatment of cardiopulmonary-associated cachexia. Intern Med. 2006;45:127–134. [PubMed]
106. Inui A. Cancer anorexia-cachexia syndrome: current issues in research and management. CA Cancer J Clin. 2002;52:72–91. [PubMed]
107. Gorter RW. Cancer cachexia and cannabinoids. Forsch Komplementarmed. 1999;6 Suppl 3:21–22.[PubMed]
108. Mitchelson F. Pharmacological agents affecting emesis. A review (Part II) Drugs. 1992;43:443–463.[PubMed]
109. Jatoi A, Windschitl HE, Loprinzi CL, Sloan JA, Dakhil SR, Mailliard JA, Pundaleeka S, Kardinal CG, Fitch TR, Krook JE, et al. Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study. J Clin Oncol. 2002;20:567–573.[PubMed]
110. Strasser F, Luftner D, Possinger K, Ernst G, Ruhstaller T, Meissner W, Ko YD, Schnelle M, Reif M, Cerny T. Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group. J Clin Oncol. 2006;24:3394–3400. [PubMed]
111. Marks DL, Butler AA, Turner R, Brookhart G, Cone RD. Differential role of melanocortin receptor subtypes in cachexia. Endocrinology. 2003;144:1513–1523. [PubMed]
112. Scarlett JM, Marks DL. The use of melanocortin antagonists in cachexia of chronic disease. Expert Opin Investig Drugs. 2005;14:1233–1239. [PubMed]
113. DeBoer MD, Marks DL. Therapy insight: Use of melanocortin antagonists in the treatment of cachexia in chronic disease. Nat Clin Pract Endocrinol Metab. 2006;2:459–466. [PubMed]
114. Oliff A, Defeo-Jones D, Boyer M, Martinez D, Kiefer D, Vuocolo G, Wolfe A, Socher SH. Tumors secreting human TNF/cachectin induce cachexia in mice. Cell. 1987;50:555–563. [PubMed]
115. Langstein HN, Doherty GM, Fraker DL, Buresh CM, Norton JA. The roles of gamma-interferon and tumor necrosis factor alpha in an experimental rat model of cancer cachexia. Cancer Res. 1991;51:2302–2306. [PubMed]
116. Strassmann G, Fong M, Kenney JS, Jacob CO. Evidence for the involvement of interleukin 6 in experimental cancer cachexia. J Clin Invest. 1992;89:1681–1684. [PMC free article][PubMed]
117. Costelli P, Carbó N, Tessitore L, Bagby GJ, Lopez-Soriano FJ, Argilés JM, Baccino FM. Tumor necrosis factor-alpha mediates changes in tissue protein turnover in a rat cancer cachexia model. J Clin Invest.1993;92:2783–2789. [PMC free article][PubMed]
118. Murray S, Schell K, McCarthy DO, Albertini MR. Tumor growth, weight loss and cytokines in SCID mice. Cancer Lett. 1997;111:111–115. [PubMed]
119. Matthys P, Heremans H, Opdenakker G, Billiau A. Anti-interferon-gamma antibody treatment, growth of Lewis lung tumours in mice and tumour-associated cachexia. Eur J Cancer. 1991;27:182–187. [PubMed]
120. Strassmann G, Kambayashi T. Inhibition of experimental cancer cachexia by anti-cytokine and anti-cytokine-receptor therapy. Cytokines Mol Ther. 1995;1:107–113. [PubMed]
121. Ramos EJ, Suzuki S, Marks D, Inui A, Asakawa A, Meguid MM. Cancer anorexia-cachexia syndrome: cytokines and neuropeptides. Curr Opin Clin Nutr Metab Care. 2004;7:427–434. [PubMed]
122. Inui A. Cancer anorexia-cachexia syndrome: are neuropeptides the key? Cancer Res. 1999;59:4493–4501. [PubMed]
123. Yamamoto N, Kawamura I, Nishigaki F, Tsujimoto S, Naoe Y, Inami M, Elizabeth L, Manda T, Shimomura K. Effect of FR143430, a novel cytokine suppressive agent, on adenocarcinoma colon26-induced cachexia in mice. Anticancer Res. 1998;18:139–144. [PubMed]
124. Sampaio EP, Sarno EN, Galilly R, Cohn ZA, Kaplan G. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med. 1991;173:699–703. [PMC free article][PubMed]
125. Gordon JN, Goggin PM. Thalidomide and its derivatives: emerging from the wilderness. Postgrad Med J. 2003;79:127–132. [PMC free article][PubMed]
126. Gordon JN, Trebble TM, Ellis RD, Duncan HD, Johns T, Goggin PM. Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial. Gut. 2005;54:540–545. [PMC free article][PubMed]
127. Monk JP, Phillips G, Waite R, Kuhn J, Schaaf LJ, Otterson GA, Guttridge D, Rhoades C, Shah M, Criswell T, et al. Assessment of tumor necrosis factor alpha blockade as an intervention to improve tolerability of dose-intensive chemotherapy in cancer patients. J Clin Oncol. 2006;24:1852–1859. [PubMed]
128. Tisdale MJ. Mechanism of lipid mobilization associated with cancer cachexia: interaction between the polyunsaturated fatty acid, eicosapentaenoic acid, and inhibitory guanine nucleotide-regulatory protein.Prostaglandins Leukot Essent Fatty Acids. 1993;48:105–109. [PubMed]
129. Anti M, Marra G, Armelao F, Bartoli GM, Ficarelli R, Percesepe A, De Vitis I, Maria G, Sofo L, Rapaccini GL. Effect of omega-3 fatty acids on rectal mucosal cell proliferation in subjects at risk for colon cancer. Gastroenterology. 1992;103:883–891. [PubMed]
130. Rose DP, Connolly JM. Effects of dietary omega-3 fatty acids on human breast cancer growth and metastases in nude mice. J Natl Cancer Inst. 1993;85:1743–1747. [PubMed]
131. Colomer R, Moreno-Nogueira JM, García-Luna PP, García-Peris P, García-de-Lorenzo A, Zarazaga A, Quecedo L, del Llano J, Usán L, Casimiro C. N-3 fatty acids, cancer and cachexia: a systematic review of the literature. Br J Nutr. 2007;97:823–831. [PubMed]
132. Moses AW, Slater C, Preston T, Barber MD, Fearon KC. Reduced total energy expenditure and physical activity in cachectic patients with pancreatic cancer can be modulated by an energy and protein dense oral supplement enriched with n-3 fatty acids. Br J Cancer. 2004;90:996–1002. [PMC free article][PubMed]
133. Barber MD, Ross JA, Preston T, Shenkin A, Fearon KC. Fish oil-enriched nutritional supplement attenuates progression of the acute-phase response in weight-losing patients with advanced pancreatic cancer.J Nutr. 1999;129:1120–1125. [PubMed]
134. Barber MD, Ross JA, Voss AC, Tisdale MJ, Fearon KC. The effect of an oral nutritional supplement enriched with fish oil on weight-loss in patients with pancreatic cancer. Br J Cancer. 1999;81:80–86.[PMC free article][PubMed]
135. Barber MD, McMillan DC, Preston T, Ross JA, Fearon KC. Metabolic response to feeding in weight-losing pancreatic cancer patients and its modulation by a fish-oil-enriched nutritional supplement. Clin Sci (Lond) 2000;98:389–399. [PubMed]
136. Barber MD, Fearon KC. Tolerance and incorporation of a high-dose eicosapentaenoic acid diester emulsion by patients with pancreatic cancer cachexia. Lipids. 2001;36:347–351. [PubMed]
137. Bruera E, Strasser F, Palmer JL, Willey J, Calder K, Amyotte G, Baracos V. Effect of fish oil on appetite and other symptoms in patients with advanced cancer and anorexia/cachexia: a double-blind, placebo-controlled study. J Clin Oncol. 2003;21:129–134. [PubMed]
138. Burns CP, Halabi S, Clamon GH, Hars V, Wagner BA, Hohl RJ, Lester E, Kirshner JJ, Vinciguerra V, Paskett E. Phase I clinical study of fish oil fatty acid capsules for patients with cancer cachexia: cancer and leukemia group B study 9473. Clin Cancer Res. 1999;5:3942–3947. [PubMed]
139. Burns CP, Halabi S, Clamon G, Kaplan E, Hohl RJ, Atkins JN, Schwartz MA, Wagner BA, Paskett E. Phase II study of high-dose fish oil capsules for patients with cancer-related cachexia. Cancer. 2004;101:370–378. [PubMed]
140. Fearon KC, Von Meyenfeldt MF, Moses AG, Van Geenen R, Roy A, Gouma DJ, Giacosa A, Van Gossum A, Bauer J, Barber MD, et al. Effect of a protein and energy dense N-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: a randomised double blind trial. Gut.2003;52:1479–1486. [PMC free article][PubMed]
141. Gogos CA, Ginopoulos P, Salsa B, Apostolidou E, Zoumbos NC, Kalfarentzos F. Dietary omega-3 polyunsaturated fatty acids plus vitamin E restore immunodeficiency and prolong survival for severely ill patients with generalized malignancy: a randomized control trial. Cancer. 1998;82:395–402. [PubMed]
142. Jatoi A, Rowland K, Loprinzi CL, Sloan JA, Dakhil SR, MacDonald N, Gagnon B, Novotny PJ, Mailliard JA, Bushey TI, et al. An eicosapentaenoic acid supplement versus megestrol acetate versus both for patients with cancer-associated wasting: a North Central Cancer Treatment Group and National Cancer Institute of Canada collaborative effort. J Clin Oncol. 2004;22:2469–2476. [PubMed]
143. Kenler AS, Swails WS, Driscoll DF, DeMichele SJ, Daley B, Babineau TJ, Peterson MB, Bistrian BR. Early enteral feeding in postsurgical cancer patients. Fish oil structured lipid-based polymeric formula versus a standard polymeric formula. Ann Surg. 1996;223:316–333. [PMC free article][PubMed]
144. Swails WS, Kenler AS, Driscoll DF, DeMichele SJ, Babineau TJ, Utsunamiya T, Chavali S, Forse RA, Bistrian BR. Effect of a fish oil structured lipid-based diet on prostaglandin release from mononuclear cells in cancer patients after surgery. JPEN J Parenter Enteral Nutr. 1997;21:266–274. [PubMed]
145. Wigmore SJ, Ross JA, Falconer JS, Plester CE, Tisdale MJ, Carter DC, Fearon KC. The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer. Nutrition.1996;12:S27–S30. [PubMed]
146. Wigmore SJ, Barber MD, Ross JA, Tisdale MJ, Fearon KC. Effect of oral eicosapentaenoic acid on weight loss in patients with pancreatic cancer. Nutr Cancer. 2000;36:177–184. [PubMed]
147. Dewey A, Baughan C, Dean T, Higgins B, Johnson I. Eicosapentaenoic acid (EPA, an omega-3 fatty acid from fish oils) for the treatment of cancer cachexia. Cochrane Database Syst Rev. 2007;(1):CD004597.[PubMed]
148. Anker SD, Coats AJ. How to recover from renaissance? The significance of the results of recover, renaissance, renewal and attach. Int J Cardiol. 2002;86:123–130. [PubMed]
149. Zuijdgeest-Van Leeuwen SD, Dagnelie PC, Wattimena JL, Van den Berg JW, Van der Gaast A, Swart GR, Wilson JH. Eicosapentaenoic acid ethyl ester supplementation in cachectic cancer patients and healthy subjects: effects on lipolysis and lipid oxidation. Clin Nutr. 2000;19:417–423. [PubMed]
150. Mazzotta P, Jeney CM. Anorexia-cachexia syndrome: a systematic review of the role of dietary polyunsaturated Fatty acids in the management of symptoms, survival, and quality of life. J Pain Symptom Manage. 2009;37:1069–1077. [PubMed]
151. Persson C, Glimelius B, Rönnelid J, Nygren P. Impact of fish oil and melatonin on cachexia in patients with advanced gastrointestinal cancer: a randomized pilot study. Nutrition. 2005;21:170–178. [PubMed]
152. Fearon KC, Barber MD, Moses AG, Ahmedzai SH, Taylor GS, Tisdale MJ, Murray GD. Double-blind, placebo-controlled, randomized study of eicosapentaenoic acid diester in patients with cancer cachexia.J Clin Oncol. 2006;24:3401–3407. [PubMed]
153. Olaku O, White JD. Herbal therapy use by cancer patients: a literature review on case reports. Eur J Cancer. 2011;47:508–514. [PMC free article][PubMed]
154. Fujitsuka N, Asakawa A, Uezono Y, Minami K, Yamaguchi T, Niijima A, Yada T, Maejima Y, Sedbazar U, Sakai T, et al. Potentiation of ghrelin signaling attenuates cancer anorexia-cachexia and prolongs survival. Transl Psychiatry. 2011;1:e23. [PMC free article][PubMed]
155. Huang CF, Lin SS, Liao PH, Young SC, Yang CC. The immunopharmaceutical effects and mechanisms of herb medicine. Cell Mol Immunol. 2008;5:23–31. [PMC free article][PubMed]
157. Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, Krook JE, Wilwerding MB, Rowland KM, Camoriano JK, Novotny PJ, Christensen BJ. Randomized comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/cachexia. J Clin Oncol.1999;17:3299–3306. [PubMed]
158. Lai V, George J, Richey L, Kim HJ, Cannon T, Shores C, Couch M. Results of a pilot study of the effects of celecoxib on cancer cachexia in patients with cancer of the head, neck, and gastrointestinal tract.Head Neck. 2008;30:67–74. [PubMed]
159. McMillan DC, Wigmore SJ, Fearon KC, O’Gorman P, Wright CE, McArdle CS. A prospective randomized study of megestrol acetate and ibuprofen in gastrointestinal cancer patients with weight loss. Br J Cancer. 1999;79:495–500. [PMC free article][PubMed]
160. Cerchietti LC, Navigante AH, Castro MA. Effects of eicosapentaenoic and docosahexaenoic n-3 fatty acids from fish oil and preferential Cox-2 inhibition on systemic syndromes in patients with advanced lung cancer. Nutr Cancer. 2007;59:14–20. [PubMed]
161. Lundholm K, Gelin J, Hyltander A, Lönnroth C, Sandström R, Svaninger G, Körner U, Gülich M, Kärrefors I, Norli B. Anti-inflammatory treatment may prolong survival in undernourished patients with metastatic solid tumors. Cancer Res. 1994;54:5602–5606. [PubMed]
162. Reid J, Hughes CM, Murray LJ, Parsons C, Cantwell MM. Non-steroidal anti-inflammatory drugs for the treatment of cancer cachexia: a systematic review. Palliat Med. 2013;27:295–303. [PubMed]
163. Solheim TS, Fearon KC, Blum D, Kaasa S. Non-steroidal anti-inflammatory treatment in cancer cachexia: a systematic literature review. Acta Oncol. 2013;52:6–17. [PubMed]
164. Kim YS, Sainz RD. Beta-adrenergic agonists and hypertrophy of skeletal muscles. Life Sci.1992;50:397–407. [PubMed]
165. Agbenyega ET, Wareham AC. Effect of clenbuterol on skeletal muscle atrophy in mice induced by the glucocorticoid dexamethasone. Comp Biochem Physiol Comp Physiol. 1992;102:141–145. [PubMed]
166. Rajab P, Fox J, Riaz S, Tomlinson D, Ball D, Greenhaff PL. Skeletal muscle myosin heavy chain isoforms and energy metabolism after clenbuterol treatment in the rat. Am J Physiol Regul Integr Comp Physiol. 2000;279:R1076–R1081. [PubMed]
167. Hinkle RT, Hodge KM, Cody DB, Sheldon RJ, Kobilka BK, Isfort RJ. Skeletal muscle hypertrophy and anti-atrophy effects of clenbuterol are mediated by the beta2-adrenergic receptor. Muscle Nerve.2002;25:729–734. [PubMed]
168. Yang YT, McElligott MA. Multiple actions of beta-adrenergic agonists on skeletal muscle and adipose tissue. Biochem J. 1989;261:1–10. [PMC free article][PubMed]
169. Mersmann HJ. Overview of the effects of beta-adrenergic receptor agonists on animal growth including mechanisms of action. J Anim Sci. 1998;76:160–172. [PubMed]
170. Busquets S, Figueras MT, Fuster G, Almendro V, Moore-Carrasco R, Ametller E, Argilés JM, López-Soriano FJ. Anticachectic effects of formoterol: a drug for potential treatment of muscle wasting. Cancer Res.2004;64:6725–6731. [PubMed]
171. Penna F, Busquets S, Toledo M, Pin F, Massa D, López-Soriano FJ, Costelli P, Argilés JM. Erythropoietin administration partially prevents adipose tissue loss in experimental cancer cachexia models. J Lipid Res. 2013;54:3045–3051. [PMC free article][PubMed]
172. van Halteren HK, Bongaerts GP, Verhagen CA, Kamm YJ, Willems JL, Grutters GJ, Koopman JP, Wagener DJ. Recombinant human erythropoietin attenuates weight loss in a murine cancer cachexia model. J Cancer Res Clin Oncol. 2004;130:211–216. [PubMed]
173. Kanzaki M, Soda K, Gin PT, Kai T, Konishi F, Kawakami M. Erythropoietin attenuates cachectic events and decreases production of interleukin-6, a cachexia-inducing cytokine. Cytokine. 2005;32:234–239.[PubMed]
174. Sanders PM, Russell ST, Tisdale MJ. Angiotensin II directly induces muscle protein catabolism through the ubiquitin-proteasome proteolytic pathway and may play a role in cancer cachexia. Br J Cancer.2005;93:425–434. [PMC free article][PubMed]
175. Springer J, Tschirner A, Haghikia A, von Haehling S, Lal H, Grzesiak A, Kaschina E, Palus S, Pötsch M, von Websky K, et al. Prevention of liver cancer cachexia-induced cardiac wasting and heart failure. Eur Heart J. 2014;35:932–941. [PMC free article][PubMed]
176. de Gramont A, de Gramont A, Chibaudel B, Larsen AK, Tournigand C, André T. The evolution of adjuvant therapy in the treatment of early-stage colon cancer. Clin Colorectal Cancer. 2011;10:218–226.[PubMed]
177. Mantovani G, Macciò A, Madeddu C, Gramignano G, Lusso MR, Serpe R, Massa E, Astara G, Deiana L. A phase II study with antioxidants, both in the diet and supplemented, pharmaconutritional support, progestagen, and anti-cyclooxygenase-2 showing efficacy and safety in patients with cancer-related anorexia/cachexia and oxidative stress. Cancer Epidemiol Biomarkers Prev. 2006;15:1030–1034. [PubMed]
178. Kumar NB, Kazi A, Smith T, Crocker T, Yu D, Reich RR, Reddy K, Hastings S, Exterman M, Balducci L, et al. Cancer cachexia: traditional therapies and novel molecular mechanism-based approaches to treatment. Curr Treat Options Oncol. 2010;11:107–117. [PMC free article][PubMed]
179. Couch M, Lai V, Cannon T, Guttridge D, Zanation A, George J, Hayes DN, Zeisel S, Shores C. Cancer cachexia syndrome in head and neck cancer patients: part I. Diagnosis, impact on quality of life and survival, and treatment. Head Neck. 2007;29:401–411. [PubMed]
180. Lundholm K, Daneryd P, Bosaeus I, Körner U, Lindholm E. Palliative nutritional intervention in addition to cyclooxygenase and erythropoietin treatment for patients with malignant disease: Effects on survival, metabolism, and function. Cancer. 2004;100:1967–1977. [PubMed]
181. Baldwin C, Spiro A, Ahern R, Emery PW. Oral nutritional interventions in malnourished patients with cancer: a systematic review and meta-analysis. J Natl Cancer Inst. 2012;104:371–385. [PubMed]
182. Lenk K, Schuler G, Adams V. Skeletal muscle wasting in cachexia and sarcopenia: molecular pathophysiology and impact of exercise training. J Cachexia Sarcopenia Muscle. 2010;1:9–21.[PMC free article][PubMed]
183. Toledo M, Busquets S, Sirisi S, Serpe R, Orpí M, Coutinho J, Martínez R, López-Soriano FJ, Argilés JM. Cancer cachexia: physical activity and muscle force in tumour-bearing rats. Oncol Rep. 2011;25:189–193. [PubMed]
184. Baltgalvis KA, Berger FG, Peña MM, Davis JM, White JP, Carson JA. Muscle wasting and interleukin-6-induced atrogin-I expression in the cachectic Apc (Min/+) mouse. Pflugers Arch. 2009;457:989–1001.[PMC free article][PubMed]
185. Weber MA, Krakowski-Roosen H, Schröder L, Kinscherf R, Krix M, Kopp-Schneider A, Essig M, Bachert P, Kauczor HU, Hildebrandt W. Morphology, metabolism, microcirculation, and strength of skeletal muscles in cancer-related cachexia. Acta Oncol. 2009;48:116–124. [PubMed]
186. Aulino P, Berardi E, Cardillo VM, Rizzuto E, Perniconi B, Ramina C, Padula F, Spugnini EP, Baldi A, Faiola F, et al. Molecular, cellular and physiological characterization of the cancer cachexia-inducing C26 colon carcinoma in mouse. BMC Cancer. 2010;10:363. [PMC free article][PubMed]
187. Radbruch L, Elsner F, Trottenberg P, Strasser F, Fearon K. Clinical practice guidelines on cancer cachexia in advanced cancer patients. Aachen: Department of Palliative Medicinen/European Palliative Care Research Collaborative; 2010.
188. Ardies CM. Exercise, cachexia, and cancer therapy: a molecular rationale. Nutr Cancer. 2002;42:143–157. [PubMed]
189. al-Majid S, McCarthy DO. Cancer-induced fatigue and skeletal muscle wasting: the role of exercise.Biol Res Nurs. 2001;2:186–197. [PubMed]
190. Oldervoll LM, Loge JH, Lydersen S, Paltiel H, Asp MB, Nygaard UV, Oredalen E, Frantzen TL, Lesteberg I, Amundsen L, et al. Physical exercise for cancer patients with advanced disease: a randomized controlled trial. Oncologist. 2011;16:1649–1657. [PMC free article][PubMed]
191. Argilés JM, Busquets S, López-Soriano FJ, Costelli P, Penna F. Are there any benefits of exercise training in cancer cachexia? J Cachexia Sarcopenia Muscle. 2012;3:73–76. [PMC free article][PubMed]
192. Aagaard P. Making muscles “stronger”: exercise, nutrition, drugs. J Musculoskelet Neuronal Interact.2004;4:165–174. [PubMed]
193. Bossola M, Muscaritoli M, Costelli P, Grieco G, Bonelli G, Pacelli F, Fanelli FR, Doglietto GB, Baccino FM. Increased muscle proteasome activity correlates with disease severity in gastric cancer patients.Ann Surg. 2003;237:384–389. [PMC free article][PubMed]
Kakeksia tarkoittaa vaikeasta sairaudesta tai ravinnon puutteesta aiheutuvaa kuihtumista, väsymistä, lihaskudoskatoa, vaikeaa aliravitsemusta ja laihtumista. Mahdollisia tilaan johtavia sairauksia ovat krooniset infektiot ja syövät. Myös monista muista sairauksista, kuten AIDS:issa tai tuberkuloosistakärsivissä voi olla kakeksian merkkejä. Vaikea sydämen vajaatoiminta aiheuttaa kardiaalista kakeksiaa. Kakektisilla vanhuksilla tilan taustalla ei välttämättä ole mitään havaittavaa sairautta.
Yleistynyt tulehdusreaktio liittyy kakeksiaan olennaisesti.
Syöpäpotilaista kakeksiasta kärsivät erityisesti keuhkosyöpää ja ruoansulatuselimistön syöpiä sairastavat. Yleensä tila liittyy edenneeseen tautiin. Kakeksiasta ei voi täysin toipua, vaikka yrittäisi syödä enemmän