Anorexia and metabolic alterations are the main components of the cachectic syndrome. Glucose intolerance, fat depletion, muscle protein catabolism and other alterations are involved in the development of cancer cachexia, a multi-organ syndrome. Nutritional approach strategies are not satisfactory in reversing the cachectic syndrome. The aim of the present review is to deal with the recent therapeutic targeted approaches that have been designed to fight and counteract wasting in cancer patients. Indeed, some promising targeted therapeutic approaches include ghrelin agonists, selective androgen receptor agonists, β-blockers and antimyostatin peptides. However, a multi-targeted approach seems absolutely essential to treat patients affected by cancer cachexia. This approach should not only involve combinations of drugs but also nutrition and an adequate program of physical exercise, factors that may lead to a synergy, essential to overcome the syndrome. This may efficiently reverse the metabolic changes described above and, at the same time, ameliorate the anorexia. Defining this therapeutic combination of drugs/nutrients/exercise is an exciting project that will stimulate many scientific efforts. Other aspects that will, no doubt, be very important for successful treatment of cancer wasting will be an optimized design of future clinical trials, together with a protocol for staging cancer patients in relation to their degree of cachexia. This will permit that nutritional/metabolic/pharmacological support can be started early in the course of the disease, before severe weight loss occurs. Indeed, timing is crucial and has to be taken very seriously when applying the therapeutic approach.

Background: cancer cachexia, a multi-organ syndrome

Cancer cachexia, characterized by body weight loss (of at least 5%, and often associated with anorexia), an inflammatory state and muscle and adipose tissue wasting, is a multi-organ syndrome associated with the presence of a tumour. Since skeletal muscle represents almost 50% of body weight in humans, for a long time research on cancer cachexia has been mainly devoted to this skeletal tissue. However, the syndrome is indeed a fully multi-organ one involving many types of cells, including, in addition to skeletal muscle, adipose tissues, heart, liver, gastrointestinal tract and brain [1] (Figure 1). The cachectic state involves alterations in carbohydrate, lipid and protein metabolism [2]. According to an international consensus: ‘cachexia, is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. The prominent clinical feature of cachexia is weight loss in adults (corrected for fluid retention) or growth failure in children (excluding endocrine disorders). Anorexia, inflammation, insulin resistance and increased muscle protein breakdown are frequently associated with cachexia. Cachexia is distinct from starvation, age-related loss of muscle mass, primary depression, malabsorption and hyperthyroidism and is associated with increased morbidity' [3].

Cancer cachexia as a multi-organ syndrome.

Figure 1.
Cancer cachexia as a multi-organ syndrome.

The cancer cachexia pyramid represents the majority of factors involved in the syndrome. Clearly, cancer cachexia affects, in addition to skeletal muscle, many other organs such as heart, brain liver, bone and adipose tissues.

Figure 1.
Cancer cachexia as a multi-organ syndrome.

The cancer cachexia pyramid represents the majority of factors involved in the syndrome. Clearly, cancer cachexia affects, in addition to skeletal muscle, many other organs such as heart, brain liver, bone and adipose tissues.

In spite of the fact that anorexia represents a very important event in the development of cachexia, it has been proven that total parenteral nutrition does not stop the loss of body weight. Therefore, it seems quite evident that metabolic alterations present in the patient (increased energy inefficiency, insulin resistance and abnormal carbohydrate metabolism, adipose tissue dissolution and hypertriglyceridemia, and muscle wasting) have a key role in the development of cachexia [4]. Bearing this in mind, the development of different therapeutic approaches has focused either on increasing food intake or on reversing catabolism and increasing the anabolic drive of the cancer patient (Figure 2).

Pathophysiology of cancer cachexia: targets for therapy.

Figure 2.
Pathophysiology of cancer cachexia: targets for therapy.

Anorexia and metabolic disturbances constitute the two factors that determine the altered energy balance that leads to weight loss. Therefore, either increasing food intake or counteracting metabolic alterations are acceptable strategies to counteract cachexia. This can be accomplished by combining drugs, nutrients, nutraceuticals and exercise, thus providing both an anabolic response together with a catabolic blockade.

Figure 2.
Pathophysiology of cancer cachexia: targets for therapy.

Anorexia and metabolic disturbances constitute the two factors that determine the altered energy balance that leads to weight loss. Therefore, either increasing food intake or counteracting metabolic alterations are acceptable strategies to counteract cachexia. This can be accomplished by combining drugs, nutrients, nutraceuticals and exercise, thus providing both an anabolic response together with a catabolic blockade.

Drugs

In humans, megestrol acetate — a synthetic, orally active derivative of the naturally occurring hormone progesterone — improves appetite, caloric intake and nutritional status [5]. The mechanism that mediates the weight gain is mostly unknown, although it has been proposed that it may be partially mediated by neuropeptide Y (NPY), a potent central appetite stimulant. Interestingly, in experimental animals, megestrol acetate increases not only food intake but also lean mass and physical performance [6]. Medroxyprogesterone — another progesterone derivative — has been shown to decrease the in vitro production of serotonin and cytokines [interleukin-1 (IL-1), interleukin-6 (IL-6) and TNF-α] by peripheral blood mononuclear cells of cancer patients [5]. These cytokines have been implicated in the cachectic-anorexic response. Nanocrystal suspensions of megestrol acetate are easy to use and represent an improvement in bioavailability [7]. Megestrol acetate is the standard drug in cancer cachexia treatment in many countries over the world [8] (Table 1, Figure 3). And, although these progestational agents do not constitute a late development in cachexia treatment, they are a main component of multimodal treatment in several trials (Table 2).

Metabolic targets for the main therapeutic strategies used for cancer cachexia.

Figure 3.
Metabolic targets for the main therapeutic strategies used for cancer cachexia.

The therapeutic options for cancer cachexia treatment, in relation to their specific action at the metabolic level, are shown. Basically, they can be grouped in treatments that increase food intake, decrease pro-cachectic cytokine synthesis/action or act on protein turnover in skeletal muscle or heart. AA, amino acids.

Figure 3.
Metabolic targets for the main therapeutic strategies used for cancer cachexia.

The therapeutic options for cancer cachexia treatment, in relation to their specific action at the metabolic level, are shown. Basically, they can be grouped in treatments that increase food intake, decrease pro-cachectic cytokine synthesis/action or act on protein turnover in skeletal muscle or heart. AA, amino acids.

Table 1
Main therapeutic strategies for cancer cachexia
Therapeutic strategyKey references
Stimulating appetite 
 Megestrol acetate [5,7
 Ghrelin agonists [1113,16,17,20,22
 MC4 receptor antagonists [23,24
 Serotonin antagonists [25,27
 Anamorelin Helsinn Therapeutics 
Interfering with metabolic alterations 
 Pro-cachectic cytokine antagonists [31,39,40,4244
 Anti-cachectic cytokines [4649,59
 COX-2 inhibitors [5052
 β2 adrenergic agonists [54,55,57
 ACE inhibitors [6365
 β-blockers [6769
 SARMs [7072,74
 Myostatin antagonists [80,81,8385
 Proteasome inhibitors [89,90
 Phosphodiesterase inhibitors [91,92
 Statins [96
 ω-polyunsaturated fatty acids [101,103,105,106
Therapeutic strategyKey references
Stimulating appetite 
 Megestrol acetate [5,7
 Ghrelin agonists [1113,16,17,20,22
 MC4 receptor antagonists [23,24
 Serotonin antagonists [25,27
 Anamorelin Helsinn Therapeutics 
Interfering with metabolic alterations 
 Pro-cachectic cytokine antagonists [31,39,40,4244
 Anti-cachectic cytokines [4649,59
 COX-2 inhibitors [5052
 β2 adrenergic agonists [54,55,57
 ACE inhibitors [6365
 β-blockers [6769
 SARMs [7072,74
 Myostatin antagonists [80,81,8385
 Proteasome inhibitors [89,90
 Phosphodiesterase inhibitors [91,92
 Statins [96
 ω-polyunsaturated fatty acids [101,103,105,106
Table 2
Selected therapeutic approaches for cancer cachexia
DrugCompanyTypePathological conditionClinical trialTarget
ACE031 Acceleron Pharma Soluble activin receptor type IIB Healthy volunteers Phase I Anticatabolic 
ALD518 Alder Biopharmaceuticals Humanized IL-6 monoclonal antibody Cancer Phase II Anticatabolic 
AMG745 Amgen Peptibody against myostatin Sarcopenia Phase II Anticatabolic 
Anamorelin Helsinn Therapeutics Ghrelin receptor agonist Cancer Phase III Anabolic 
APD209 Acacia Pharma Formoterol (β-2 agonist) + megestrol acetate Cancer Phase IIa Anabolic/anticatabolic 
Bimagrumab (BYM3389) Novartis and MorphoSys Anti-ActRII receptors Inclusion body myositis Pilot study Unknown 
BL-6020/979 Santhera Pharmaceuticals MC4 receptor antagonist Cancer Pre-clinical Anabolic 
Carfilzomib Amgen Proteasome inhibitor Cancer Pre-clinical Anticatabolic 
Celecoxib (Celebrex) Pfizer COX-2 inhibitor Cancer Phase II Anticatabolic 
Cyproheptadine (Periactin) Sigma-Tau Serotonin antagonist Cancer Phase III (in market) Anabolic 
Enobosarm (Ostarine, MK 2866) GTx Selective androgen receptor modulator (SARM) Cancer Phase III Anabolic 
EPA Nestle, Danone, Abbott, Fresenius, Smartfish Nutraceutical Cancer Phase II/III Anabolic/anticatabolic 
Etanercept Amgen Soluble TNF-α receptor Cancer Phase I Anticatabolic 
GLPG0492 Galapagos Selective androgen receptor modulator (SARM) Healthy volunteers Phase I Anabolic 
HMB Abbott Short-chain fatty acid Cancer phase II Anabolic/anticatabolic 
Ibutamoran (MK-0677) Tocris Bioscience GH secregatogue Hip Fractures Phase IIb Anticatabolic 
IL-15 Immunex/Amgen Cytokine Cancer Pre-clinical Anticatabolic 
Lenalidomide (Revlimid) Celgene TNF-α inhibitor Cancer Phase II Anticatabolic 
LY2495655 Ely Lilly Myostatin antibody Cancer Phase II Anticatabolic 
Macimorelin (AEZS-130) Aeterna Zentaris Ghrelin agonist stimulating GH secretion Cancer Phase II Anabolic 
Megace ES Strativa Megestrol acetate (nanocristal) AIDS In market Anabolic 
MT-102 PsiOxus Therapeutics β-blocker Cancer Phase II Anabolic/anticatabolic 
OHR/AVR 118 OHR Pharma Peptide nucleic acid immunomodulator Cancer Phase IIb Anticatabolic 
Ruxolitinib Incyte JAK1/2 inhibitor Cancer Phase II Anticatabolic 
Sildenafil Pfizer PDE5 inhibitor Cancer Phase I Anabolic 
SUN11031 Asubio Pharmaceuticals Synthetic human ghrelin COPD Phase IIb Anabolic 
Tesamorelin (ThGRF) Theratechnologies Growth Hormone Releasing Factor analogue COPD, hip fracture surgery Phase II Anabolic 
Thalidomide Celgene TNF-α inhibitor Cancer In market Anabolic 
VT-122 Vicus Therapeutics β-blocker + COX inhibitor Cancer Phase II Anabolic/anticatabolic 
DrugCompanyTypePathological conditionClinical trialTarget
ACE031 Acceleron Pharma Soluble activin receptor type IIB Healthy volunteers Phase I Anticatabolic 
ALD518 Alder Biopharmaceuticals Humanized IL-6 monoclonal antibody Cancer Phase II Anticatabolic 
AMG745 Amgen Peptibody against myostatin Sarcopenia Phase II Anticatabolic 
Anamorelin Helsinn Therapeutics Ghrelin receptor agonist Cancer Phase III Anabolic 
APD209 Acacia Pharma Formoterol (β-2 agonist) + megestrol acetate Cancer Phase IIa Anabolic/anticatabolic 
Bimagrumab (BYM3389) Novartis and MorphoSys Anti-ActRII receptors Inclusion body myositis Pilot study Unknown 
BL-6020/979 Santhera Pharmaceuticals MC4 receptor antagonist Cancer Pre-clinical Anabolic 
Carfilzomib Amgen Proteasome inhibitor Cancer Pre-clinical Anticatabolic 
Celecoxib (Celebrex) Pfizer COX-2 inhibitor Cancer Phase II Anticatabolic 
Cyproheptadine (Periactin) Sigma-Tau Serotonin antagonist Cancer Phase III (in market) Anabolic 
Enobosarm (Ostarine, MK 2866) GTx Selective androgen receptor modulator (SARM) Cancer Phase III Anabolic 
EPA Nestle, Danone, Abbott, Fresenius, Smartfish Nutraceutical Cancer Phase II/III Anabolic/anticatabolic 
Etanercept Amgen Soluble TNF-α receptor Cancer Phase I Anticatabolic 
GLPG0492 Galapagos Selective androgen receptor modulator (SARM) Healthy volunteers Phase I Anabolic 
HMB Abbott Short-chain fatty acid Cancer phase II Anabolic/anticatabolic 
Ibutamoran (MK-0677) Tocris Bioscience GH secregatogue Hip Fractures Phase IIb Anticatabolic 
IL-15 Immunex/Amgen Cytokine Cancer Pre-clinical Anticatabolic 
Lenalidomide (Revlimid) Celgene TNF-α inhibitor Cancer Phase II Anticatabolic 
LY2495655 Ely Lilly Myostatin antibody Cancer Phase II Anticatabolic 
Macimorelin (AEZS-130) Aeterna Zentaris Ghrelin agonist stimulating GH secretion Cancer Phase II Anabolic 
Megace ES Strativa Megestrol acetate (nanocristal) AIDS In market Anabolic 
MT-102 PsiOxus Therapeutics β-blocker Cancer Phase II Anabolic/anticatabolic 
OHR/AVR 118 OHR Pharma Peptide nucleic acid immunomodulator Cancer Phase IIb Anticatabolic 
Ruxolitinib Incyte JAK1/2 inhibitor Cancer Phase II Anticatabolic 
Sildenafil Pfizer PDE5 inhibitor Cancer Phase I Anabolic 
SUN11031 Asubio Pharmaceuticals Synthetic human ghrelin COPD Phase IIb Anabolic 
Tesamorelin (ThGRF) Theratechnologies Growth Hormone Releasing Factor analogue COPD, hip fracture surgery Phase II Anabolic 
Thalidomide Celgene TNF-α inhibitor Cancer In market Anabolic 
VT-122 Vicus Therapeutics β-blocker + COX inhibitor Cancer Phase II Anabolic/anticatabolic 

The orexigenic mediator ghrelin, a novel endogenous ligand for the growth hormone secretagogue receptor, and secreted by the stomach and pancreas, has been reported as having a key role in increasing appetite and, therefore, food intake (Table 1, Figure 3). In addition, this peptide has important metabolic effects and regulates energy metabolism through growth hormone-dependent and -independent mechanisms [9]. Thus, administration of ghrelin constitutes a new therapeutic strategy for the treatment of cancer cachexia [10]. Pre-clinical studies have shown that ghrelin administration to cachectic tumour-bearing animals results in an improvement in both appetite and body weight, together with an improvement in lean body mass [1113]. In addition, ghrelin administration to rats prevents cisplatin-induced mechanical hyperalgesia — increased pain sensitivity — and cachexia [14]. In fact, cisplatin-induced anorexia is mediated through reduced hypothalamic ghrelin secretion. In addition, ghrelin seems to attenuate gastrointestinal epithelial damage induced by doxorubicin [15]. These results support ghrelin as a protective factor against the toxic effects of chemotherapeutic agents. Several clinical trials with ghrelin or ghrelin mimetics have been performed or are currently ongoing (Table 2). A couple of phase II randomized, placebo-controlled, double-blind studies (NCT00219817 and NCT00267358), using an oral ghrelin mimetic, anamorelin (Helsinn Therapeutics), a ghrelin receptor agonist that can be administered orally, have led to positive results in non-small cell lung cancer (NSCLC) patients showing an improvement in lean body mass, total body mass and hand grip strength [16]. However, two double-blinded phase II trials (ROMANA 1 and ROMANA 2, NCT01387269 and NCT01387282, respectively) (Helsinn Pharmaceuticals) in incurable stage II/IV NSCLC patients showed that anamorelin (100 mg/day for 12 weeks) increased body weight and improved FAACT anorexia/cachexia scores [16,17], but failed to improve hand grip strength [18], In a post-hoc analysis of the two phase II studies, the same group concluded that anamorelin increased both lean and fat mass as well as in fatigue [19]. Interestingly, Takayama et al. reported, in a phase II randomized trial where NSCLC patients were daily given 100 mg of anamorelin, that an increase in lean body mass, appetite, quality of life and performance status was observed following anamorelin administration [20]. In addition, significant elevations in both IGF-1 and IGFBP-3 plasma concentrations were observed, suggesting an improvement in protein synthesis.

Another appetite stimulant involved in clinical trials is AEZS-130 (macimorelin), an oral peptidomimetic growth hormone secretagogue (Aeterna Zentaris) (Table 2), now in phase II (NCT01614990), and the endpoints of the trial being changes in body weight, IGF-1 levels and quality of life [21]. Finally, Asubio Pharmaceuticals is involved in a phase II clinical trial (NCT00698828) with synthetic human ghrelin (SUN11031) in COPD patients [22].

The melanocortin (MC4) receptor participates in the anorexigenic cascade by decreasing NPY, thus causing a decrease in food intake (Table 1, Figure 3). Using MC4 receptor antagonists seems an effective way to prevent anorexia, loss of lean body mass and basal energy expenditure in pre-clinical studies involving cancer cachexia [23]. Santhera Pharmaceuticals has developed several orally active MC4 receptor antagonists for the treatment of cancer cachexia (Table 2). Oral gavage of SNT207707, SNT209858 and BL-6020/979 [24] (Table 2) resulted in both increased food intake and decreased body weight and muscle mass losses in mice bearing the C26 colon adenocarcinoma. In spite of these promising results, no data on cancer patients are available and therefore future clinical studies are warranted.

Clinical and pre-clinical studies suggest that anorexia may be mediated by an increased serotonergic activity in the brain [25] (Table 1, Figure 3). Bearing this in mind, attempts to block serotonin activity during cancer cachexia have involved the administration of cyproheptadine (Table 2), a serotonin antagonist with antihistaminic properties, often used for allergy treatment. Clinical data (NCT01132547) suggested that it had appetite- and weight-enhancing effects in children suffering from cancer-related cachexia [26]; however, it did not prevent progressive weight loss in patients with advanced malignant disease [27]. Future clinical trials with other antiserotonergic drugs are, therefore, necessary to test the potential of the serotonergic system, as a therapy for cancer cachexia.

MIC-1/GDF15, a cytokine belonging to the transforming growth factor-β (TGF-β) superfamily is able to induce anorexia by acting on feeding centres in the hypothalamus and brainstem, eventually leading to cachexia. Interestingly, the cytokine is produced by cancer cells [28]. In pre-clinical studies [29], the circulating concentrations of MIC-1/GDF15 required to cause the anorexia/cachexia syndrome are similar to those found in cancer patients. In addition, in patients with advanced lung and gastrointestinal tumours, the levels correlated with survival and nutritional status [30]. Weight loss in patients with oesophageal tumours is also related to the levels of the cytokine [31]. In fact, cytokines are able to act on multiple target sites such as bone marrow, myocytes, hepatocytes, adipocytes, endothelial cells and neurons, where they generate a complex cascade of responses leading to the wasting associated with cachexia.

TNF-α, IL-1, IL-6 and interferon-γ (IFN-γ) are the main cytokines implicated in cachexia. Interestingly, these cytokines share the same metabolic effects and their activities are closely interrelated. In many studies, they exhibit synergic effects when administered together. Therefore, therapeutic strategies have been based on either blocking their synthesis or their action (Table 1, Figure 3). Thalidomide, a drug unfortunately associated with tragedy — its use as a sedative in pregnant women caused more than 10 000 cases of severe malformations in newborn children — suppresses TNF-α synthesis in monocytes in vitro and is able to normalize elevated TNF-α levels in vivo. A randomized placebo control 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 [32]. However, more recent data — a double-blind placebo-controlled randomized study (NCT00379353) — do not show any beneficial effects of thalidomide on cancer-related anorexia-cachexia symptoms, following the Edmonton Symptom Assessment Scale (ESAS) [33]. A thalidomide derivative (lenalidomide) (Table 2) — with a better toxicity profile than thalidomide — developed by Celgene and currently approved for treating myelodysplastic syndromes is now being tested in a phase II clinical trial (NCT01127386) with advanced cancer patients [34] (Table 2). Using other anti-TNF strategies such as etanercept (a fusion protein directed against the p75 TNF-α receptor) has led to a poor clinical outcome in cancer patients. However, a clinical pilot study (NCT00201812) with several advanced malignancies involving patients treated with etanercept combined with an antitumour agent (docetaxel) [35] (Table 2) showed less fatigue and improved tolerability of the antitumoural treatment [36]. Another phase II trial (NCT00040885) with infliximab — an anti-TNF-α monoclonal antibody — was unsuccessful in improving symptoms of cachexia (lean body mass) in pancreatic cancer patients [37].

Survival in cancer patients is inversely correlated with circulating IL-6 levels [38,39]. In a mouse model of cancer cachexia, tocilizumab, an IL-6 monoclonal antibody, improved cachexia [39]. A humanized monoclonal anti-IL-6 antibody (ALD518, Alder Biopharmaceuticals, Table 2) increased haemoglobin levels and prevented muscle wasting in cancer patients [40]. In pre-clinical and in a phase II trial (NCT00866970), ALD518 targeting IL-6 appears well tolerated and ameliorates NSCLC-related anaemia and cachexia [41]. Along the same lines, a phase II clinical trial (NCT02072057) with ruxolitinib — an inhibitor of Janus kinases (JAKs), activators of the STAT transcription factor — in patients with tumour-associated chronic wasting diseases is now ongoing [42]. The IL-6 intrasignalling pathway takes place via activation of the JAKs. Targeting both TNF-α and IL-6 by means of a broad-spectrum peptide nucleic acid (OHR118, OHR Pharmaceutical) (Table 2) resulted in increases in body weight and physical performance in patients with advanced cancer in a phase II trial (NCT01206335) (Table 2) [43,44].

In a pre-clinical mouse model of pancreatic cancer cachexia, Greco et al. have described that blockade of TGF-β, lessens cachexia, reducing mortality and metabolic alterations [45]. In fact, according to Waning et al., TGF-β mediates muscle weakness associated with bone metastases in mice [46]. Indeed, during tumour-induced bone destruction, TGF-β up-regulates Nox4 — an NADPH oxidase — resulting in alterations in skeletal muscle proteins (oxidation). Among these proteins, the ryanodine receptor/Ca2+ release channel (RyR1) is oxidized. The altered RyR1 channels leak Ca2+, resulting in lower intracellular signalling required for adequate muscle contraction [46].

The production of the above-mentioned cytokines, known as catabolic pro-inflammatory cytokines, is not the only factor involved in the metabolic changes associated with cancer cachexia. Indeed, the so-called anti-inflammatory cytokines, such as IL-4, IL-10 IL-12 and IL-15, are also involved. Indeed, IL-15 has been reported to be an anabolic factor for skeletal muscle [47,48]. IL-15 decreases protein degradation and DNA fragmentation while increasing uncoupling protein-3 (UCP3) expression in skeletal muscle [47]. The action of the cytokine is directly upon skeletal muscle [49]. Pre-clinical studies indicate that IL-15 leads to an improvement of muscle mass and performance in tumour-bearing animals (Table 2) [48]. Martínez-Hernández et al. have demonstrated an important association between serum IL-15 and changes in weight and muscle mass in cancer patients, suggesting a possible role of the cytokine as a body composition marker in weight-losing cancer patients [50].

Since large amounts of prostaglandins — cell growth may be controlled by the interconversion of different types of these compounds — are found both in tumour tissue and plasma from cancer patients, several studies have examined the role of non-steroidal anti-inflammatory drugs (NSAIDs) on tumour growth and cachexia. Hussey and Tisdale have studied the effects of the COX-2 inhibitor meloxicam on tumour growth and cachexia in the murine adenocarcinoma MAC16 [51] (Table 1, Figure 3). Their results suggest that the inhibitor is able to effectively attenuate cachexia, possibly by exercising a direct effect on skeletal muscle protein degradation. Celecoxib, a COX-2 inhibitor developed by Pfizer (Table 2), has shown efficacy in a phase II study involving cachectic cancer patients [52]. Treatment with the inhibitor increased lean body mass grip force and quality of life [52]. However, Reid et al., in a systematic review, concluded that there are insufficient studies to support a clear benefit of NSAIDs in the treatment of cancer cachexia [53].

Pre-clinical studies using formoterol — a β2-adrenergic agonist with low cardiac toxicity [54] — have shown that the drug is able to reverse muscle wasting associated with cancer [55] (Table 1, Figure 3). Essentially, formoterol treatment increases the rate of protein synthesis while inhibiting the rate of muscle proteolysis. Interestingly, this β2-agonist is also able to diminish the increased rate of muscle apoptosis present in tumour-bearing animals, together with facilitating muscle regeneration by stimulating satellite cells [55,56]. A combination treatment of formoterol and the soluble myostatin receptor ActRIIB has been able to completely reserve muscle wasting in tumour-bearing rats [57], the results emphasizing the importance of combining drugs in the treatment of cancer cachexia. A phase IIa study (NCT00895726) investigating the effects of a combination of formoterol and megestrol acetate (APD209) in 13 cachectic cancer patients has been undertaken by Acacia Pharma [58] (Table 2). Six of the seven patients that completed the treatment period showed improved muscle size and strength, and three patients had improved levels of daily physical activity [58] (Table 2).

Erythropoietin (EPO) administration to cancer patients — with subnormal or even normal haemoglobin levels — results in clinical benefit. Interestingly, Kanzaki et al. have shown that EPO — in a pre-clinical cancer cachexia model — decreases the production of the pro-cachectic cytokine IL-6 [59]. This may be linked with the attenuation of cachectic manifestations. EPO treatment also improves metabolic and exercise capacity via an increased erythrocyte count [59]. In a pre-clinical mouse model of cancer cachexia, the combination of EPO administration and aerobic exercise has led to a significant decrease in muscle wasting [60].

Patients with cancer cachexia have important abnormalities in heart mass and function, the so-called cardiac cachexia. In fact, cardiac arrest is often the main cause of death — determined at autopsy — associated with cancer. From this point of view, several drugs have been used to counteract cardiac cachexia associated with cancer. Thus, administration of enalapril reduces the risk of weight loss and it is associated with improved survival [61]. In the patients treated with the inhibitor, increased subcutaneous fat (increased skin fold thickness) and greater muscle bulk (increased mid-upper arm and thigh circumferences) are observed, together with a significant elevation in plasma albumin and the haematocrit [61]. Inhibitors of the angiotensin-converting enzyme (ACE) have been tested in pre-clinical models with success in increasing both muscle and fat mass (Figure 3) [62,63]. Some evidence also exists concerning the potential of ACE inhibitors to ameliorate cancer cachexia in NSCLC patients [64]. Angiotensin receptor blockers can also be used in the treatment of cachexia. Thus, one of this compounds, telmisartan, can be used as an add-on therapy with 5-fluorouracil [65] or cisplatin [66] or other traditional chemotherapeutic agents (Table 1). Telmisartan inhibits TNF-α-induced IL-6 expression at the transcriptional level through the activation of PPAR-γ [67].

β-blockers can reduce body energy expenditure and improve efficiency of substrate utilization (Figure 3). Some of them do combine many different pharmacological effects (Table 1). Espindolol (MT-102, PsiOxus Therapeutics) (Table 2) is a non-specific β12-adrenergic receptor antagonist that exhibits effects through β and central 5-HT1α receptors to demonstrate pro-anabolic, anti-catabolic, and appetite-stimulating actions [68]. The ACT-ONE trial (NCT01238107) showed that espindolol 10 mg twice daily was able to revert weight loss, improve fat free mass, and maintain fat mass and improve handgrip strength in cachectic patients with NSCLC or colorectal cancer [69]. VT-122 combines a non-selective β-blocker, propanolol (used in controlling high blood pressure), and etodolac, a COX-2 inhibitor. Data from a phase II clinical study (NCT00527319) clearly show an improvement in lean body mass in NSCLC patients [70].

In spite of the fact that derivatives of gonadal steroids have important side effects, such as masculinization, fluid retention and hepatic toxicity, treatment with these drugs facilitates nitrogen protein accumulation, therefore counteracting the progressive nitrogen loss associated with muscle wasting. In fact, the use of non-steroidal selective androgen receptor modulators (SARMs) holds promise as a new class of function-promoting anabolic therapies for several clinical conditions that manifest muscle wasting (Table 1, Figure 3). Different SARMs are being tested in clinical trials at the present moment; one of them is enobosarm (GTx, Inc.) (Table 2). In a phase IIb, double-blind, placebo-controlled study (NCT00467844), involving NSCLC, colorectal cancer, non-Hodgkin's lymphoma, chronic lymphocytic leukaemia, or breast cancer patients, enobosarm treatment led to significant improvements in lean body mass, physical function and quality of life [71]. These positive results have led to the design of phase III trials. On these lines, Crawford et al. reported a study design and rationale for the phase III clinical development program of enobosarm, for the prevention and treatment of muscle wasting in oncology patients (POWER Trials) [72]. To assess enobosarm's effect on both prevention and treatment of muscle wasting, in each pivotal POWER trial, subjects will receive placebo or enobosarm 3 mg orally once daily for 147 days. Physical function will be assessed as stair climb power (SCP), and lean body mass assessed by dual-energy X-ray absorptiometry (DXA), these being the co-primary efficacy endpoints in both trials assessed at day 84 [72]. Preliminary data report an increase in lean body mass and improvement in SCP (POWER1) (NCT01355484). POWER2 (NCT01355497) also shows an increase in lean body mass, whereas no clinical improvement in SCP test and handgrip strength is seen [73]. GLPG0492 (Galapagos) (Table 2) is another SARM that has shown efficacy in the treatment of muscle wasting associated with immobilization in a pre-clinical model [74]. At present, a phase I trial (NCT01397370) is being undertaken [75].

Although it has been known for a long time that growth hormone (GH) improves whole body protein balance in cancer patients [76] and that the hormone can attenuate weight loss and preserve host body composition in tumour-bearing rats undergoing chemotherapy with doxorubicin without stimulating tumour growth [77], it has also been suggested that GH therapy for cachexia is not convenient because of the possibility of tumour growth stimulation [78]. Theratechnologies has introduced a GH-releasing factor analogue (ThGRF; tesamorelin) and it is at present in a phase II trial with COPD patients (NCT01388920) [79] (Table 2). Ibutamoren (MK-0677) — a potent GH secretagogue that works through the ghrelin receptor — improves stair climb and decreases falls in patients who had had hip fractures (NCT00128115) [80].

Myostatin, a TGF-β superfamily member, is a negative regulator of muscle growth and development (Figure 3). Bearing this in mind, antimyostatin strategies have been used in clinical trials involving cachectic patients (Table 1). From this point of view, a phase II study (NCT00975104) in sarcopenic patients has been undertaken using AMG745, a peptibody against myostatin [81] (Table 2). Similarly, Acceleron Pharma has performed a phase I study (NCT00755638) with ACE031 (Table 2), a soluble activin receptor type IIB [82]. Bimagrumab (BYM338), an activin II receptor antibody (Table 2), has also been studied in relation with cachexia in patients with inclusion myositis [83]. BYM338 is able to bind ActRIIB 200 times better than ActRIIA, promoting skeletal muscle hypertrophy when administered in vivo. When administered in association with glucocorticoids, BYM338 was able to prevent skeletal muscle mass loss and preserved muscle function, facilitating the recovery from muscle atrophy [84]. A humanized monoclonal antibody LY2495655 (Table 2) has been used in sarcopenic patients in a phase II trial (NCT01604408), involving subjects who recently reported falls and low muscle strength and power [85]. Patients receiving the antibody showed an increase in lean mass and a significant improvement of muscle power expressed as improved stair-climbing time, fast gait speed, and chair rise with arms. A phase II study (NCT01505530) is now being held in pancreatic cancer patients although no results are yet available [86]. Finally, REGN1033 is a fully humanized myostatin antibody and pre-clinical studies demonstrate its efficacy in preventing muscle loss in aged mice or in young mice subject to immobilization or dexamethasone treatment. A phase II study (NCT01963598) on safety and efficacy has been completed in sarcopenic subjects although the results are not yet available [87].

Increased proteolysis in skeletal muscle during cachexia involves activation of the ubiquitin/proteasome system in muscle [88]. Taking this into consideration, inhibitors of this proteolytic system such as peptide aldehyde, lactacystin and β-lactone — which effectively can block up to 90% of the degradation of normal proteins and short-lived proteins in the cells — could be potential drugs for the treatment of muscle wasting [89] (Table 1, Figure 3). However, the toxicity of such compounds is fairly high, since they are not specific inhibitors of the proteolytic system in muscle tissue. Bearing this in mind, a drug that could specifically block myofibrillar protein degradation is still waiting to be found. Inhibitors of the proteasome have been used as anticancer drugs — since the proteasome has a main role in cell division — in multiple myeloma patients. The use of these drugs has lead to contradictory results in the treatment of muscle wasting in pre-clinical models. Thus, bortezomib did not show any significant effects in the treatment of cancer cachexia in rats bearing the cachectic Yoshida hepatoma AH-130 ascites tumour model [90]. Conversely, carfilzomib inhibits skeletal muscle proteolysis and apoptosis, reducing cachexia in a pre-clinical mouse model [91] (Table 2).

Phosphodiesterase 5 inhibitors may also represent viable pharmacologic interventions to improve muscle function (Figure 3). On these lines, augmentation of nitric oxide–cyclic guanosine monophosphate signalling by short-term daily administration of the phosphodiesterase 5 inhibitor sildenafil increases protein synthesis, alters protein expression and nitrosylation, and reduces fatigue in human skeletal muscle [92]. A clinical phase I trial with one of these drugs, sildenafil (NCT02106871) for fatigue in pancreatic cancer is now recruiting [93] (Tables 1 and 2).

Cancer cachexia and type II diabetes share common metabolic characteristics, including weight loss, insulin resistance and increased hepatic gluconeogenesis. From this point of view, recent interest has developed around antidiabetic drugs — such as metformin — for the treatment of muscle wasting in cancer. An interesting study revels that metformin improves protein metabolism in skeletal muscle in tumour-bearing rats [94].

A very innovative and revolutionary strategy to fight muscle wasting in cancer is the use of stem cells with the aim of replacing degenerated muscle tissue [95]. Whereas adult stem cells are tissue specific and have limited capacity to be expanded, ex vivo pluripotent stem cells have the capacity to differentiate into any cell type while possessing unlimited in vitro self-renewal. Scott et al. described a methodology for large-scale isolation of satellite cells from skeletal muscle [95]. This could then be applied as a therapeutic strategy to stimulate muscle regeneration [96].

Another interesting approach that has led to promising results in pre-clinical models of cancer cachexia is the use of statins such as simvastatin (Table 1). Indeed, a study involving the cachectic Yoshida AH-130 ascites hepatoma has shown that simvastatin attenuated body weight loss and preserved muscle mass [97].

Finally, other strategies include the modulation of intestinal microbiota, which seems to be able to improve survival in a pre-clinical model of cancer cachexia [98,99], or the blockade of fatty acid oxidation in skeletal muscle. Indeed, this enhanced oxidation seems to be involved in the development of the muscle atrophy. Blocking this excessive fatty acid oxidation has been effective in improving muscle mass and body weight in cancer cachexia models [100].

Nutrients and nutraceuticals

Nutrition is an essential element in cancer care and patients report a high interest and need; however, a recent study has shown that many patients do not have access to high quality nutrition therapy either during or after cancer treatment [101]. Although some studies demonstrate a beneficial effect for nutritional advice [102,103], another study — a 2-year randomized controlled trial (NCT00459589) — showed that early dietary counselling was efficient in increasing intake but had no beneficial effect on mortality or secondary outcomes [104]. While standard nutrition supplements have not led to positive results in cancer cachexia, the use of nutrients in combination with nutraceuticals — the so-called specialized nutrition — has given more positive results (Figure 2).

ω3-polyunsaturated fatty acids (PUFA), present in large amounts in fish oil, have been proposed as very active in reducing either tumour growth or muscle wasting (Table 1, Figure 3). An improvement in the lean body mass and improved quality of life was observed in a randomized double-blind trial using a protein and energy dense ω3-fatty acid-enriched oral supplement [105], provided that its consumption was equal or superior to 2.2 g eicosapentaenoic acid (EPA)/day. However, data arising from a large multicentre double-blind placebo-controlled trial indicate that EPA administration alone is not successful in the treatment of weight-losing patients with advanced gastrointestinal or lung cancer [106]. Moreover, a meta-analysis based on five trials concluded that there were insufficient data to establish whether oral EPA was better than placebo [107]. Comparisons of EPA combined with a protein energy supplementation versus a protein energy supplementation (without EPA) in the presence of megestrol acetate provided no evidence that EPA improves symptoms associated with the cachexia syndrome often seen in patients with advanced cancer [108]. In spite of this, several recent trials suggest that EPA-enriched nutrition results in positive outcomes in cancer patients [109,110] (Table 2).

Another interesting nutraceutical with anti-cachectic potential is β-hydroxy-β-methylbutyrate (HMB) (Table 2). This metabolite of leucine has been proposed as partially responsible for the effects induced by leucine on muscle protein synthesis [111,112]. Different pre-clinical studies on muscle atrophy induced by cachexia report that HMB administration attenuates muscle wasting by decreasing protein degradation and increasing protein synthesis [112114]. Although a mixture of HMB, glutamine and arginine (HMB/Arg/Gln) showed activity for increasing lean body mass among patients with cancer cachexia [115], a phase II trial (NCT00053053) was unable to adequately test the ability of HMB/Arg/Gln to reverse or prevent lean body mass wasting among cancer patients [116]. Recently, it has been described that HMB is actually more effective than leucine in attenuating body weight loss in an experimental model of cachexia [117]. A clinical phase II trial (NCT01607879) to counteract muscle loss in men with prostate cancer on androgen ablation is currently recruiting [118]. In systematic reviews of randomized trials involving HMB it is concluded that further well-designed clinical studies are needed to confirm effectiveness and mode of action of the amino acid, particularly in pathological conditions [119].

Conclusion: towards a multimodal approach

During the last few years, it has become very clear that a combination of nutrition, nutraceuticals and drugs is a much-preferred therapeutic approach than just looking for a single drug ‘magic bullet’ (Figure 4). In fact, the treatment of cancer cachexia has to involve not only drugs and/or nutrients, but also a possibilistic program of physical exercise. Indeed, in cancer patients — either suffering from cachexia or not — an exercise program is able to improve their quality of life [120,121]. This is accomplished by inducing metabolic alterations that result in changes in body composition. A study has shown clear benefits — on cachectic cancer (head and neck) patients — of an exercise program (12 weeks: 2–3 sets of 8–15 repetitions maximum of seven conventional exercises) [122]. Indeed, with an increase of 4.2% in lean body mass, enhanced muscle strength and quality of life were observed [122]. Similarly, in the same type of cancer patients, McNeely et al. demonstrated improved shoulder muscle function following resistance exercise training [123]. Exercise programs have also been able to increase muscle strength and endurance, the 6-minute walk distance, up-and-go time, the number of arm curls and the number of chair stands in lung cancer patients [124]. A systematic review reports beneficial effects for breast cancer survivors [125]. Concerning the mechanisms involved in the effects of exercise training programs, it seems very clear that an anti-inflammatory status is accomplished with decreases in pro-inflammatory cytokines — such as TNF-α — and increases in IL-10, a clear anti-inflammatory cytokine [120]. The decrease in inflammatory status is accompanied by reduction in oxidative stress [120]. Elevations in IGF-1 and in PGC-1 α in skeletal muscle have also been associated with the beneficial effects of exercise on cancer [120].

Efficacy of multimodal therapy for cancer cachexia.

Figure 4.
Efficacy of multimodal therapy for cancer cachexia.

It is unlikely that a single drug may reverse the cachectic process. Only the sequential application of different treatments/approaches may allow, in a nearby future, to obtain 100% efficiency in cachexia treatment.

Figure 4.
Efficacy of multimodal therapy for cancer cachexia.

It is unlikely that a single drug may reverse the cachectic process. Only the sequential application of different treatments/approaches may allow, in a nearby future, to obtain 100% efficiency in cachexia treatment.

Muscaritoli et al. have defined the so-called TARGET approach, which is a good way of interpreting the multimodal approach [126]. It actually integrates active interventions and research programs related with the onset and progression of cancer cachexia. This approach includes Teaching (nutrition, metabolic alterations in cancer), Awareness (of the negative impact of cancer cachexia), Recognition (diagnosis and staging), Genetics (inherited susceptibility), Exercise (physical activity) and Treatment [126]. The MENAC (Multimodality Exercise/Nutrition Anti-inflammatory treatment for Cachexia) trial [127] represents a good example of a multimodal approach. This ongoing phase III trial is enrolling lung, cholangio- and pancreatic carcinoma cancer patients and includes nutritional counselling, oral nutrition supplementation (including EPA), a physical exercise program and an anti-inflammatory (ibuprofen) treatment [128]. A combined multitargeted approach in a randomized placebo-controlled trial using celecoxib, L-carnitine, curcumin and lactoferrin was able to improve the nutritional and immunometabolic alterations of cachexia, ameliorate patient quality of life and correct cancer-related anaemia [129]. Practical (individual reports) multimodal care programs for cancer cachexia have been recently published [130].

Another important factor that may positively contribute to cancer cachexia treatment is a proper staging of the cachectic condition in cancer patients [131,132]. This would allow for an adequate treatment at the different phases of cachexia [133]. Timing is very important and has to be considered seriously when designing the therapeutic approach. Any nutritional/metabolic/pharmacological support should be started early in the course of the disease, before severe weight loss occurs and appropriate treatment should be applied at every phase of the cachectic syndrome.

More research should also be devoted to finding new biomarkers for cancer cachexia. Indeed, many cancer patients are treated only when a significant amount of weight loss is detected, or when the patients suffer from certain limitations in their daily living activities. Biomarkers may serve to detect the changes before any clinical manifestations arise, facilitating treatment and, possibly, improving prognosis. Progress has certainly been made involving biomarkers [134] but more research is needed in this field to find an easy measurable — either blood or urine present — early and specific muscle-wasting biomarker.

Another key aspect to consider is the design of appropriate trials. Indeed, ongoing trials have a rather heterogeneous design and include an excessively wide span of different types of tumours with different degrees of cachexia. In fact, a unified approach is requested in a recent consensus document [135]. Many of the most promising drug candidates are completely new molecules and, therefore, particular attention has to be focused on safety issues and not just side effects, but also long-term treatment associated problems, together with the issue of interaction with other drugs. This last point is particularly relevant since, as we have mentioned, the ideal treatment for cancer cachexia is multimodal, involving different drugs and nutraceuticals. Endpoints — particularly primary — are also something absolutely essential. Lean body mass or, even better, muscle mass, together with a measurement of function, such as total daily physical activity, are good candidates.

In conclusion, the future multimodal treatment (Figure 4) of the cachectic syndrome will no doubt combine different approaches to efficiently counteract metabolic alterations while improving the energy intake of the patients. Defining this therapeutic multimodal combination of factors is an exciting project that will stimulate many scientific efforts.

Abbreviations

     
  • ACE

    angiotensin-converting enzyme

  •  
  • ActRIIA, ActRIIB

    activin A receptors, type IIA and IIB

  •  
  • COPD

    chronic obstructive pulmonary disease

  •  
  • COX-2

    cyclooxygenase-2

  •  
  • EPA

    eicosapentaenoic acid

  •  
  • EPO

    erythropoietin

  •  
  • FAACT

    functional assessment of anorexia/cachexia therapy

  •  
  • GH

    growth hormone

  •  
  • HMB

    β-hydroxy-β-methylbutyrate

  •  
  • IFN-γ

    interferon-γ

  •  
  • IGF-1

    insulin-like growth factor-1

  •  
  • IGFBP-3

    insulin-like growth factor-binding protein 3

  •  
  • IL

    interleukin

  •  
  • JAK

    Janus kinase

  •  
  • MC4

    melanocortin

  •  
  • MIC-1/GDF15

    macrophage inhibitory cytokine-1

  •  
  • NPY

    neuropeptide Y

  •  
  • NSAID

    non-steroidal anti-inflammatory drug

  •  
  • NSCLC

    non-small cell lung cancer

  •  
  • PGC-1

    peroxisome proliferator-activated receptor-gamma coactivator 1 alpha

  •  
  • PPAR-γ

    peroxisome proliferator-activated receptor-gamma

  •  
  • RyR1

    ryanodine receptor/Ca2+ release channel

  •  
  • SARM

    selective androgen receptor modulator

  •  
  • SCP

    stair climb power

  •  
  • STAT

    signal transducers and activators of transcription

  •  
  • TGF-β

    transforming growth factor-β

Funding

This work was supported by a grant from the Ministerio de Ciencia y Tecnología (MCyT) [SAF2015-65589].

Competing Interests

The Authors declare that there are no competing interests associated with the manuscript.

References

References
1
Argilés
,
J.M.
,
Stemmler
,
B.
,
López-Soriano
,
F.J.
and
Busquets
,
S.
(
2015
)
Nonmuscle tissues contribution to cancer cachexia
.
Mediators Inflamm.
2015
,
1
9
doi:
2
Argilés
,
J.M.
(
2017
)
The 2015 ESPEN Sir David Cuthbertson lecture: inflammation as the driving force of muscle wasting in cancer
.
Clin. Nutr.
36
,
798
803
doi:
3
Evans
,
W.J.
,
Morley
,
J.E.
,
Argilés
,
J.
,
Bales
,
C.
,
Baracos
,
V.
,
Guttridge
,
D.
et al
(
2008
)
Cachexia: a new definition
.
Clin. Nutr.
27
,
793
799
doi:
4
Argilés
,
J.M.
,
Busquets
,
S.
,
Stemmler
,
B.
and
López-Soriano
,
F.J.
(
2014
)
Cancer cachexia: understanding the molecular basis
.
Nat. Rev. Cancer
14
,
754
762
doi:
5
Argilés
,
J.M.
,
Anguera
,
A.
and
Stemmler
,
B.
(
2013
)
A new look at an old drug for the treatment of cancer cachexia: megestrol acetate
.
Clin. Nutr.
32
,
319
324
doi:
6
Busquets
,
S.
,
Serpe
,
R.
,
Sirisi
,
S.
,
Toledo
,
M.
,
Coutinho
,
J.
,
Martínez
,
R.
et al
(
2010
)
Megestrol acetate: its impact on muscle protein metabolism supports its use in cancer cachexia
.
Clin. Nutr.
29
,
733
737
doi:
7
Jang
,
K.
,
Yoon
,
S.
,
Kim
,
S.-E.
,
Cho
,
J.-Y.
,
Yoon
,
S.H.
,
Lim
,
K.S.
et al
(
2014
)
Novel nanocrystal formulation of megestrol acetate has improved bioavailability compared with the conventional micronized formulation in the fasting state
.
Drug Des. Devel. Ther.
8
,
851
doi:
8
Segura
,
A.
,
Pardo
,
J.
,
Jara
,
C.
,
Zugazabeitia
,
L.
,
Carulla
,
J.
,
de las Peñas
,
R.
et al
(
2005
)
An epidemiological evaluation of the prevalence of malnutrition in Spanish patients with locally advanced or metastatic cancer
.
Clin. Nutr.
24
,
801
814
doi:
9
Tesauro
,
M.
,
Schinzari
,
F.
,
Caramanti
,
M.
,
Lauro
,
R.
and
Cardillo
,
C.
(
2010
)
Cardiovascular and metabolic effects of ghrelin
.
Curr. Diabetes Rev.
6
,
228
235
doi:
10
Argilés
,
J.M.
and
Stemmler
,
B.
(
2013
)
The potential of ghrelin in the treatment of cancer cachexia
.
Expert Opin. Biol. Ther.
13
,
67
76
doi:
11
Hanada
,
T.
,
Toshinai
,
K.
,
Kajimura
,
N.
,
Nara-Ashizawa
,
N.
,
Tsukada
,
T.
,
Hayashi
,
Y.
et al
(
2003
)
Anti-cachectic effect of ghrelin in nude mice bearing human melanoma cells
.
Biochem. Biophys. Res. Commun.
301
,
275
279
doi:
12
Wang
,
W.
,
Andersson
,
M.
,
Iresjö
,
B.-M.
,
Lönnroth
,
C.
and
Lundholm
,
K.
(
2006
)
Effects of ghrelin on anorexia in tumor-bearing mice with eicosanoid-related cachexia
.
Int. J. Oncol.
28
,
1393
1400
PMID:
[PubMed]
13
DeBoer
,
M.D.
,
Zhu
,
X.X.
,
Levasseur
,
P.
,
Meguid
,
M.M.
,
Suzuki
,
S.
,
Inui
,
A.
et al
(
2007
)
Ghrelin treatment causes increased food intake and retention of lean body mass in a rat model of cancer cachexia
.
Endocrinology
148
,
3004
3012
doi:
14
Garcia
,
J.M.
,
Cata
,
J.P.
,
Dougherty
,
P.M.
and
Smith
,
R.G.
(
2008
)
Ghrelin prevents cisplatin-induced mechanical hyperalgesia and cachexia
.
Endocrinology
149
,
455
460
doi:
15
Yakabi
,
K.
,
Sadakane
,
C.
,
Noguchi
,
M.
,
Ohno
,
S.
,
Ro
,
S.
,
Chinen
,
K.
et al
(
2010
)
Reduced ghrelin secretion in the hypothalamus of rats due to cisplatin-induced anorexia
.
Endocrinology
151
,
3773
3782
doi:
16
Garcia
,
J.M.
,
Boccia
,
R.V
,
Graham
,
C.D.
,
Yan
,
Y.
,
Duus
,
E.M.
,
Allen
,
S.
et al
(
2015
)
Anamorelin for patients with cancer cachexia: an integrated analysis of two phase 2, randomised, placebo-controlled, double-blind trials
.
Lancet Oncol.
16
,
108
116
doi:
17
Temel
,
J.S.
,
Currow
,
D.C.
,
Fearon
,
K.
,
Yan
,
Y.
,
Friend
,
J.
and
Abernethy
,
A.P.
(
2015
)
Anamorelin in patients with advanced non-small cell lung cancer and cachexia: results from the phase III studies ROMANA 1 and 2
.
J. Clin. Oncol.
33
,
175
doi:
18
Temel
,
J.S.
,
Abernethy
,
A.P.
,
Currow
,
D.C.
,
Friend
,
J.
,
Duus
,
E.M.
,
Yan
,
Y.
et al
(
2016
)
Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials
.
Lancet Oncol.
17
,
519
531
doi:
19
Currow
,
D.C.
,
Temel
,
J.S.
,
Abernethy
,
A.P.
,
Giorgino
,
R.
,
Friend
,
J.
and
Fearon
,
K.
(
2016
)
Efficacy of anamorelin in cachectic patients with non-small cell lung cancer (NSCLC) and low BMI (<20 kg/m2): Post-hoc analysis of two phase III studies
.
J. Clin. Oncol.
34
,
203
203
doi:
20
Takayama
,
K.
,
Katakami
,
N.
,
Yokoyama
,
T.
,
Atagi
,
S.
,
Yoshimori
,
K.
,
Kagamu
,
H.
et al
(
2016
)
Anamorelin (ONO-7643) in Japanese patients with non-small cell lung cancer and cachexia: results of a randomized phase 2 trial
.
Support. Care Cancer
24
,
3495
3505
doi:
21
ClinicalTrials.gov [internet]. Bethesda (MD): National Library of Medicine (US) Feb 29, 2000 - . Identifier NCT01614990, Pilot Clinical Trial of Repeated Doses of Macimorelin to Assess Safety and Efficacy in Patients With Cancer Cachexia; June 5, 2012, Available from https://clinicaltrials.gov/ct2/show/study/NCT01614990
22
Levinson
,
B.
and
Gertner
,
J.
(
2012
)
Randomized study of the efficacy and safety of SUN11031 (synthetic human ghrelin) in cachexia associated with chronic obstructive pulmonary disease
.
e-SPEN J.
7
,
e171
e175
doi:
23
Weyermann
,
P.
,
Dallmann
,
R.
,
Magyar
,
J.
,
Anklin
,
C.
,
Hufschmid
,
M.
,
Dubach-Powell
,
J.
et al
(
2009
)
Orally available selective melanocortin-4 receptor antagonists stimulate food intake and reduce cancer-induced cachexia in mice
.
PLoS ONE
4
,
e4774
doi:
24
Dallmann
,
R.
,
Weyermann
,
P.
,
Anklin
,
C.
,
Boroff
,
M.
,
Bray-French
,
K.
,
Cardel
,
B.
et al
(
2011
)
The orally active melanocortin-4 receptor antagonist BL-6020/979: a promising candidate for the treatment of cancer cachexia
.
J. Cachexia Sarcopenia Muscle
2
,
163
174
doi:
25
Laviano
,
A.
,
Inui
,
A.
,
Marks
,
D.L.
,
Meguid
,
M.M.
,
Pichard
,
C.
,
Rossi Fanelli
,
F.
et al
(
2008
)
Neural control of the anorexia-cachexia syndrome
.
AJP Endocrinol. Metab.
295
,
E1000
E1008
doi:
26
Couluris
,
M.
,
Mayer
,
J.L.R.
,
Freyer
,
D.R.
,
Sandler
,
E.
,
Xu
,
P.
and
Krischer
,
J.P.
(
2008
)
The effect of cyproheptadine hydrochloride (periactin) and megestrol acetate (megace) on weight in children with cancer/treatment-related cachexia
.
J. Pediatr. Hematol. Oncol.
30
,
791
797
doi:
27
Kardinal
,
C.G.
,
Loprinzi
,
C.L.
,
Schaid
,
D.J.
,
Hass
,
A.C.
,
Dose
,
A.M.
,
Athmann
,
L.M.
et al
(
1990
)
A controlled trial of cyproheptadine in cancer patients with anorexia and/or cachexia
.
Cancer
65
,
2657
2662
<2657::AID-CNCR2820651210>3.0.CO;2-S
28
Wang
,
X.
,
Li
,
Y.
,
Tian
,
H.
,
Qi
,
J.
,
Li
,
M.
,
Fu
,
C.
et al
(
2014
)
Macrophage inhibitory cytokine 1 (MIC-1/GDF15) as a novel diagnostic serum biomarker in pancreatic ductal adenocarcinoma
.
BMC Cancer
14
,
578
doi:
29
Tsai
,
V.W.W.
,
Lin
,
S.
,
Brown
,
D.A.
,
Salis
,
A.
and
Breit
,
S.N.
(
2016
)
Anorexia–cachexia and obesity treatment may be two sides of the same coin: role of the TGF-b superfamily cytokine MIC-1/GDF15
.
Int. J. Obes.
40
,
193
197
doi:
30
Vigano
,
A.
,
Lerner
,
L.
,
Tao
,
N.
,
Krieger
,
B.
,
Feng
,
B.
,
Nicoletti
,
R.
et al
(
2014
)
Abstract 4650: from bench to bedside: are cytokines still relevant biomarkers for staging cancer cachexia
.
Cancer Res.
73
doi:
31
Lu
,
Z.-H.
,
Yang
,
L.
,
Yu
,
J.-W.
,
Lu
,
M.
,
Li
,
J.
,
Zhou
,
J.
et al
(
2014
)
Weight loss correlates with macrophage inhibitory cytokine-1 expression and might influence outcome in patients with advanced esophageal squamous cell carcinoma
.
Asian Pac. J. Cancer Prev.
15
,
6047
6052
doi:
32
Gordon
,
J.N.
,
Trebble
,
T.M.
,
Ellis
,
R.D.
,
Duncan
,
H.D.
,
Johns
,
T.
and
Goggin
,
P.M.
(
2005
)
Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial
.
Gut
54
,
540
545
doi:
33
Yennurajalingam
,
S.
,
Willey
,
J.S.
,
Palmer
,
J.L.
,
Allo
,
J.
,
Fabbro
,
E.D.
,
Cohen
,
E.N.
et al
(
2012
)
The role of thalidomide and placebo for the treatment of cancer-related anorexia-cachexia symptoms: results of a double-blind placebo-controlled randomized study
.
J. Palliat. Med.
15
,
1059
1064
doi:
34
ClinicalTrials.gov [internet]. Bethesda (MD): National Library of Medicine (US) Feb 29, 2000 - . Identifier NCT01127386, Lenalidomide for Lean Body Mass and Muscle Strength in Inflammatory Cancer Cachexia Syndrome; May 12, 2010, Available from https://clinicaltrials.gov/ct2/show/NCT01127386
35
ClinicalTrials.gov [internet]. Bethesda (MD): National Library of Medicine (US) Feb 29, 2000 - . Identifier NCT00201812, Phase I & Biological Study of Etanercept & Weekly Docetaxel in Patients With Advanced Solid Tumors, September 12, 2005, Available from https://clinicaltrials.gov/ct2/show/NCT00201812
36
Monk
,
J.P.
,
Phillips
,
G.
,
Waite
,
R.
,
Kuhn
,
J.
,
Schaaf
,
L.J.
,
Otterson
,
G.A.
et al
(
2006
)
Assessment of tumor necrosis factor α blockade as an intervention to improve tolerability of dose-intensive chemotherapy in cancer patients
.
J. Clin. Oncol.
24
,
1852
1859
doi:
37
Jatoi
,
A.
,
Ritter
,
H.L.
,
Dueck
,
A.
,
Nguyen
,
P.L.
,
Nikcevich
,
D.A.
,
Luyun
,
R.F.
et al
(
2010
)
A placebo-controlled, double-blind trial of infliximab for cancer-associated weight loss in elderly and/or poor performance non-small cell lung cancer patients (N01C9)
.
Lung Cancer
68
,
234
239
doi:
38
Suh
,
S.-Y.
,
Choi
,
Y.S.
,
Yeom
,
C.H.
,
Kwak
,
S.M.
,
Yoon
,
H.M.
,
Kim
,
D.G.
et al
(
2013
)
Interleukin-6 but not tumour necrosis factor-α predicts survival in patients with advanced cancer
.
Support. Care Cancer
21
,
3071
3077
doi:
39
Ando
,
K.
,
Takahashi
,
F.
,
Kato
,
M.
,
Kaneko
,
N.
,
Doi
,
T.
,
Ohe
,
Y.
et al
(
2014
)
Tocilizumab, a proposed therapy for the cachexia of Interleukin6-expressing lung cancer
.
PLoS ONE
9
,
e102436
doi:
40
Rigas
,
J.R.
,
Schuster
,
M.
,
Orlov
,
S.V.
,
Milovanovic
,
B.
,
Prabhash
,
K.
,
Smith
,
J.T.
and
the ALD5 study group.
(
2010
)
Efect of ALD518, a humanized anti-IL-6 antibody, on lean body mass loss and symptoms in patients with advanced non-small cell lung cancer (NSCLC): Results of a phase II randomized, double-blind safety and efficacy trial
.
2010 ASCO Annual Meeting
,
Chicago IL, U.S.A.
,
4–8 June 2010
,
Abstract 7622
41
Schuster
,
M.
,
Rigas
,
J.R.
,
Orlov
,
S.V.
,
Milovanovic
,
B.
,
Prabhash
,
K.
,
Smith
,
J.T.
and
the ALD5 study group.
ALD518, a humanized anti-IL-6 antibody, treats anemia in patients with advanced non-small cell lung cancer (NSCLC): Results of a phase II, randomized, double-blind, placebo-controlled trial
.
2010 ASCO Annual Meeting
,
Chicago IL, U.S.A.
,
4–8 June 2010
,
Abstract 7631
42
Mesa
,
R.A.
,
Verstovsek
,
S.
,
Gupta
,
V.
,
Mascarenhas
,
J.O.
,
Atallah
,
E.
,
Burn
,
T.
et al
(
2015
)
Effects of ruxolitinib treatment on metabolic and nutritional parameters in patients with myelofibrosis from COMFORT-I
.
Clin. Lymphoma. Myeloma Leuk.
15
,
214.e1
221.e1
doi:
43
Chasen
,
M.
(
2013
)
Phase II Data on OHR/AVR118 in Advanced Cancer Patients With Cachexia. Int. Cachexia Conf. Kobe, Japan
44
Chasen
,
M.
,
Hirschman
,
S.Z.
and
Bhargava
,
R.
(
2011
)
Phase II study of the novel peptide-nucleic acid OHR118 in the management of cancer-related anorexia/cachexia
.
J. Am. Med. Dir. Assoc.
12
,
62
67
doi:
45
Greco
,
S.H.
,
Tomkötter
,
L.
,
Vahle
,
A.-K.
,
Rokosh
,
R.
,
Avanzi
,
A.
,
Mahmood
,
S.K.
et al
(
2015
)
TGF-β blockade reduces mortality and metabolic changes in a validated murine model of pancreatic cancer cachexia
.
PLoS ONE
10
,
e0132786
doi:
46
Waning
,
D.L.
,
Mohammad
,
K.S.
,
Reiken
,
S.
,
Xie
,
W.
,
Andersson
,
D.C.
,
John
,
S.
et al
(
2015
)
Excess TGF-β mediates muscle weakness associated with bone metastases in mice
.
Nat. Med.
21
,
1262
1271
doi:
47
Figueras
,
M.
,
Busquets
,
S.
,
Carbó
,
N.
,
Barreiro
,
E.
,
Almendro
,
V.
,
Argilés
,
J.M.
et al
(
2004
)
Interleukin-15 is able to suppress the increased DNA fragmentation associated with muscle wasting in tumour-bearing rats
.
FEBS Lett.
569
,
201
206
doi:
48
Argilés
,
J.M.
,
López-Soriano
,
F.J.
and
Busquets
,
S.
(
2009
)
Therapeutic potential of interleukin-15: a myokine involved in muscle wasting and adiposity
.
Drug Discov. Today
14
,
208
213
doi:
49
Busquets
,
S.
,
Figueras
,
M.T.
,
Meijsing
,
S.
,
Carbó
,
N.
,
Quinn
,
L.S.
,
Almendro
,
V.
et al
(
2005
)
Interleukin-15 decreases proteolysis in skeletal muscle: a direct effect
.
Int. J. Mol. Med.
16
,
471
476
PMID:
[PubMed]
50
Martínez-Hernández
,
P.L.
,
Hernanz-Macías
,
Á.
,
Gómez-Candela
,
C.
,
Grande-Aragón
,
C.
,
Feliu-Batlle
,
J.
,
Castro-Carpeño
,
J.
et al
(
2012
)
Serum interleukin-15 levels in cancer patients with cachexia
.
Oncol. Rep.
28
,
1443
1452
doi:
51
Hussey
,
H.J.
and
Tisdale
,
M.J.
(
2000
)
Effect of the specific cyclooxygenase-2 inhibitor meloxicam on tumour growth and cachexia in a murine model
.
Int. J. Cancer
87
,
95
100
doi:
52
Mantovani
,
G.
,
Macciò
,
A.
,
Madeddu
,
C.
,
Serpe
,
R.
,
Antoni
,
G.
,
Massa
,
E.
et al
(
2010
)
Phase II nonrandomized study of the efficacy and safety of COX-2 inhibitor celecoxib on patients with cancer cachexia
.
J. Mol. Med.
88
,
85
92
doi:
53
Reid
,
J.
,
Hughes
,
C.M.
,
Murray
,
L.J.
,
Parsons
,
C.
and
Cantwell
,
M.M.
(
2013
)
Non-steroidal anti-inflammatory drugs for the treatment of cancer cachexia: a systematic review
.
Palliat. Med.
27
,
295
303
doi:
54
Toledo
,
M.
,
Springer
,
J.
,
Busquets
,
S.
,
Tschirner
,
A.
,
López-Soriano
,
F.J.
,
Anker
,
S.D.
et al
(
2014
)
Formoterol in the treatment of experimental cancer cachexia: effects on heart function
.
J. Cachexia Sarcopenia Muscle
5
,
315
320
doi:
55
Busquets
,
S.
,
Figueras
,
M.T.
,
Fuster
,
G.
,
Almendro
,
V.
,
Moore-Carrasco
,
R.
,
Ametller
,
E.
et al
(
2004
)
Anticachectic effects of formoterol: a drug for potential treatment of muscle wasting
.
Cancer Res.
64
,
6725
6731
doi:
56
Ametller
,
E.
,
Busquets
,
S.
,
Fuster
,
G.
,
Figueras
,
M.T.
,
Olivan
,
M.
,
de Oliveira
,
C.C.F.
et al
(
2011
)
Formoterol may activate rat muscle regeneration during cancer cachexia
.
Insciences J.
1
,
1
17
doi:
57
Toledo
,
M.
,
Busquets
,
S.
,
Penna
,
F.
,
Zhou
,
X.
,
Marmonti
,
E.
,
Betancourt
,
A.
et al
(
2016
)
Complete reversal of muscle wasting in experimental cancer cachexia: additive effects of activin type II receptor inhibition and β-2 agonist
.
Int. J. Cancer
138
,
2021
2029
doi:
58
Greig
,
C.A.
,
Johns
,
N.
,
Gray
,
C.
,
MacDonald
,
A.
,
Stephens
,
N.A.
,
Skipworth
,
R.J.E.
et al
(
2014
)
Phase I/II trial of formoterol fumarate combined with megestrol acetate in cachectic patients with advanced malignancy
.
Support. Care Cancer
22
,
1269
1275
doi:
59
Kanzaki
,
M.
,
Soda
,
K.
,
Gin
,
P.T.
,
Kai
,
T.
,
Konishi
,
F.
and
Kawakami
,
M.
(
2005
)
Erythropoietin attenuates cachectic events and decreases production of interleukin-6, a cachexia-inducing cytokine
.
Cytokine
32
,
234
239
doi:
60
Pin
,
F.
,
Busquets
,
S.
,
Toledo
,
M.
,
Camperi
,
A.
,
Lopez-Soriano
,
F.J.
,
Costelli
,
P.
et al
(
2015
)
Combination of exercise training and erythropoietin prevents cancer-induced muscle alterations
.
Oncotarget
6
,
43202
43215
doi:
61
Adigun
,
A.Q.
and
Ajayi
,
A.A.
(
2001
)
The effects of enalapril-digoxin-diuretic combination therapy on nutritional and anthropometric indices in chronic congestive heart failure: preliminary findings in cardiac cachexia
.
Eur. J. Heart Fail.
3
,
359
363
doi:
62
Murphy
,
K.T.
,
Chee
,
A.
,
Trieu
,
J.
,
Naim
,
T.
and
Lynch
,
G.S.
(
2013
)
Inhibition of the renin-angiotensin system improves physiological outcomes in mice with mild or severe cancer cachexia
.
Int. J. Cancer
133
,
1234
1246
doi:
63
Springer
,
J.
,
Tschirner
,
A.
,
Haghikia
,
A.
,
von Haehling
,
S.
,
Lal
,
H.
,
Grzesiak
,
A.
et al
(
2014
)
Prevention of liver cancer cachexia-induced cardiac wasting and heart failure
.
Eur. Heart J.
35
,
932
941
doi:
64
Schanze
,
N.
and
Springer
,
J.
(
2012
)
Evidence for an effect of ACE inhibitors on cancer cachexia
.
J. Cachexia Sarcopenia Muscle
3
,
139
doi:
65
Sukumaran
,
S.
,
Patel
,
H.J.
and
Patel
,
B.M.
(
2016
)
Evaluation of role of telmisartan in combination with 5-fluorouracil in gastric cancer cachexia
.
Life Sci.
154
,
15
23
doi:
66
Patel
,
B.M.
and
Damle
,
D.
(
2013
)
Combination of telmisartan with cisplatin controls oral cancer cachexia in rats
.
BioMed Res. Int.
2013
,
1
10
doi:
67
Ichiki
,
T.
,
Tian
,
Q.
,
Imayama
,
I.
and
Sunagawa
,
K.
(
2016
)
Abstract 5249: telmisartan manifests powerful anti-inflammatory effects beyond class effects of angiotensin II type 1 blocker by inhibiting tumor necrosis factor α-induced interleukin 6 expressions through peroxisome proliferator activated receptorγ activation
.
Circulation
118
,
S_513
68
Lainscak
,
M.
and
Laviano
,
A.
(
2016
)
ACT-ONE - ACTION at last on cancer cachexia by adapting a novel action β-blocker
.
J. Cachexia Sarcopenia Muscle
7
,
400
402
doi:
69
Stewart Coats
,
A.J.
,
Ho
,
G.F.
,
Prabhash
,
K.
,
von Haehling
,
S.
,
Tilson
,
J.
,
Brown
,
R.
et al
(
2016
)
Espindolol for the treatment and prevention of cachexia in patients with stage III/IV non-small cell lung cancer or colorectal cancer: a randomized, double-blind, placebo-controlled, international multicentre phase II study (the ACT-ONE trial)
.
J. Cachexia Sarcopenia Muscle
7
,
355
365
doi:
70
Bhattacharyya
,
G.S.
(
2015
)
Vicus Therapeutics Announces Safety and Survival Benefit of VT-122 in Combination with Anti-Cancer Therapies for Advanced Liver and Pancreatic Cancers
71
Dobs
,
A.S.
,
Boccia
,
R.V
,
Croot
,
C.C.
,
Gabrail
,
N.Y.
,
Dalton
,
J.T.
,
Hancock
,
M.L.
et al
(
2013
)
Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial
.
Lancet Oncol.
14
,
335
345
doi:
72
Crawford
,
J.
,
Prado
,
C.M.M.
,
Johnston
,
M.A.
,
Gralla
,
R.J.
,
Taylor
,
R.P.
,
Hancock
,
M.L.
et al
(
2016
)
Study design and rationale for the phase 3 clinical development program of enobosarm, a selective androgen receptor modulator, for the prevention and treatment of muscle wasting in cancer patients (POWER trials)
.
Curr. Oncol. Rep.
18
,
37
doi:
73
Srinath
,
R.
and
Dobs
,
A.
(
2014
)
Enobosarm (GTx-024, S-22): a potential treatment for cachexia
.
Future Oncol.
10
,
187
194
doi:
74
Blanqué
,
R.
,
Lepescheux
,
L.
,
Auberval
,
M.
,
Minet
,
D.
,
Merciris
,
D.
,
Cottereaux
,
C.
et al
(
2014
)
Characterization of GLPG0492, a selective androgen receptor modulator, in a mouse model of hindlimb immobilization
.
BMC Musculoskelet Disord.
15
,
291
doi:
75
ClinicalTrials.gov [internet]. Bethesda (MD): National Library of Medicine (US) Feb 29, 2000 - . Identifier NCT01397370, Multiple Ascending Dose Study of GLPG0492 in Healthy Subjects, July 18, 2011, Available from https://clinicaltrials.gov/ct2/show/NCT01397370
76
Wolf
,
R.F.
,
Pearlstone
,
D.B.
,
Newman
,
E.
,
Heslin
,
M.J.
,
Gonenne
,
A.
,
Burt
,
M.E.
et al
(
1992
)
Growth hormone and insulin reverse net whole body and skeletal muscle protein catabolism in cancer patients
.
Ann. Surg.
216
,
280
290
doi:
77
Ng
,
B.
,
Wolf
,
R.F.
,
Weksler
,
B.
,
Brennan
,
M.F.
and
Burt
,
M.
(
1993
)
Growth hormone administration preserves lean body mass in sarcoma-bearing rats treated with doxorubicin
.
Cancer Res.
53
,
5483
5486
PMID:
[PubMed]
78
Le Bouc
,
Y.
and
Brioude
,
F.
(
2012
)
Is there a relationship between the growth hormone dose and tumoral or cardiovascular complications?
Bull. Acad. Natl Med.
196
,
127
135
;
discussion 135–137
PMID:
[PubMed]
79
ClinicalTrials.gov [internet]. Bethesda (MD): National Library of Medicine (US) Feb 29, 2000 - . Identifier NCT01388920, Efficacy and Safety Study of Tesamorelin in Chronic Obstructive Pulmonary Disease (COPD) Subjects With Muscle Wasting, July 5, 2011, Available from https://clinicaltrials.gov/ct2/show/NCT01388920
80
Adunsky
,
A.
,
Chandler
,
J.
,
Heyden
,
N.
,
Lutkiewicz
,
J.
,
Scott
,
B.B.
,
Berd
,
Y.
et al
(
2011
)
MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fracture: a multicenter, randomized, placebo-controlled phase IIb study
.
Arch. Gerontol. Geriatr.
53
,
183
189
doi:
81
ClinicalTrials.gov [internet]. Bethesda (MD): National Library of Medicine (US) Feb 29, 2000 - . Identifier NCT00975104 , AMG 745 in Subjects With Age-associated Muscle Loss, September 10, 2009, Available from https://clinicaltrials.gov/ct2/show/NCT00975104
82
ClinicalTrials.gov [internet]. Bethesda (MD): National Library of Medicine (US) Feb 29, 2000 - . Identifier NCT00755638, A Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Study of ACE-031 (ActRIIB-IgG1) in Healthy Postmenopausal Volunteers, September 17, 2008, Available from https://clinicaltrials.gov/ct2/show/NCT00755638
83
[No authors listed]
(
2013
)
Abstracts of the 7th cachexia conference, Kobe/Osaka, Japan, December 9–11, 2013
.
J. Cachexia Sarcopenia Muscle
4
,
295
343
doi:
84
Lach-Trifilieff
,
E.
,
Minetti
,
G.C.
,
Sheppard
,
K.
,
Ibebunjo
,
C.
,
Feige
,
J.N.
,
Hartmann
,
S.
et al
(
2014
)
An antibody blocking activin type II receptors induces strong skeletal muscle hypertrophy and protects from atrophy
.
Mol. Cell. Biol.
34
,
606
618
doi:
85
Becker
,
C.
,
Lord
,
S.R.
,
Studenski
,
S.A.
,
Warden
,
S.J.
,
Fielding
,
R.A.
,
Recknor
,
C.P.
et al
(
2015
)
Myostatin antibody (LY2495655) in older weak fallers: a proof-of-concept, randomised, phase 2 trial
.
Lancet Diabetes Endocrinol.
3
,
948
957
doi:
86
ClinicalTrials.gov [internet]. Bethesda (MD): National Library of Medicine (US) Feb 29, 2000 - . Identifier NCT01505530, A Phase 2 Study of LY2495655 in Participants With Pancreatic Cancer, January 4, 2012, Available from https://clinicaltrials.gov/ct2/show/NCT01505530
87
ClinicalTrials.gov [internet]. Bethesda (MD): National Library of Medicine (US) Feb 29, 2000 - . Identifier NCT01963598 , Study of the Safety and Efficacy of REGN1033 (SAR391786) in Patients With Sarcopenia, October 11, 2013, Available from https://clinicaltrials.gov/ct2/show/NCT01963598
88
Llovera
,
M.
,
García-Martínez
,
C.
,
Agell
,
N.
,
Marzábal
,
M.
,
López-Soriano
,
F.J.
and
Argilés
,
J.M.
(
1994
)
Ubiquitin gene expression is increased in skeletal muscle of tumour-bearing rats
.
FEBS Lett.
338
,
311
318
doi:
89
Argilés
,
J.M.
,
López-Soriano
,
F.J.
and
Busquets
,
S.
(
2008
)
Novel approaches to the treatment of cachexia
.
Drug Discov. Today
13
,
73
78
doi:
90
Penna
,
F.
,
Bonetto
,
A.
,
Aversa
,
Z.
,
Minero
,
V.G.
,
Rossi Fanelli
,
F.
,
Costelli
,
P.
et al
(
2016
)
Effect of the specific proteasome inhibitor bortezomib on cancer-related muscle wasting
.
J. Cachexia Sarcopenia Muscle
7
,
345
354
doi:
91
Wang
,
Q.
,
Li
,
C.
,
Peng
,
X.
,
Kang
,
Q.
,
Deng
,
D.
,
Zhang
,
L.
et al
(
2015
)
Combined treatment of carfilzomib and z-VAD-fmk inhibits skeletal proteolysis and apoptosis and ameliorates cancer cachexia
.
Med. Oncol.
32
,
100
doi:
92
Reichenbach
,
A.
,
Al-Hiti
,
H.
,
Malek
,
I.
,
Pirk
,
J.
,
Goncalvesova
,
E.
,
Kautzner
,
J.
et al
(
2013
)
The effects of phosphodiesterase 5 inhibition on hemodynamics, functional status and survival in advanced heart failure and pulmonary hypertension: a case-control study
.
Int. J. Cardiol.
168
,
60
65
doi:
93
Study of Sildenafil as a Therapy for Fatigue in Pancreatic Cancer - Full Text View - ClinicalTrials.gov
94
Oliveira
,
A.G.
and
Gomes-Marcondes
,
M.C.C.
(
2016
)
Metformin treatment modulates the tumour-induced wasting effects in muscle protein metabolism minimising the cachexia in tumour-bearing rats
.
BMC Cancer
16
,
418
doi:
95
Scott
,
I.C.
,
Tomlinson
,
W.
,
Walding
,
A.
,
Isherwood
,
B.
and
Dougall
,
I.G.
(
2013
)
Large-scale isolation of human skeletal muscle satellite cells from post-mortem tissue and development of quantitative assays to evaluate modulators of myogenesis
.
J. Cachexia Sarcopenia Muscle
4
,
157
169
doi:
96
Rinaldi
,
F.
and
Perlingeiro
,
R.C.R.
(
2014
)
Stem cells for skeletal muscle regeneration: therapeutic potential and roadblocks
.
Transl. Res.
163
,
409
417
doi:
97
Palus
,
S.
,
von Haehling
,
S.
,
Flach
,
V.C.
,
Tschirner
,
A.
,
Doehner
,
W.
,
Anker
,
S.D.
et al
(
2013
)
Simvastatin reduces wasting and improves cardiac function as well as outcome in experimental cancer cachexia
.
Int. J. Cardiol.
168
,
3412
3418
doi:
98
Bindels
,
L.B.
,
Neyrinck
,
A.M.
,
Claus
,
S.P.
,
Le Roy
,
C.I.
,
Grangette
,
C.
,
Pot
,
B.
et al
(
2016
)
Synbiotic approach restores intestinal homeostasis and prolongs survival in leukaemic mice with cachexia
.
ISME J.
10
,
1456
1470
doi:
99
Castellani
,
C.
,
Singer
,
G.
,
Kaiser
,
M.
,
Kaiser
,
T.
,
Huang
,
J.
,
Sperl
,
D.
et al
(
2017
)
Neuroblastoma causes alterations of the intestinal microbiome, gut hormones, inflammatory cytokines, and bile acid composition
.
Pediatr. Blood Cancer
64
,
e26425
doi:
100
Fukawa
,
T.
,
Yan-Jiang
,
B.C.
,
Min-Wen
,
J.C.
,
Jun-Hao
,
E.T.
,
Huang
,
D.
,
Qian
,
C.-N.
et al
(
2016
)
Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia
.
Nat. Med.
22
,
666
671
doi:
101
Maschke
,
J.
,
Kruk
,
U.
,
Kastrati
,
K.
,
Kleeberg
,
J.
,
Buchholz
,
D.
,
Erickson
,
N.
et al
(
2017
)
Nutritional care of cancer patients: a survey on patients’ needs and medical care in reality
.
Int. J. Clin. Oncol.
22
,
200
206
doi:
102
Ravasco
,
P.
(
2015
)
Nutritional approaches in cancer: relevance of individualized counseling and supplementation
.
Nutrition
31
,
603
604
doi:
103
De Waele
,
E.
,
Mattens
,
S.
,
Honoré
,
P.M.
,
Spapen
,
H.
,
De Grève
,
J.
and
Pen
,
J.J.
(
2015
)
Nutrition therapy in cachectic cancer patients. The tight caloric control (TiCaCo) pilot trial
.
Appetite
91
,
298
301
doi:
104
Bourdel-Marchasson
,
I.
,
Blanc-Bisson
,
C.
,
Doussau
,
A.
,
Germain
,
C.
,
Blanc
,
J.-F.
,
Dauba
,
J.
et al
(
2014
)
Nutritional advice in older patients at risk of malnutrition during treatment for chemotherapy: a two-year randomized controlled trial
.
PLoS ONE
9
,
e108687
doi:
105
Fearon
,
K.C.H.
,
Von Meyenfeldt
,
M.F.
,
Moses
,
A.G.W.
,
van Geenen
,
R.
,
Roy
,
A.
,
Gouma
,
D.J.
et al
(
2003
)
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
52
,
1479
1486
doi:
106
Fearon
,
K.C.H.
,
Barber
,
M.D.
,
Moses
,
A.G.
,
Ahmedzai
,
S.H.
,
Taylor
,
G.S.
,
Tisdale
,
M.J.
et al
(
2006
)
Double-blind, placebo-controlled, randomized study of eicosapentaenoic acid diester in patients with cancer cachexia
.
J. Clin. Oncol.
24
,
3401
3407
doi:
107
Ries
,
A.
,
Trottenberg
,
P.
,
Elsner
,
F.
,
Stiel
,
S.
,
Haugen
,
D.
,
Kaasa
,
S.
et al
(
2012
)
A systematic review on the role of fish oil for the treatment of cachexia in advanced cancer: an EPCRC cachexia guidelines project
.
Palliat. Med.
26
,
294
304
doi:
108
Jatoi
,
A.
,
Rowland
,
K.
,
Loprinzi
,
C.L.
,
Sloan
,
J.A.
,
Dakhil
,
S.R.
,
MacDonald
,
N.
et al
(
2004
)
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.
22
,
2469
2476
doi:
109
Read
,
J.A.
,
Beale
,
P.J.
,
Volker
,
D.H.
,
Smith
,
N.
,
Childs
,
A.
and
Clarke
,
S.J.
(
2007
)
Nutrition intervention using an eicosapentaenoic acid (EPA)-containing supplement in patients with advanced colorectal cancer. effects on nutritional and inflammatory status: a phase II trial
.
Support. Care Cancer
15
,
301
307
doi:
110
Ryan
,
A.M.
,
Reynolds
,
J.V
,
Healy
,
L.
,
Byrne
,
M.
,
Moore
,
J.
,
Brannelly
,
N.
et al
(
2009
)
Enteral nutrition enriched with eicosapentaenoic acid (EPA) preserves lean body mass following esophageal cancer surgery: results of a double-blinded randomized controlled trial
.
Ann. Surg.
249
,
355
363
doi:
111
Eley
,
H.L.
,
Russell
,
S.T.
and
Tisdale
,
M.J.
(
2008
)
Attenuation of depression of muscle protein synthesis induced by lipopolysaccharide, tumor necrosis factor, and angiotensin II by β-hydroxy-β-methylbutyrate
.
AJP Endocrinol. Metab.
295
,
E1409
E1416
doi:
112
Eley
,
H.L.
,
Russell
,
S.T.
,
Baxter
,
J.H.
,
Mukerji
,
P.
and
Tisdale
,
M.J.
(
2007
)
Signaling pathways initiated by β-hydroxy-β-methylbutyrate to attenuate the depression of protein synthesis in skeletal muscle in response to cachectic stimuli
.
AJP Endocrinol. Metab.
293
,
E923
E931
doi:
113
Kornasio
,
R.
,
Riederer
,
I.
,
Butler-Browne
,
G.
,
Mouly
,
V.
,
Uni
,
Z.
and
Halevy
,
O.
(
2009
)
β-hydroxy-β-methylbutyrate (HMB) stimulates myogenic cell proliferation, differentiation and survival via the MAPK/ERK and PI3K/Akt pathways
.
Biochim. Biophys. Acta, Mol. Cell Res.
1793
,
755
763
doi:
114
Smith
,
H.J.
,
Mukerji
,
P.
and
Tisdale
,
M.J.
(
2005
)
Attenuation of proteasome-induced proteolysis in skeletal muscle by β-hydroxy-β-methylbutyrate in cancer-induced muscle loss
.
Cancer Res.
65
,
277
283
PMID:
[PubMed]
115
May
,
P.E.
,
Barber
,
A.
,
D'Olimpio
,
J.T.
,
Hourihane
,
A.
and
Abumrad
,
N.N.
(
2002
)
Reversal of cancer-related wasting using oral supplementation with a combination of β-hydroxy-β-methylbutyrate, arginine, and glutamine
.
Am. J. Surg.
183
,
471
479
doi:
116
Berk
,
L.
,
James
,
J.
,
Schwartz
,
A.
,
Hug
,
E.
,
Mahadevan
,
A.
,
Samuels
,
M.
et al
(
2008
)
A randomized, double-blind, placebo-controlled trial of a β-hydroxyl β-methyl butyrate, glutamine, and arginine mixture for the treatment of cancer cachexia (RTOG 0122)
.
Support. Care Cancer
16
,
1179
1188
doi:
117
Mirza
,
K.A.
,
Pereira
,
S.L.
,
Voss
,
A.C.
and
Tisdale
,
M.J.
(
2014
)
Comparison of the anticatabolic effects of leucine and Ca-β-hydroxy-β-methylbutyrate in experimental models of cancer cachexia
.
Nutrition
30
,
807
813
doi:
118
ClinicalTrials.gov [internet]. Bethesda (MD): National Library of Medicine (US) Feb 29, 2000 - . Identifier NCT01607879, Use of β-hydroxy-β-methylbutyrate to Counteract Muscle Loss in Men With Prostate Cancer on Androgen Ablation, April 20, 2012, Available from https://clinicaltrials.gov/ct2/show/NCT01607879
119
Molfino
,
A.
,
Gioia
,
G.
,
Rossi Fanelli
,
F.
and
Muscaritoli
,
M.
(
2013
)
β-hydroxy-β-methylbutyrate supplementation in health and disease: a systematic review of randomized trials
.
Amino Acids
45
,
1273
1292
doi:
120
Lira
,
F.S.
,
Antunes
,
B..M.M.
,
Seelaender
,
M.
and
Neto
,
J.C.R.
(
2015
)
The therapeutic potential of exercise to treat cachexia
.
Curr. Opin. Support. Palliat. Care
9
,
317
324
doi:
121
Alves
,
C.R.R.
,
da Cunha
,
T.F.
,
da Paixão
,
N.A.
and
Brum
,
P.C.
(
2015
)
Aerobic exercise training as therapy for cardiac and cancer cachexia
.
Life Sci.
125
,
9
14
doi:
122
Lønbro
,
S.
,
Dalgas
,
U.
,
Primdahl
,
H.
,
Johansen
,
J.
,
Nielsen
,
J.L.
,
Aagaard
,
P.
et al
(
2013
)
Progressive resistance training rebuilds lean body mass in head and neck cancer patients after radiotherapy – results from the randomized DAHANCA 25B trial
.
Radiother. Oncol.
108
,
314
319
doi:
123
McNeely
,
M.L.
,
Parliament
,
M.B.
,
Seikaly
,
H.
,
Jha
,
N.
,
Magee
,
D.J.
,
Haykowsky
,
M.J.
et al
(
2015
)
Sustainability of outcomes after a randomized crossover trial of resistance exercise for shoulder dysfunction in survivors of head and neck cancer
.
Physiother. Canada
67
,
85
93
doi:
124
Peddle-McIntyre
,
C.J.
,
Bell
,
G.
,
Fenton
,
D.
,
McCargar
,
L.
and
Courneya
,
K.S.
(
2012
)
Feasibility and preliminary efficacy of progressive resistance exercise training in lung cancer survivors
.
Lung Cancer
75
,
126
132
doi:
125
Cheema
,
B.
,
Gaul
,
C.A.
,
Lane
,
K.
and
Fiatarone Singh
,
M.A.
(
2008
)
Progressive resistance training in breast cancer: a systematic review of clinical trials
.
Breast Cancer Res. Treat.
109
,
9
26
doi:
126
Muscaritoli
,
M.
,
Molfino
,
A.
,
Lucia
,
S.
and
Rossi Fanelli
,
F.
(
2015
)
Cachexia: a preventable comorbidity of cancer. A T.A.R.G.E.T. approach
.
Crit. Rev. Oncol. Hematol.
94
,
251
259
doi:
127
Fossen
,
C.
Pre-MENAC study presentation - PRC, NTNU
128
ClinicalTrials.gov [internet]. Bethesda (MD): National Library of Medicine (US) Feb 29, 2000 - . Identifier NCT02330926, Multimodal Intervention for Cachexia in Advanced Cancer Patients Undergoing Chemotherapy, December 31, 2014, Available from https://clinicaltrials.gov/ct2/show/NCT02330926
129
Madeddu
,
C.
,
Gramignano
,
G.
,
Tanca
,
L.
,
Cherchi
,
M.C.
,
Floris
,
C.A.
and
Macciò
,
A.
(
2014
)
A combined treatment approach for cachexia and cancer-related anemia in advanced cancer patients: a randomized placebo-controlled trial
.
J. Clin. Oncol.
32
,
189
189
doi:
130
Maddocks
,
M.
,
Hopkinson
,
J.
,
Conibear
,
J.
,
Reeves
,
A.
,
Shaw
,
C.
and
Fearon
,
K.C.H.
(
2016
)
Practical multimodal care for cancer cachexia
.
Curr. Opin. Support. Palliat. Care
10
,
298
305
doi:
131
Argilés
,
J.M.
,
López-Soriano
,
F.J.
,
Toledo
,
M.
,
Betancourt
,
A.
,
Serpe
,
R.
and
Busquets
,
S.
(
2011
)
The cachexia score (CASCO): a new tool for staging cachectic cancer patients
.
J. Cachexia Sarcopenia Muscle
2
,
87
93
doi:
132
Argilés
,
J.M.
,
Betancourt
,
A.
,
Guàrdia-Olmos
,
J.
,
Peró-Cebollero
,
M.
,
López-Soriano
,
F.J.
,
Madeddu
,
C.
et al
(
2017
)
Validation of the CAchexia SCOre (CASCO). staging cancer patients: the use of miniCASCO as a simplified tool
.
Front. Physiol.
8
,
92
doi:
133
Fearon
,
K.
,
Strasser
,
F.
,
Anker
,
S.D.
,
Bosaeus
,
I.
,
Bruera
,
E.
,
Fainsinger
,
R.L.
et al
(
2011
)
Definition and classification of cancer cachexia: an international consensus
.
Lancet Oncol.
12
,
489
495
doi:
134
Stephens
,
N.A.
,
Skipworth
,
R.J.E.
,
Gallagher
,
I.J.
,
Greig
,
C.A.
,
Guttridge
,
D.C.
,
Ross
,
J.A.
et al
(
2015
)
Evaluating potential biomarkers of cachexia and survival in skeletal muscle of upper gastrointestinal cancer patients
.
J. Cachexia Sarcopenia Muscle
6
,
53
61
doi:
135
Fearon
,
K.C.H.
,
Argiles
,
J.M.
,
Baracos
,
V.E.
,
Bernabei
,
R.
,
Coats
,
A.J.S.
,
Crawford
,
J.
et al
(
2015
)
Request for regulatory guidance for cancer cachexia intervention trials
.
J. Cachexia Sarcopenia Muscle
6
,
272
274
doi: