Drugs in development for treatment of patients with cancer-related anorexia and cachexia syndrome.

Cancer-related anorexia and cachexia syndrome (CACS) is a complex multifactorial condition, with loss of lean body mass, chronic inflammation, severe metabolic derangements, reduced food intake, reduced physical activity, and poor quality of life as key symptoms. Cachexia recognizes different phases or stages, moving from precachexia through overt cachexia to advanced or refractory cachexia. The purpose of this review is to describe currently effective approaches for the treatment of cachexia, moving forward to drugs and treatments already shown to be effective but needing further clinical trials to confirm their efficacy. We then introduce novel promising investigational drugs and approaches which, based on a strong rationale from the most recent data on the molecular targets/pathways driving the pathophysiology of cachexia, need to be tested either in currently ongoing or appropriate future clinical trials to confirm their clinical potential. Although different drugs and treatments have been tested, we can speculate that a single therapy may not be completely successful. Indeed, considering the complex clinical picture and the multifactorial pathogenesis of CACS, we believe that its clinical management requires a multidisciplinary and multitargeted approach. In our opinion, appropriate treatment for cachexia should target the following conditions: inflammatory status, oxidative stress, nutritional disorders, muscle catabolism, immunosuppression, quality of life, and above all, fatigue. A comprehensive list of the most interesting and effective multitargeted treatments is reported and discussed, with the aim of suggesting the most promising with regard to clinical outcome. A critical issue is that of testing therapies at the earliest stages of cachexia, possibly at the precachexia stage, with the aim of preventing or delaying the development of overt cachexia and thereby obtaining the best possible clinical outcome for patients.

Introduction

Cancer-related anorexia and cachexia syndrome (CACS) is a debilitating clinical condition that affects the course of several chronic diseases, including chronic heart failure, chronic obstructive pulmonary disease, chronic kidney disease, and especially cancer. During its progression, cancer induces changes in the host immune system and energy metabolism that affect the clinical status of the patient so profoundly that it can result in death.1 The following symptoms are associated with these events and involve various organs and systems: anorexia, nausea, weight loss (with a reduction in lean body mass and adipose tissue), increased energy metabolism (with changes in glucose, lipid, and protein metabolism), immunosuppression, and fatigue. All these symptoms ultimately result in the clinical picture of CACS, which, unless counteracted, has a negative impact on quality of life for patients.2 A recent consensus defined cachexia as “a complex metabolic syndrome associated with an underlying inflammatory disease and characterized by the loss of muscle with or without loss of fat mass”.3 The pathophysiology of cachexia is common, at least in part, in the different diseases, and represents the main background of cachexia symptoms. In this review, we focus on CACS, the mechanisms of which are shared by chronic illnesses.

It is well established that proinflammatory cytokines, including interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α, which are produced by the activated immune system and by tumor cells, are involved in the pathophysiology of CACS and the associated metabolic changes.4 It may be hypothesized that the synthesis and release of proinflammatory cytokines may lead to an efficient antineoplastic effect during the initial phases of neoplastic disease. However, the inability of the immune system to counteract tumor growth ultimately results in chronic cytokine activity, with irreversible effects on cell metabolism, body composition, nutritional status, and immune system efficiency.5 In turn, proinflammatory cytokines promote the synthesis of acute-phase proteins, which contribute to the pathogenesis of altered energy metabolism.6 Proinflammatory cytokines, together with tumor-derived factors, such as proteolysis-inducing factors and the recently discovered myostatin,7 also play a central role in the pathogenesis of muscle wasting via activation of the ubiquitin-proteasome proteolytic pathway.8

A major clinical feature of CACS is loss of muscle mass, leading to fatigue, impairment of normal activity, and eventually death.9 Muscle wasting is the result of multiple alterations at both the molecular and metabolic levels, leading to a disturbance in the balance between protein degradation and protein synthesis, whereas loss of muscle mass is mainly related to enhanced use of muscle proteins as an energy source to supply the increased energy needs of patients with cachexia.

Anorexia, which is also induced by proinflammatory cytokines,10,11 is often associated with CACS, leading to reduced food intake. However, anorexia alone cannot account for the complex alterations characterizing this syndrome, thus confirming that cachexia is not just a consequence of malnutrition, but that other events are involved in its pathogenesis.12

In this context, the finding that cancer patients in advanced stages of the disease show severe impairment of immune function, characterized by a cell-mediated immunity deficit, elevated serum levels of proinflammatory cytokines, and acute-phase proteins (fibrinogen and C-reactive protein), is very relevant13 and encompasses the chronic inflammation status typical of CACS.14 The exact time when these changes occur is difficult to establish, but they are probably due to an interaction between the tumor and host. The tumor and its continuous growth are responsible for increased energy expenditure and progressive weight loss.15 Moreover, tumor growth is accompanied by chronic activation of the immune system as it triggers a response to counteract the tumor. The immune response is also energetically costly (25%–30% of the basal metabolic rate, ie, 1750–2080 kJ/day).16

From the evidence discussed above, it is intuitive that the clinical management of CACS is complex and requires a multidisciplinary and multipharmacological approach.17,18 Appropriate treatment of CACS should include drugs that address the following conditions: inflammatory state, nutritional disorder, metabolic derangements, immunological defects, poor quality of life, and, in particular, fatigue. Accordingly, treatment for CACS should include as primary endpoints the following variables, which were recently identified as key in cachexia:19 an increase in lean body mass and functional activity (grip strength, physical activity measured by either the six-minute walk test, arm band device, or three-step treadmill test); a decrease in resting energy expenditure; and improvement of fatigue. Moreover, the following variables should be included as secondary end-points: increased appetite, improved quality of life assessed by EORTC-QLQ-C30, and a decrease in proinflammatory cytokines (IL-6, and TNF-α). In fact, only full knowledge of the pathophysiology of CACS will enable identification of the most appropriate drugs to counteract the constitutive symptoms. A comprehensive summary of potentially available drugs for CACS is shown in Table 1.

Table 1

Comprehensive summary of drugs potentially available for cachexia in cancer patients

Ineffective treatments

• Cyproheptadine

• Hydrazine

• Metoclopramide

• Pentoxifylline

Drugs commonly used

• Progestagens

○ Megestrol acetate

○ Medroxyprogesterone acetate

• Corticosteroids

• Anabolic agents (oxandrolone)

Drugs with a strong rationale that failed or showed equivocal results in clinical trials

• Omega-3 fatty acids

• Cannabinoids (dronabinol)

• Bortezomib

Drugs with confirmed clinical results

• COX-2 inhibitors

• Thalidomide

• Melatonin

• Insulin

• Branch-chained amino acids

Investigational drugs with clinical effectiveness to be confirmed

• Ghrelin and ghrelin mimetics

• Melanocortin antagonists

• Drugs targeting inflammatory cytokines

• Selective androgen receptor modulators

• Myostatin inhibitors

• β-adrenoceptor agonists

Investigational new drugs registered at ClinicalTrials.gov

Multimodal therapy

Treatment of CACS

Progestagens

Progestagens were the first agents used for the treatment of CACS and are currently the only agents approved in Europe for its treatment. An extensive amount of literature is available on megestrol acetate and medroxyprogesterone acetate (MPA) for the treatment of patients with cancer.20 Megestrol acetate and MPA are equivalent in terms of effectiveness in the treatment of CACS. However, megestrol acetate has been more widely investigated for its effect on cachexia21 than MPA.20 The positive effects of megestrol acetate on weight and well-being have been observed at oral doses in the range of 160–1600 mg/day. However, because megestrol acetate may be associated with severe dose-related adverse effects, starting treatment at a low dose (160 mg/day) and titrating the dose upwards according to clinical response is recommended.22 MPA has been used at doses in the range of 300–4000 mg/day. In a placebo-controlled study by Simons et al,23 a significant improvement in appetite and body weight was achieved using an oral dose of MPA in the range of 500–1000 mg/day. Moreover, a systematic review of MPA for the treatment of CACS found that there were no significant differences between high and low doses.24 Therefore, an MPA dose of 500–1000 mg/day orally can be recommended in clinical practice. Both megestrol acetate and MPA may have adverse effects, including an increased risk of thromboembolic events, peripheral edema, breakthrough bleeding, hyperglycemia, hypertension, and Cushing’s syndrome. Recently, an oral suspension formulation of megestrol acetate was developed using nanocrystal technology. Preclinical pharmacokinetic data suggest that this formulation of megestrol acetate can produce a more rapid clinical response by rapidly increasing plasma megestrol acetate levels.25 The US Food and Drug Administration (FDA) approved the oral suspension for the treatment of acquired immune deficiency syndrome-related cachexia, and this drug is currently under evaluation for approval to treat CACS associated with other conditions.

Corticosteroids

Several randomized, placebo-controlled studies have shown that corticosteroids achieve a limited (up to one month) improvement in appetite, food intake, nausea, and feeling of well-being. However, none of these studies showed an increase in body weight.26–30 The rapid beneficial effect of corticosteroids on mood and behavior significantly improves quality of life. The mechanism of action of corticosteroids in CACS is not well understood, although inhibition of prostaglandin activity and suppression of IL-1 and TNF-α production and release are the most well recognized targets.22 The specific drug, dose, and route of administration of corticosteroids are not well established: however, low doses, equivalent to less than 1 mg/kg of prednisone, are recommended in clinical practice. Further, because of their well known adverse effects, short-term (no more than 1–2 months) or alternating use of these agents is recommended in the management of CACS.

Anabolic agents

Anabolic androgens are synthetic derivatives of testosterone, with a greater anabolic effect and less androgenic activity than testosterone. Studies on the use of these anabolic agents in cachectic patients have been limited largely to patients with chronic obstructive pulmonary disease and human immunodeficiency virus/acquired immune deficiency syndrome, in whom positive effects on body weight, lean body mass, and several functional parameters were observed. However, few studies have been carried out to date in patients with CACS.

Recently, a prospective, randomized Phase III trial compared the effects of oxandrolone 10 mg twice daily and megestrol acetate 800 mg daily on weight, body composition, and quality of life in 155 adult patients with solid tumors and weight loss while receiving chemotherapy. This study showed that patients treated with oxandrolone experienced an increase in lean body mass, a reduction in fat mass, and fewer self-reported anorectic symptoms.31 The side effects of these agents include elevated transaminase levels (especially with nandrolone), decreased high-density lipoprotein levels, interactions with oral anticoagulants, oral hypoglycemics, and adrenal steroids, and hypogonadism (with decreased systemic testosterone levels). Oxandrolone is administered orally (at approved dose concentrations of 5–20 mg/day) and has a better safety profile and less potential for hepatic toxicity and virilizing effects than other androgens. This agent is well tolerated in women.32

Drugs with confirmed clinical results

Nonsteroidal anti-inflammatory drugs

COX-2 selective inhibitors

The development of selective COX-2 inhibitors has resulted in safer modulation of cancer-associated inflammation, and these agents could help alleviate or control CACS. Moreover, the selective COX-2 inhibitors have shown potent inhibitory and preventive effects on tumor growth in animal models; therefore, their antineoplastic activity may contribute to their ability to counteract cachexia. In particular, use of celecoxib, a selective COX-2 inhibitor, has been investigated. Lai et al33 randomized 11 cachectic patients with head and neck or gastrointestinal cancer to receive celecoxib 200 mg twice daily or placebo for three weeks. The patients on celecoxib reported good compliance and no adverse events were observed. Patients on celecoxib also showed a nonsignificant increase in body weight (mean change +1.0 kg versus −1.3 kg in the placebo group) and a significant increase in quality of life. A recent nonrandomized, prospective Phase II study investigated celecoxib 300 mg/day for four months in 24 patients with advanced cancer.34 The results indicated a significant decrease in levels of the proinflammatory cytokine, TNF-α, and a significant increase in lean body mass. In addition, significant improvements were observed in quality of life, performance status, Glasgow Prognostic Score, and grip strength. Patient compliance was good and no severe toxicities were observed. On the basis of these results, celecoxib can be included as a component in the combined treatment approach to target the inflammatory environment of CACS.

A randomized Phase II trial assessing the feasibility of recruitment and retention of patients with advanced non-small cell lung cancer (NSCLC) undertaking a 12-week multimodal intervention of celecoxib, oral nutritional supplements, and physical exercise is due for completion by December 2014.35

Thalidomide

Thalidomide has complex immunomodulatory and anti-inflammatory properties. It downregulates the production of TNF-α and other proinflammatory cytokines, inhibits transcription factor nuclear factor (NF-kB), downregulates COX-2, and inhibits angiogenesis. Therefore, thalidomide is a novel and rational treatment approach for CACS. In a randomized, placebo-controlled trial, thalidomide was found to be well tolerated and effective in slowing weight loss and improving arm muscle mass and physical function in 33 patients with advanced pancreatic cancer and CACS.36 Recently, a meta-analysis was performed to assess whether thalidomide is an effective treatment for CACS,37 and the authors concluded that there is inadequate evidence to recommend the use of this drug in clinical practice. Further large, well conducted, randomized controlled trials are needed to assess properly the true benefits of thalidomide alone and in combination in CSCS.

Lenalidomide (Revlimid™, Celgene Corporation, Summit, NJ, USA) is a derivative of thalidomide now approved by the FDA for the treatment of myelodysplastic syndromes. A randomized, multicenter Phase II trial is presently underway assessing the efficacy of lenalidomide in enhancing lean body mass and grip strength in patients with advanced cancer.35

Melatonin

Del Fabbro et al38 performed a randomized, double-blind, 28-day trial of melatonin 20 mg versus placebo in patients with advanced lung or gastrointestinal cancer and a history of weight loss ≥5%. Assessments included weight, symptoms on the Edmonton Symptom Assessment Scale, and quality of life using the Functional Assessment of Anorexia/Cachexia Therapy questionnaire. After interim analysis of 48 patients, the study was closed because of futility. There were no significant differences between the treatment groups with regard to appetite or other symptoms, weight, Functional Assessment of Anorexia/Cachexia Therapy score, toxicity, or survival from baseline to day 28. Therefore, oral melatonin 20 mg at night did not improve appetite, weight, or quality of life compared with placebo.

Investigational drugs with clinical effectiveness to be confirmed

Ghrelin and ghrelin mimetics

Ghrelin is a 28-amino acid peptide produced by the P/D1 cells of the stomach, and stimulates secretion of growth hormone (GH, through the GH secretagogue-1a [GHS-1a] receptor), promotes food intake (through the orexigenic neuropeptide Y system), and decreases sympathetic nerve activity. Based on animal and short-term human trials, the evidence for use of ghrelin and GHS-R agonists in the treatment of CACS seems promising. Synthetic human ghrelin has been shown to improve muscle wasting and functional capacity in patients with cardiopulmonary-associated cachexia.39 Single-dose intravenous administration of ghrelin to cancer patients with cachexia did not show univocal efficacy in increasing food intake. In a randomized placebo-controlled trial, RC-1291 (anamorelin, an orally active small molecule GHS-R agonist) was administered to 81 patients with a variety of cancers (predominantly lung cancer) over a 12-week period. RC-1291 improved total body mass and there was a trend towards increased lean body mass, but quality of life was unchanged.40 More recently, anamorelin was shown to increase body weight and anabolic hormone levels in healthy volunteers. This drug was also investigated as a treatment for CACS in 16 patients with different types of cancer, and achieved a significant increase in body weight and improvement in patient-reported symptoms, including appetite, compared with placebo.41 However, these were small Phase I and Phase II trials, so their results should be interpreted with caution. A randomized, double-blind, placebo-controlled Phase III trial is presently enrolling up to 477 patients with NSCLC and CACS to measure lean body mass and muscle strength. This trial, sponsored by Helsinn Therapeutics (Bridgewater, NJ, USA), started recruiting in 2011 and is expected to be completed by 2014 (see Table 2). A caveat to the use of ghrelin agonists for treating CACS is the potential for stimulating tumor growth. Ghrelin and its receptor are expressed in many tumor cells and may contribute to tumor progression. Although no clinical study has reported an increased tumor incidence with administration of ghrelin, the studies to date have been short-term only. Therefore, further randomized, controlled studies are warranted before the use of ghrelin can be translated into clinical practice.

Table 2

Investigational new drugs registered at ClinicalTrials.gov for the treatment of cachexia in cancer patients

ClinicalTrials.gov identifier	Title	Purpose	Intervention	Phase	Estimated enrolment	Start date	Completion
NCT01387269	Safety and efficacy of anamorelin HCl in patients with NSCLC-C (ROMANA 1)	Administration of anamorelin in patients with stage lll–IV NSCLC-C is expected to increase appetite, lean body mass, weight gain, and muscle strength.	Anamorelin HCl Placebo	III	477	July 2011	July 2013
NCT01387282	Safety and efficacy of anamorelin HCl in patients with NSCLC-C (ROMANA 2)	Administration of anamorelin in patients with stage lll–IV NSCLC-C is expected to increase appetite, lean body mass, weight gain, and muscle strength.	Anamorelin HCl Placebo	III	477	July 2011	July 2013
NCT01206335	Open-label study with OHR/AVR118 in patients with advanced cancer and anorexia-cachexia	To determine whether patients with advanced cancer who receive OHR/AVR 118 solution injected into the skin can achieve improvement in quality of life. Based on a previous study in patients with acquired immune deficiency syndrome, possible benefits may include improved appetite and strength, weight gain, improved mood, and decreased fatigue.	OHR/AVR118	II	20	September 2010	February 2013
NCT01614990	Pilot clinical trial of repeated doses of macimorelin to assess safety and efficacy in patients with cancer-related cachexia	To evaluate the safety and efficacy of repeated oral administration of macimorelin at different doses daily for 1 week in the treatment of cancer-related cachexia.	Macimorelin Placebo	II	26	May 2012	August 2013
NCT01767857	Study using MABpl to increase overall survival in patients with colorectal cancer and weight loss	To determine if the true human monoclonal antibody MABp 1 can prolong life in patients with colorectal carcinoma who are losing weight.	MABpl Megestrol acetate	III	656	February 2013	December 2014
NCT01419145	Feasibility study of multimodal exercise/nutrition/anti-inflammatory treatment for cachexia (Pre-MENAC study)	A multicenter, open, randomized Phase II study comparing a multimodal intervention (oral nutritional supplements, celecoxib, physical exercise) for cachexia versus standard cancer care.	Multimodal intervention Standard care	II	40	October 2011	October 2014
NCT01433263	Randomized, double-blind, placebo-controlled, multicenter study of BYM338 for treatment of cachexia in patients with stage IV NSCLC or stage lll/IV adenocarcinoma of the pancreas	A safety and efficacy clinical study of the investigational medicinal product BYM338 for treatment of unintentional weight loss in patients with cancer of the lung or pancreas.	BYM338 active drug Placebo	II	50	August 2011	May 2013
NCT01501396	Treatment of CACS with mirtazapine and megestrol acetate	To study the safety and efficacy of megestrol acetate ± mirtazapine in treating cancer patients with weight loss and loss of appetite. To date, no pharmacologic interventions have been approved by the FDA to treat CACS. Megestrol acetate has been shown to increase appetite in cancer patients. Adding mirtazapine may provide a more effective treatment and help improve quality of life.	Megestrol acetate Arm Β (megestrol + mirtazapine)	II	140	April 2012	April 2015
NCT00489593	Phase 1 dose-finding pilot study of the safety and tolerability of olanzapine in patients with advanced cancer and weight loss	To find the highest tolerable dose of olanzapine that can be given to patients with advanced cancer who are experiencing weight loss. Researchers want to determine if olanzapine can help decrease weight loss in patients who are experiencing it because of cancer. How this drug affects performance status, cancer-related symptoms, and nutritional status in patients with advanced cancer will also be studied.	Olanzapine	I	57	October 26	April 2014 Study ongoing but not recruiting participants

Abbreviations: CACS, cancer anorexia-cachexia syndrome; NSCLC-C, non-small cell lung cancer and cachexia; FDA, US Food and Drug Administration; HCl, hydrochloride.

AEZS-130 is an oral peptidomimetic growth hormone secretagogue developed by Æterna Zentaris Inc (Quebec, Canada), and was shown to be well tolerated in healthy subjects.35 A proof-of-concept study in patients with cancer and cachexia was planned to start in 2011.

Melanocortin antagonists

Among the appetite stimulants, a promising approach is targeting of the melanocortin-4 receptor. Interesting results were observed in colon-26 tumor-bearing mice,42 and clinical studies of this agent are planned.35

Drugs targeting inflammatory cytokines

The most effective anti-inflammatory drugs have been those targeting TNF-α and IL-6. A humanized monoclonal anti-IL-6 antibody, ALD518 (Alder Biopharmaceuticals Inc, Bothell, WA, USA), may also benefit patients with cancer-associated cachexia because its administration increases hemoglobin levels and prevents reduction in lean body mass in those with advanced NSCLC.43

Greater benefits may be conferred when TNF-α and IL-6 are targeted simultaneously. OHR Pharmaceutical Inc (New York, NY, USA) have developed the broad-spectrum peptide nucleic acid immune modulator drug, OHR/AVR118, which targets both TNF-α and IL-6 and maintains immune homeostasis. In a Phase II study, eight of 21 enrolled patients with advanced cancer completed the study, and showed an improvement in anorexia, dyspepsia, strength (assessed by grip strength), and depression.44 A Phase IIb trial is currently assessing the efficacy of OHR/AVR118 in improving appetite and enhancing body mass, lean mass, strength (assessed by grip strength), and quality of life in patients with recurrent or advanced cancer and was expected to be completed before the end of November 2011.

A humanized anti-IL-6 antibody (BMS-945429) was shown to be safe and well tolerated during early clinical studies in patients with NSCLC, with treatment improving lung symptoms and reversing fatigue, with a trend towards a decrease in loss of lean body mass.45 These findings are consistent with the results of a Phase II trial that assessed selumetinib (an inhibitor of MAPK1 and IL-6 secretion) in 20 patients with cholangiocarcinoma.46 Overall, 84% of patients in this trial showed a mean muscle gain of 2.3 kg.46

Selective androgen receptor modulators

Due to the lack of selectivity of anabolic androgens, a need for more selective anabolic agents has emerged, resulting in the development of nonsteroidal selective androgen receptor modulators (SARMs). These agents have the potential to elicit beneficial anabolic effects in a tissue-selective manner, while avoiding many of the side effects observed with steroidal agents. The first nonsteroidal SARM was reported in 1998, and many of the major pharmaceutical companies have disclosed the specific chemical structure of different SARMs. Currently, the agent furthest into clinical development is enobosarm (GTx Inc, Memphis, TN, USA) for the potential prevention and treatment of muscle wasting in patients with cancer. In a Phase IIb clinical trial (ClinicalTrials. gov, NCT00467844) in patients with CACS, treatment with enobosarm significantly improved lean body mass, physical performance, and quality of life compared with baseline. Currently, two Phase III trials (ClinicalTrials.gov, NCT01355484 and NCT01355497) are recruiting patients with NSCLC to assess the effects of enobosarm on muscle wasting. Further, enobosarm has potential in the treatment of other forms of muscle loss, including chronic sarcopenia; a Phase IIb trial in patients with chronic sarcopenia, a Phase II trial in patients with COPD and selective muscle loss, and a Phase II trial in burns patients with muscle wasting have been planned by GTx, but have not as yet started recruiment.9

Myostatin inhibitors

Myostatin and activin are members of the transforming growth factor-beta (TGF-β) superfamily, and signal via the activin type IIB (ActRIIB) receptor to regulate skeletal muscle mass and function in a negative manner. They achieve this by several mechanisms, including inhibiting myogenesis and the Akt/mTOR pathway involved in muscle protein synthesis and increasing the expression of ubiquitin ligases to increase muscle proteolysis. Much research has focused on the therapeutic potential of inhibiting myostatin and more recently on treating CACS by inhibiting the ActRIIB receptor. PF-354 (Pfizer Global Research and Development, Groton, CT, USA), an inhibitory myostatin antibody, prevented muscle wasting and weakness in tumor-bearing mice,35 but the increases in muscle mass were not as great as those achieved using an ActRIIB decoy receptor (sActRIIB), indicating that greater hypertrophic effects could be achieved by simultaneous inhibition of multiple TGF-β ligands.47 Workers at Amgen Research (Thousand Oaks, CA, USA) showed that administration of sActRIIB not only prevented muscle wasting, but completely reversed prior weight loss and prolonged survival in C-26 tumor-bearing mice.47 A Phase II trial investigating whether AMG 745 (Amgen Research) can attenuate age-related muscle wasting was terminated prior to patient enrollment, and it is unknown whether Amgen Research will continue developing this compound.

The ActRIIB decoy, ACE-031, is being developed by Acceleron Pharma Inc (Cambridge, MA, USA) and was shown to be well tolerated and to increase lean mass in healthy postmenopausal women. Further development of ACE-031 is planned.

BYM338, a human antibody acting as a myostatin inhibitor, is being developed by Novartis Pharmaceuticals (Hanover, NJ, USA) to treat CACS. In August 2011, a multicenter, randomized double-blind placebo-controlled Phase II trial was initiated to investigate whether BYM338 can attenuate the loss of body mass in cachectic patients with stage IV NSCLC or stage III/IV pancreatic cancer. The estimated enrolment is 50 patients. The primary outcome is an increase in thigh muscle volume, and trial completion is expected in May 2013. The exact targets of BYM338 are not currently known (see Table 2).

LY2495655 is another antimyostatin monoclonal antibody. A multi center, randomized, double-blind, placebocontrolled Phase II trial in patients with locally advanced or meta static pancreatic cancer will investigate two different doses of LY2495655 in combination with gemcitabine.48 Overall survival is the primary outcome of this study, with secondary endpoints including muscle mass and physical performance.

β-adrenoceptor agonists

The hypertrophic effects of β2-adrenoceptor agonists, such as formoterol, in cachectic tumor-bearing rodents are well established.49 APD209 (Acacia Pharma Ltd, Harston Mill, UK) is an oral fixed-dose combination of formoterol and megestrol, and a Phase IIa study investigating the effects of eight weeks of treatment in 13 patients with CACS was recently completed. Six of the seven patients who completed the study demonstrated improved muscle size and strength, and three patients had increased levels of daily physical activity. Few patients reported side effects, such as muscle tremor or tachycardia. Acacia Pharma is currently planning larger randomized studies of this agent.

MT-102 (PsiOxus Therapeutics Ltd, Billericay, UK) is an anabolic/catabolic transforming agent with properties including nonspecific β1-adrenergic and β2-adrenergic receptor antagonism, intrinsic sympathomimetic activity, and 5-HT1a receptor antagonism. MT-102 increased food intake, body mass, fat and lean muscle mass, physical activity levels, and survival time in cachectic tumor-bearing rats.50 A multicenter, randomized, double-blind Phase II trial was initiated in April 2011 to investigate whether up to 16 weeks of treatment with MT-102 would improve the rate of change in body mass compared with placebo in at least 132 patients with stage III and IV NSCLC or colorectal cancer and CACS.51 The estimated study completion date was August 2012, and enrolled patients who completed the 16-week treatment period and still taking randomized, double-blind trial medication were offered the opportunity to join in a subsequent trial with a separate primary endpoint.

Investigational new drugs registered at ClinTrials.gov

The investigational new drugs registered at ClinicalTrials.gov for the treatment of CACS are shown in Table 2.

Multimodal therapy

To date, studies on CACS therapy using various single interventions have had limited success. The main features of cachexia, ie, progressive loss of muscle mass and function, are minimally influenced by the nutritional and pharmacological tools currently available. The lack of efficacy of monotherapy is due to the multifactorial pathogenesis of cachexia. Therefore, a combination of dietary, nutritional, and pharmacological approaches targeting the main factors contributing to cachexia may be able to normalize the metabolic milieu and thus reverse cachexia-related symptoms that impact quality of life for patients.18 Several studies in the last decade have investigated the combination of megestrol acetate with other drugs.

The combination of megestrol acetate with tetrahydrocannabinol52 and with eicosapentaenoic acid53 did not provide any benefits compared with use of megestrol acetate alone. However, megestrol acetate with ibuprofen was more effective than either drug used alone.54

An interesting pilot study performed by Cerchietti et al55 demonstrated the efficacy of a combined approach in a homogeneous group of 15 patients with lung adenocarcinoma and evidence of systemic immune metabolic syndrome, which was defined by the authors as a distressing systemic syndrome characterized by weight loss, anorexia, fatigue, performance status ≤2, and an acute-phase protein response. The multitargeted approach consisted of MPA 500 mg twice daily and celecoxib 200 mg twice daily as well as oral food supplementation for six weeks. This combined treatment significantly improved the rate of change in body weight, nausea, early satiety, fatigue, appetite, and performance status. In a subsequent study, the same authors56 randomized 22 patients with advanced lung cancer and systemic immune metabolic syndrome to receive either fish oil 2 g three times daily plus placebo or fish oil 2 g times daily plus celecoxib 200 mg twice daily. All patients in both groups received oral food supplementation. After six weeks of treatment, patients in both arms showed a significantly increased appetite, improvement in fatigue, and lower C-reactive protein levels compared with baseline. Patients in the celecoxib group showed improved body weight and muscle strength compared with baseline and a significantly lower C-reactive protein level and greater muscle strength and body weight than patients who received placebo.

Lundholm et al57 assessed whether a combined approach, including daily insulin plus anti-inflammatory treatment (indomethacin), rHuEPO, and specialized nutritional care (oral supplements plus home parenteral nutrition), attenuated the progression of cancer-related cachexia and improved metabolism and physical functioning in 138 unselected patients with advanced gastrointestinal cancer. The combined treatment significantly stimulated carbohydrate intake, decreased serum-free fatty acids, and increased whole body fat, whereas fat free lean tissue mass was unaffected. Moreover, the combined treatment improved metabolic efficiency during exercise, but did not increase maximum capacity during exertion and spontaneous physical activity.

The safety and efficacy of a combined approach was also tested by Mantovani et al in controlled clinical studies of cachectic patients with advanced tumors at different anatomical sites. First, a Phase II study,58 carried out according to a Simon’s two-stage design in a population of 39 patients with advanced cancer and CACS, showed that a combined approach, which included antioxidants + L-carnitine + eicosapentaenoic acid supplementation + celecoxib + MPA, was both safe and effective in increasing body weight and lean body mass, decreasing proinflammatory cytokines, improving quality of life parameters, and ameliorating symptoms of fatigue.

On the basis of these positive results, Mantovani et al carried out a randomized Phase III trial in 332 patients with CACS to establish the most effective and safest treatment for CACS with regard to the primary endpoints of increased lean body mass, decreased resting energy expenditure, and improvement of fatigue, and included several significant secondary endpoints, ie, improvement in appetite, improvement in quality of life, increase in grip strength, decrease in Glasgow Prognostic Score, and decrease in proinflammatory cytokine levels.59 All patients were given basic treatment with polyphenols plus antioxidant agents, ie, α-lipoic acid carbocysteine, and vitamins A, C, and E, all orally administered. The patients were then randomly assigned to one of five treatment arms: arm 1, MPA 500 mg/day or megestrol acetate 320 mg/day; arm 2, oral supplementation with eicosapentaenoic acid; arm 3, L-carnitine 4 g/day; arm 4, thalidomide 200 mg/day; or arm 5, a combination of the above. The treatment duration was four months. Analysis of variance showed a significant difference between the treatment arms, and post hoc analysis showed the superiority of the combination arm (arm 5) over the others for all primary endpoints.

Subsequently, Mantovani et al60 carried out a randomized Phase III study to assess the efficacy of a combination including carnitine and celecoxib ± megestrol acetate for the treatment of CACS. Analysis of changes from baseline showed that lean body mass as well as physical performance increased significantly in both arms. No significant difference was found between the treatment arms, and treatment was well tolerated. These results suggest that this two-drug combination may be a feasible, effective, and safe approach for CACS in clinical practice.

Macciò et al61 performed a randomized Phase III study in a large selected population of patients with advanced gynecological cancer to assess the safety and efficacy of a multitargeted approach including megestrol acetate, celecoxib, antioxidants (carboxycysteine and lipoic acid), and L-carnitine versus megestrol acetate alone as standard treatment for CACS. These drugs were selected on the basis of monotherapy studies published by Mantovani et al for their ability to target the inflammation, oxidative stress, and metabolic impairment, which are mainly involved in the pathogenesis of symptoms and impaired quality of life in patients with CACS.13,14,34,62 The combination treatment arm was found to be more effective than megestrol acetate alone in improving lean body mass, resting energy expenditure, fatigue, and global quality of life. Moreover, serum markers of inflammation (IL-6 and C-reactive protein) and oxidative stress decreased significantly in the combination arm, but did not change in the arm receiving megestrol acetate alone. Of note in this study, the gain in lean body mass and global improvement in quality of life and subjective symptoms, such as fatigue, which were observed in the combination therapy arm, were associated with a decrease in the inflammation-based Glasgow Prognostic Score. Therefore, the efficacy of the combined treatment in terms of modulation of the inflammatory response associated with improvement in the primary endpoints confirms our hypothesis that the main symptoms of CACS in patients with advanced cancer are driven by systemic inflammation. Moreover, the efficacy of the combination treatment was associated with a significant increase in leptin levels, which may reflect amelioration of metabolic and energy efficiency, as characterized by a reduced resting energy expenditure and an attenuated inflammatory response. These results suggest that monitoring of leptin levels during treatment for CACS can be a useful and relevant parameter of metabolic response.

A multitargeted approach to CACS should be undertaken within the context of the “best supportive care”, which includes optimal management of symptoms and careful psychosocial counseling.

Conclusion

Although various treatments for CACS have been tested, from the results presented here, we can speculate that a single therapy may not be completely successful. Most trials with synthetic progestagens, although currently the only drugs approved for treatment of CACS in Europe, have not been shown to improve lean body mass and functional activity, nor have they been shown to improve global quality of life. Further, their significant adverse effects should be taken into account. Among the effective agents, corticosteroids may be useful for their rapid beneficial effects on mood and sense of well-being. However, because of their side effects, short-term and/or alternating administration is recommended. Among the drugs with confirmed clinical efficacy, COX-2 inhibitors and anabolic agents, such as oxandrolone, are well placed to achieve good results. Investigational drugs with potential clinical effectiveness yet to be demonstrated include ghrelin and ghrelin mimetics, SARMs, and drugs targeting inflammatory cytokines, such as OHR/AVR 118 and other anti IL-6 antibodies. Other drugs under investigation include the myostatin inhibitors and β-adrenoceptor agonists, such APD209 and MT-102.

Considering the complex clinical picture and multifactorial pathogenesis of CACS, we believe that the clinical management of this condition requires a multidisciplinary and multitargeted approach. The recent randomized Phase III clinical trial of five different treatments59 should be considered as a template for future approaches. The clearly defined and appropriate endpoints used in that study should also be a reference for future trials, with primary endpoints including lean body mass, resting energy expenditure and fatigue, and secondary endpoints including muscle strength, anorexia, physical activity levels, quality of life, survival, and levels of proinflammatory cytokines.35

Finally, considering that cachexia is a progressive disease starting with precachexia, moving through different stages into overt clinical cachexia, and finally to advanced or refractory cachexia, and that not all patients will progress through the complete spectrum, it is critical to test therapies at the earliest stages of cachexia, possibly at the precachexia stage, with the aim of preventing or delaying the development of overt cachexia, to obtain the best possible clinical outcome for patients.