Current pharmacotherapy options for cancer anorexia and cachexia

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1 See discussions, stats, and author profiles for this publication at: Current pharmacotherapy options for cancer anorexia and cachexia Article in Expert Opinion on Pharmacotherapy October 2012 DOI: / Source: PubMed CITATIONS 15 READS authors, including: Antonio Macciò Azienda Ospedaliera Brotzu 149 PUBLICATIONS 2,963 CITATIONS Giovanni Mantovani Università degli studi di Cagliari 89 PUBLICATIONS 3,729 CITATIONS SEE PROFILE SEE PROFILE Available from: Clelia Madeddu Retrieved on: 18 September 2016

2 Review Current pharmacotherapy options for cancer anorexia and cachexia 1. Introduction 2. Treatment of anorexia/ cachexia syndrome 3. Conclusion 4. Expert opinion Antonio Macciò, Clelia Madeddu & Giovanni Mantovani Sirai Hospital, Department of Obstetrics and Gynecology, Carbonia, Italy Introduction: Anorexia and cachexia syndrome represents a complex clinical picture that occurs in the late stage of several chronic inflammatory diseases, including cancer. Unless counteracted cancer-related anorexia and cachexia syndrome affects quality of life (QL) and survival. However, to date a standard effective treatment is lacking. Areas covered: The aim of this review is to describe the current pharmacological approaches for anorexia and cachexia syndrome, focusing on cancer-related syndrome. The several pharmacological agents tested so far are discussed, distinguishing them in unproven drugs, effective drugs, and drugs under investigation. Moreover, a section is devoted to the promising use of nutritional supplements and nutraceuticals. The emerging role of a multitargeted combined treatment approach is exhaustively reviewed. Expert opinion: Considering the complex clinical picture and the multifactorial pathogenesis of anorexia and cachexia syndrome, we believe that its clinical management requires a multidisciplinary and multipharmacological approach. In our opinion the anorexia and cachexia syndrome treatment should include drugs that target the following conditions: inflammatory status, oxidative stress, nutritional disorders, muscle catabolism, anemia, immunosuppression, and fatigue. The multidimensional therapies for anorexia and cachexia syndrome should ideally be introduced within a context of the best supportive care, which includes optimal symptom management and careful psychosocial counseling. Keywords: anorexia, antioxidants, cachexia, cancer, carnitine, fatigue, multimodal treatment, progestagens, proinflammatory cytokines, quality of life. Expert Opin. Pharmacother. [Early Online] 1. Introduction The anorexia and cachexia syndrome is a debilitating clinical condition characterizing the course of several chronic diseases, including chronic heart failure, chronic obstructive pulmonary disease, chronic kidney disease, and especially cancer. In the course of its evolution, cancer induces changes in the host immune system and energy metabolism that affect patient clinical conditions so deeply that, in some cases, 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). Immunodepression. Anemia. Fatigue / Informa UK, Ltd. ISSN All rights reserved: reproduction in whole or in part not permitted

3 A. Macciò & C. Madeddu Article highlights.. Anorexia and cachexia syndrome represents a complex clinical syndrome that occurs in the late stage of several chronic inflammatory diseases, including cancer.. No standard effective treatment of cancer-related anorexia and cachexia syndrome is yet available.. Synthetic progestagens are currently the only approved drugs for cancer-related cachexia in Europe; however, their efficacy is limited.. Considering the complex clinical picture and the multifactorial pathogenesis of anorexia and cachexia syndrome, a multidisciplinary and multipharmacological approach seem to be the most effective.. The multidimensional therapies for anorexia and cachexia syndrome should ideally be introduced within a context of the best supportive care, which includes optimal symptom management and careful psychosocial counseling. This box summarizes key points contained in the article. All these symptoms ultimately result in the clinical picture of anorexia and cachexia syndrome, which, unless counteracted, has a negative impact on patient quality of life (QL) [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 pathogenesis of cachexia is common at least in part in the different diseases, and it constitutes the main background on which the symptoms of cachexia are based. In this review we will focus on cancer-related anorexia and cachexia syndrome, which mechanisms can be translated also to other chronic illnesses. To date, it is clearly demonstrated that proinflammatory cytokines, including interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-a, which are produced both by the activated immune system and by tumor cells, are implicated in the pathogenesis of cancer-related anorexia and cachexia syndrome and associated metabolic changes [4]. It may be hypothesized that during the initial phases of neoplastic disease, the synthesis of proinflammatory cytokines may lead to an efficient antineoplastic effect. However, the inability of the immune system to definitively counteract tumor growth results in chronic cytokine activity with deleterious effects on cell metabolism, body composition, nutritional status, and immune system efficiency [5]. In turn, proinflammatory cytokines promote the synthesis of the acute phase proteins, which contribute to the pathogenesis of altered energy metabolism [6]. Proinflammatory cytokines, alongside 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, through the activation of the ubiquitin-proteasome proteolytic pathway [8]. Then, a major clinical feature of anorexia and cachexia syndrome is represented by the loss of muscle mass, which leads to fatigue, impairment of normal activities, and eventually death through respiratory failure [9]. Such muscle wasting is the result of multiple alterations both at the molecular and metabolic level, which lead to a disturbance in the balance between protein degradation and protein synthesis; this muscle mass loss is mainly related to the enhanced use of muscle proteins as energy fuel to supply the increased energy needs of cachectic patients. Anorexia, which is also induced by the action of the proinflammatory cytokines [10,11], is very often associated with anorexia and cachexia syndrome, leading to a reduced food intake. However, anorexia alone cannot account for the complex alterations that are seen in 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 at advanced disease stages exhibit a severe impairment of immune functions, which are characterized by a cell-mediated immunity deficit, elevated serum levels of proinflammatory cytokines, and inflammation acute phase proteins (fibrinogen and C-reactive protein [CRP]), is very important [13] and defines the status of chronic inflammation typical of anorexia and cachexia syndrome [14]. The exact moment when such changes occur has been difficult to establish; however, these are most likely due to the interaction between the tumor and the host. It has been well demonstrated that the presence of the tumor and its continuous growth are responsible for the increased energy expenditure and for the progressive weight loss [15]. Moreover, tumor growth is accompanied by the chronic activation of the immune system, as it mounts a response to counteract the tumor. This immune response is also energetically costly ( % of the basal metabolic rate, that is, 1, ,080 kj/day) [16]. Then, the resulting metabolic scenario consists of two systems that require a continuous supply of energy substrates, particularly glucose. In fact, glucose oxidation to CO 2 and H 2 O is the main energy source, which is produced as ATP, NADH, and FADH. An additional amount of glucose is involved in the synthesis of compounds with high reducing power, such as NADPH and reduced glutathione (GSH), through the phosphate pentose pathway. These reducing detoxificants are essential for the neutralization of reactive oxygen species (ROS), which are produced during the various steps of energy metabolism and by activated immune cells [17]. ROS are useful but potentially toxic compounds; they are characterized by the presence of an unpaired electron in the farthest external orbital, which makes these molecules particularly unstable (hydrogen peroxide, H 2 O 2 ; superoxide anion, O 2 -- ; hydroxyl radical, OH ). Therefore, the body must have a number of control mechanisms that limit ROS activity once these have been used for the scheduled objective [18]. In fact, ROS that have not been detoxified, exert both: an oxidative damage on DNA, membrane lipoproteins, enzymes, and coenzymes, which are involved in the regulation of the main cell catabolic pathways; and a key role in the etiopathogenesis of immunodepression [19,20] and anemia [21] in patients suffering of anorexia and cachexia syndrome. In advanced cancer patients symptoms, such as anorexia, nausea, and vomiting, inhibit normal nutritional intake and the regular supply of glucose, 2 Expert Opin. Pharmacother. [Early Online]

4 Current pharmacotherapy options for cancer anorexia and cachexia lipids, proteins, and antioxidant vitamins. Furthermore, proinflammatory cytokine induces metabolic alterations that impair the normal utilization of glucose as principal source of energy and antioxidant compounds [1,22]. All these events determine a metabolic condition known as oxidative stress. Then, oxidative stress, defined as an imbalance between the oxidant and antioxidant systems in favor of the oxidants, may be considered the direct evidence of the metabolic impairment that is associated with anorexia and cachexia syndrome as a consequence of i) increased production of ROS, due to energy hypermetabolism and increased activation of the immune system, and ii) associated inadequacy of detoxification systems. The finding that in advanced cancer patients high serum concentrations of cytokines and inflammatory proteins are associated with oxidative stress, characterized by high levels of ROS and low levels of the antioxidant enzymes glutathione peroxidase (GPx) and superoxide dismutase (SOD), is therefore of high relevance in the etiopathogenesis of anorexia and cachexia syndrome and its related symptoms [23]. In several studies we have demonstrated that, in advanced cancer patients, the inflammatory response is inversely related to leptin, a marker of nutritional status, which is a central mediator connecting energy metabolism and immunity [24-26]. Recently, the strong relationship between inflammation and energy metabolism changes was assessed by us in a population of 104 ovarian cancer patients at different disease stages who were enrolled upon their diagnosis before surgical or medical antineoplastic treatment [26]. In this study, the leptin levels were significantly lower in advanced cancer patients compared with the controls and early stage patients and were inversely correlated with weight, body mass index, disease stage, performance status, and the serum levels of inflammatory and oxidative stress markers. In particular, we demonstrated that IL-6, and disease stage, were independent predictive factors of leptin levels according to a multivariate regression analysis. In our several studies on cachectic patients with tumors at different sites, we consistently observed a similar correlation between leptin and the changes in the specific parameters of energy metabolism as well as in circulating levels of inflammatory and oxidative stress markers [21,23,24]. Moreover, all these studies clearly demonstrated that the deregulation of energy metabolism, with low leptin levels, and the symptoms that occur during cancer disease progression are dependent on systemic inflammation [14,27,28]. In light of these results, we may hypothesize that in advanced cancer patients the reduced leptin production functions as a signal of increased energy expenditure and low energy reserves during the progression of the neoplastic disease [29]. Thus, in cachectic cancer patients, tumor growth and immune system activation determine an overall metabolic picture that has the following characteristics [30]:. Increased glucose, lipid, and protein requirements.. Difficulty in introducing these substances with food because of anorexia, nausea, and vomiting.. Gluconeogenesis with a depletion of protein and lipid stores, which results in weight loss.. Hypoinsulinemia and/or peripheral resistance to insulin, which results in the inability to use newly formed glucose.. Loss of muscle mass.. Oxidative damage that is induced by ROS on DNA, membrane lipoproteins, enzymes, and coenzymes, which have a major role in the regulation of the main cell catabolic pathways. From the above-discussed evidence, it is intuitive that the clinical management of anorexia and cachexia syndrome is complex and requires a multidisciplinary and multipharmacological approach [31,32]. An appropriate treatment of anorexia and cachexia syndrome should include drugs that treat the following conditions (when possible): i) the inflammatory state, ii) the status of oxidative stress, iii) the nutritional disorder, iv) anemia, v) immunosuppression, and vi) fatigue. Accordingly, the treatment against anorexia and cachexia syndrome should include as primary endpoints the following parameters, which were recently identified as the defining variables of cachexia [33]: lean body mass (LBM), resting energy expenditure (REE), fatigue, and QL. Moreover, the impact of treatment on the main metabolic and inflammatory parameters that is associated with the clinical course of the disease, such as CRP, IL-6, TNF-a, leptin, ROS, GPx, and SOD, should be evaluated and will help to plan the appropriate care for cancer patients and the best supportive therapy. In fact, only the exact knowledge of the pathogenetic mechanisms of anorexia and cachexia syndrome may allow to identify the most appropriate drugs to counteract the associated symptoms. All these parameters should be assessed in the context of a psychosocial support program. Patients are becoming increasingly aware of QL issues, and physicians need to find the right balance between clinical management and patient well-being. In particular, in advanced cancer patients when recovery is not an achievable aim and survival is limited, maintaining an adequate patient QL is challenging and specific assessments should be proposed. Accordingly to this perspective, the overall care of cancer patients and their physical, psychological, and social needs should be evaluated. The concept that cancer is a disease that only affects organs should be replaced by a novel concept in which cancer is defined as a multidimensional endocrine, metabolic, immunologic systemic disease. These findings have been recently recommended by the European Guidelines for the management of cancer-related anorexia and cachexia syndrome [34], which state that The treatment approach should be multimodal. This includes detailed assessment and repeated monitoring, vigorous nutritional support, anti-inflammatory treatment, treatment of secondary gastrointestinal symptoms and other causes for decreased oral nutritional intake as well as evaluation of anti-neoplastic options to reduce the catabolic drive of the cancer. Moreover, an optimal communication, Expert Opin. Pharmacother. [Early Online] 3

5 A. Macciò & C. Madeddu awareness of patients emotional, social and spiritual needs and physical and psycho-social support are recommended. 2. Treatment of anorexia/cachexia syndrome The aim of this review is to describe the current pharmacological approaches for anorexia and cachexia syndrome, which are based on the knowledge of the etiopathogenesis of this complex syndrome. However, the management of anorexia and cachexia syndrome is challenging, and continuous changes can be expected. The PubMed/Medline database was searched to identify the several nutritional and pharmacological approaches tested for the treatment of cachexia, particularly focusing in cancer-related anorexia and cachexia syndrome. 2.1 Unproven or ineffective treatments Malnutrition is considered to be one of the main symptoms of anorexia and cachexia syndrome, which is associated with a loss of appetite and/or decreased food intake. For these reasons, historically, enteral or parenteral nutrition has been hypothesized to circumvent cancer-related cachexia. However, nutritional therapy alone cannot prevent/revert the clinical picture of cachexia, and this finding has been repeatedly demonstrated over several decades [35]. The guidelines on enteral nutrition by the European Society of Clinical Nutrition and Metabolism (ESPEN) [36] state that patients who lose weight due to insufficient nutritional intake should be provided with enteral nutrition to improve or maintain their nutritional status. The guidelines emphasize that in the presence of systemic inflammation regaining lost body cell mass with enteral nutrition alone is extremely difficult. In clinical practice, enteral nutrition should be provided when the patient cannot eat for more than 7 days or cannot maintain an adequate oral intake of food (at least 60% of the estimated energy expenditure) for more than 10 days [36]. Parenteral nutrition is addressed to patients in whom gastrointestinal function is partially or totally impaired. Parenteral nutrition is indicated for the prevention and/or treatment of malnutrition in hypo-aphagic advanced cancer patients with intestinal failure due to disease or antineoplastic treatments. ESPEN guidelines strongly recommend that parenteral nutrition should not be given to cancer patients when these patients do not indicate a decreased ability to eat [37]. Moreover, parenteral nutrition must be recommended only for patients who have a prognosis with more than 2 months of survival from the cancer but less expected survival due to malnutrition [38,39]. To date, the efficacy of enteral and parenteral nutritional support for the treatment of anorexia and cachexia syndrome has not been demonstrated and the systematic prospective studies have generally been disappointing. However, in combination with other modalities, such as synthetic progestagens, anti-inflammatory treatments or therapies that are targeted against metabolic changes, nutritional support could have a positive effect. Moreover, parenteral nutrition is associated with a number of complications including infections, central venous access complications, volume/electrolyte, and glucose imbalances [40,41]. Therefore, enteral and parenteral nutrition should be used selectively and with caution [42] in well-defined settings of patients and only after a careful evaluation of the patient and family expectations to prevent the administration of an inappropriate or life-threatening medical treatment Cyproheptadine Because anorexia and cachexia syndrome is associated with increased serotoninergic activity, a serotoninergic blockade may be beneficial in reducing symptoms. Cyproheptadine is a histamine antagonist with antiserotonergic properties and an appetite-stimulating effect. However, cyproheptadine induced only a small improvement in appetite without a significant effect on body weight in a placebo-controlled clinical trial [43] Prokinetics Many patients with cancer-related anorexia and cachexia syndrome have the symptoms of delayed gastric emptying, which increase the incidence of early satiety and negatively influence food intake: therefore, prokinetic agents can be useful as adjuvant drugs in the treatment of cachexia [44]. Metoclopramide was effective in the treatment of nausea and early satiety in cachectic cancer patients [45]; however, this drug cannot induce an increase of food intake. Furthermore, the extrapyramidal side effects of this drug have strongly limited its use [46] Pentoxifylline Because proinflammatory cytokines have a prominent role in the pathogenesis of anorexia and cachexia syndrome, pentoxifylline, which is an inhibitor of TNF-a, has been used as a rational therapeutic intervention in cachexia. Preliminary studies with pentoxifylline have not demonstrated efficacy in reversing weight loss despite evidence of TNF-a inhibition [47,48]. Furthermore, a double-blind, placebo-controlled trial of pentoxifylline therapy in patients with cancer-related cachexia did not indicate a beneficial effect on appetite or body weight [49]. 2.2 Current effective pharmacological approaches Progestagens Progestagens were the first agents used and are currently the first-line agents approved for the treatment of cancer-related anorexia and cachexia syndrome. An extensive amount of literature is available on megestrol acetate (MA) and medroxyprogesterone acetate (MPA) for the treatment of patients with cancer [50]. Both drugs are synthetic progestagens that were first used to treat hormone-sensitive tumors. Because of the observed body weight gain and appetite stimulation that were independent of the tumor response in a number of patients who received such therapy, several trials have studied 4 Expert Opin. Pharmacother. [Early Online]

6 Current pharmacotherapy options for cancer anorexia and cachexia the use of progestagens for the management of anorexia and cachexia syndrome over the last two decades. Appetite is a complex function that results from the contribution of peripheral and central nervous afferents in the ventral hypothalamus, which involves several mediators, such as adipokines, cytokines, and central neurotransmitters. Therefore, progestagens seem to be appropriate modulators of these pathways. The mechanism of action of progestagens in anorexia and cachexia syndrome may be related to glucocorticoid activity, which would make these drugs similar to corticosteroids. There is evidence that progestagens may stimulate appetite through the neuropeptide Y in the central nervous system (ventromedial hypothalamus) [51]. Furthermore, they downregulate the synthesis and release of proinflammatory cytokines, which has been demonstrated in several experimental and clinical studies, including two of our studies [52,53]. In the first study [52], the effect of MA was evaluated to determine the ability of the drug to increase appetite and body weight in cachectic patients with advancedstage head and neck cancer who were treated with cisplatinbased neoadjuvant chemotherapy. MA was administered at a dosage ranging from 160 to 320 mg/day based on the clinical response, during the interval between chemotherapy cycles for a total of three consecutive cycles. The clinical parameters that were evaluated before and after MA treatment included the objective response to chemotherapy, body weight, appetite, performance status, and QL. The serum levels and the in vitro production of IL-1a, IL-1b, IL-2, IL-6, TNF-a, and sil-2r were determined in the patients before and after MA treatment and were compared with those of healthy individuals. All of the parameters improved following MA treatment, excluding the performance status. The serum levels of all of the cytokines and IL-6 production in vitro decreased after MA treatment. Our results strongly supported the hypothesis that the beneficial therapeutic effects of MA in patients with cancer-related cachexia may be due in part to the ability of the drug to downregulate the synthesis and release of the main cytokines that are involved in anorexia and cachexia syndrome. These data have been confirmed in vitro [53] using the synthetic progestagen MPA at doses that are pharmacologically active in vivo (0.1, 0.2, and 0.4 mg/l). In fact, the concentration of MPA that was used in this study was within the range of the plasma values that were observed in patients who received oral MPA 1,500/2,000 mg/day. MPA significantly decreased the in vitro production and/or release of cytokines (IL-1, IL-6, and TNF-a) and serotonin (5-hydroxytryptamine) in patients with advanced-stage cancer. MA and MPA are equivalent in terms of effectiveness in the treatment of anorexia and cachexia syndrome with no differences between the drugs. However, MA has been the most widely studied drug for its effect on cachexia [54] compared with MPA [50]. Berenstein and Ortiz [55] conducted a literature review to evaluate the efficacy and safety of MA in palliating cachexia in patients with cancer, AIDS, and other underlying pathologies. The meta-analysis revealed a benefit of MA compared with placebo, particularly regarding appetite improvement and weight gain in cancer patients. After analyzing the QL data, clinical and statistical heterogeneity was found; therefore, no overall conclusion about the QL could be made. However, this finding was expected because an improvement in the QL in such a complex syndrome could not be obtained by using only one drug. Comprehensively, progestagens alone are effective with respect to a body weight increase (mainly water and fat mass) and an improvement in cenesthesis but are not effective at increasing LBM, which is a critical target in the treatment of cancer-related anorexia and cachexia syndrome. The positive effects of MA on weight and well-being have been observed at oral dosages that ranged from 160 to 1,600 mg/day. However, because MA use is associated with possible severe dose-related adverse effects, starting treatment at a low dosage (160 mg/day) and regulating the dose upward according to the clinical response is recommended [56]. MPA was used at dosages that ranged from 300 to 4,000 mg/day. In the placebo-controlled study by Simons et al. [57] a significant improvement in appetite and body weight was obtained using a dose of oral MPA ,000 mg/day. Moreover, a systematic review that evaluated MPA for the treatment of anorexia and cachexia syndrome found that there were no significant differences between the high and low dosages [55]. Therefore, an MPA dosage of ,000 mg/day orally can be recommended for clinical practice. Both MA and MPA may induce adverse effects, including an increased risk of thromboembolic events, peripheral edema, breakthrough bleeding, hyperglycemia, hypertension, and Cushing s syndrome. Increased mortality in elderly cachectic patients on progestagen treatment has been reported [58], which resulted from thromboembolic events [59]. Therefore, because cachexia itself is burdened by cytokineinduced thromboembolism, we strongly recommend the concomitant use of low-molecular-weight heparin s.c., which should be included in the pool of drugs that are used to treat the cachectic patient. Because the bioavailability of MA directly affects the efficacy and safety of this drug, the formulation was refined to enhance its pharmacokinetics. Such efforts recently yielded an oral suspension form that was developed using nanocrystal technology. Preclinical pharmacokinetic data suggest that, by rapidly increasing plasma MA concentrations, the MA nanocrystal oral suspension could produce a more rapid clinical response [60]. The FDA approved the oral suspension for the treatment of AIDS-related anorexia and cachexia syndrome, and this drug is currently under evaluation for approval to treat cancer-related cachexia Corticosteroids Several randomized, placebo-controlled studies demonstrated that corticosteroids induced a limited (up to a month) improvement of appetite, food intake, nausea, and the Expert Opin. Pharmacother. [Early Online] 5

7 A. Macciò & C. Madeddu sensation of well-being. However, none of these studies revealed an increase in body weight [61-65]. Anyway, the rapid beneficial effect of corticosteroids on mood and the desire to be active significantly improve patient QL. The mechanism of action of corticosteroids in anorexia and cachexia syndrome is not well understood, although the inhibition of prostaglandin activity and the suppression of IL-1 and TNF-a production are the most well-recognized targets [56]. The type, dosage, and route of administration of corticosteroids are not established; however, low dosages, less than 1 mg/ kg of prednisone equivalent, are recommended for clinical practice. Furthermore, because of the wide range of wellknown adverse effects, their short-term or alternate use may be recommended in the management of anorexia and cachexia syndrome Anabolic agents Anabolic agents can improve body composition by maintaining or improving LBM. These agents include growth hormone (GH), insulin-like growth factor (IGF)-1, testosterone, dihydrotestosterone, and testosterone analogues. Insulin, GH, and IGF-1 are involved in glucose, protein, and fat metabolism, which regulate body composition. In ACS their signaling is impaired and causes an anabolic/ catabolic imbalance. Therefore, anabolic agents are a potential target for pharmacological treatment in the setting of patient with anorexia and cachexia syndrome [66]. Strong positive effects on nitrogen balance and protein mass have been demonstrated with GH in different clinical situations, including advanced cancer patients [67]. Safety concerns arise when GH is used for cachexia treatment because increased mortality has been associated with its administration in critically ill patients [68]. Similarly, insulin treatment is limited because insulin resistance is often present in cachectic patients. To avoid these complications, targeting the post-receptor pathways could be effective. Indeed, insulin, GH, and IGF-1 receptors are tyrosine kinases, sharing the PI3K/Akt and MAPK pathway, which could be considered a pharmacological target in a multidrug treatment of cachexia. 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 HIV/AIDS in which positive effects on body weight, LBM, and several functional parameters have been documented. However, few studies have been conducted to date in patients with cancerrelated anorexia and cachexia syndrome. Recently, a prospective, randomized, Phase III trial compared the effects of oxandrolone (10 mg bid) and MA (800 mg qd) on weight, body composition, and QL in 155 adult patients with solid tumors and weight loss, who were receiving chemotherapy. The study demonstrated that patients who were treated with oxandrolone experienced an increase in LBM, a reduction in fat mass, and less self-reported anorectic symptoms [69]. The side effects of these agents include elevated transaminase concentrations (especially with nandrolone); decreased highdensity lipoprotein concentrations; an interaction with oral anticoagulants, oral hypoglycemic, and adrenal steroids; and hypogonadism (manifested by decreased systemic testosterone concentrations). Oxandrolone is orally administered (approved dosing concentrations: mg/day) and has a better safety profile and less potential for hepatic toxicity and virilizing effects than other androgens. This drug is well tolerated in women [70]. 2.3 Drugs under investigation Nonsteroidal anti-inflammatory drugs Because the etiology of cancer-related anorexia and cachexia syndrome is linked to systemic inflammation, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) that are aimed at reducing chronic inflammation is a promising option. NSAIDs inhibit prostaglandin production by ratelimiting enzymes that are known as cyclooxygenases (COX). Ibuprofen, which is an inhibitor of the enzyme COX-1, was found to decrease CRP levels [71], produce body weight gain [72] and improve survival in patients with cancer. In a controlled trial, the combination of ibuprofen and MA led to an increase in body weight [73] associated with an amelioration of QL, whereas treatment with MA alone did not prevent weight loss. Lundholm et al. [74] performed a retrospective case control study that assessed the benefit of long-term indomethacin treatment in unselected weight-losing cancer patients. The elevated REE in the cancer group was reduced with long-term indomethacin treatment, while the LBM was not influenced by indomethacin. In a randomized controlled study the administration of indomethacin (50 mg twice daily) to a heterogeneous group of advanced cancer patients was associated with an improvement of performance status, pain, and survival [75]. A recently published systematic review [76] on the use of NSAIDs for the treatment of anorexia and cachexia syndrome in advanced cancer patients provided evidence of a positive therapeutic effect on QL, performance status, inflammatory markers, weight gain, and survival. However, there was insufficient evidence to support their widespread use in clinical practice COX-2 selective inhibitors The development of selective COX-2 inhibitors has resulted in a safer modulation of cancer-associated inflammation, and these inhibitors could help alleviate or control cancerrelated cachexia. Moreover, the selective COX-2 inhibitors have shown potent antitumor growth inhibitory and antitumor preventive effects in animal models; therefore, their antineoplastic action may contribute to their ability to counteract cachexia. In particular, the use of the selective COX-2 inhibitor celecoxib has been investigated. Lai et al. [77] randomized 11 cachectic patients with head and neck and gastrointestinal cancer to receive celecoxib 200 mg twice daily 6 Expert Opin. Pharmacother. [Early Online]

8 Current pharmacotherapy options for cancer anorexia and cachexia or a placebo for 3 weeks. The patients on celecoxib reported good compliance, and no adverse events were observed. Patients who received celecoxib exhibited a nonsignificant increase in body weight (a mean change of +1.0 kg compared with the mean change of -1.3 kg in the placebo group) and a significant increase in QL. A recent Phase II non-randomized prospective study investigated celecoxib at a dose of 300 mg per day for 4 months in 24 advanced cancer patients [78]. The results indicated a significant decrease in the levels of the proinflammatory cytokine TNF-a and a significant increase in LBM. In addition, significant improvements were observed in the QL, the performance status, the Glasgow prognostic score, and grip strength. The patients demonstrated good compliance and no severe toxicities. On the basis of these results, celecoxib can be also included as a component of combined treatment approach to target the inflammatory milieu of cancer-related anorexia and cachexia syndrome Anticytokine approaches As stated in the Introduction section, proinflammatory cytokines, particularly IL-6 and TNF-a, have a prominent role in the pathogenesis of cancer-related anorexia and cachexia syndrome. The specific neutralization of these factors by antibodies in animal models of cachexia suggests that an anticytokine approach warrants clinical investigation while taking into account that no single cytokine is responsible for all of the abnormalities that are found in anorexia and cachexia syndrome Thalidomide Thalidomide has complex immunomodulatory and antiinflammatory properties. This drug downregulates the production of TNF-a and other proinflammatory cytokines, inhibits the transcription factor nuclear factor (NF) kb, downregulates COX-2, and inhibits angiogenesis. Therefore, thalidomide is a novel and rational treatment approach for cancer-related anorexia and cachexia syndrome. In a randomized, placebo-controlled trial, thalidomide was found to be well tolerated and effective at attenuating the loss of weight, and improving arm muscle mass and physical function in 33 patients with cachexia due to advanced pancreatic cancer [79]. Recently, a meta-analysis was conducted to assess whether thalidomide is an effective treatment for cancerrelated anorexia and cachexia syndrome [80]. The review authors concluded that there is inadequate evidence to recommend the use of this drug for clinical practice. Additional well-conducted, large randomized controlled trials are needed to determine the true benefits of thalidomide both singularly and in combination Anti-TNF-a monoclonal antibody (mab) Based on the experimental data on the ability of an anti-tnf-a mab to neutralize the in vitro and in vivo biological effects of TNF-a and the data from animal studies, a Phase II multicenter, randomized, double-blind, placebocontrolled study [51] evaluated the efficacy and safety of the anti-tnf-a mab infliximab in addition to gemcitabine for the treatment of anorexia and cachexia syndrome in 90 advanced pancreatic cancer patients. The study results showed that the addition of infliximab was not associated with a statistically significant improvement in LBM, performance status, physical activity, or survival compared with placebo. Similarly, a randomized placebo-controlled trial found that etanercept administered at a dose of 25 mg subcutaneously twice a week for 24 weeks did not palliate the cancer-related anorexia and cachexia syndrome in patients with advanced cancer [81]. These disappointing results were recently confirmed in a placebo-controlled, double-blind trial of infliximab for cancer-associated weight loss in the elderly and in non-small cell lung cancer patients with a poor performance status, which demonstrated that infliximab did not prevent or palliate cancer-associated weight loss and was associated with increased fatigue and an inferior global QL [82] Anti-IL-6 monoclonal antibody The therapeutic impact of anti-il-6 mab therapy on anorexia and cachexia syndrome could be clinically beneficial to cancer patients; however, currently there have been no published randomized Phase III clinical trials that used this approach [83]. In preclinical and Phase I and II trials the mab ALD518, which targets IL-6, was well tolerated and ameliorated cancer-related anemia and cachexia [84] Cannabinoids (Dronabinol) The endocannabinoid system is a widespread intercellular signaling mechanism that plays a critical role in body homeostasis. This system is involved in food intake and energy expenditure and coordinates energy balance [85]. Therefore, the endocannabinoid system may be an interesting target for the management of diseases that are characterized by imbalanced energy homeostasis, such as anorexia and cachexia syndrome. The active ingredient of marijuana, dronabinol (Î-9-tetrahydrocannabinol, THC), has a positive effect on appetite, body weight, and chemotherapy-induced nausea [86]. A controlled trial compared dronabinol versus MA versus combination therapy in cancer patients with anorexia and cachexia syndrome. MA 800 mg/day was more effective in terms of anorexia palliation and weight gain compared with oral dronabinol 2.5 mg twice daily, whereas combination therapy did not confer an additional benefit [87]. Two open studies [88,89] demonstrated improvement in mood and appetite with no significant change in body weight. A randomized controlled trial in patients with AIDS demonstrated similar results [90]. The Cannabis-In-Cachexia-Study- Group compared cannabis extract (with the standardized content of THC and cannabidiol) with THC alone and with a placebo [91] in a large group of advanced cancer patients. Cannabis extract was well tolerated; however, there Expert Opin. Pharmacother. [Early Online] 7

9 A. Macciò & C. Madeddu were no differences in body weight change, appetite, or QL between the groups. Moreover, the significant adverse effects of this drug need to be taken into account. These effects include somnolence, mental confusion, and impairment of cognitive functions, which may worsen the mental status of cancer patients with cachexia who are receiving opioids or other psychoactive drugs. The European guidelines on the use of cannabinoids for anorexia and cachexia syndrome conclude that the lack of efficacy may have been related to the dose of THC; therefore, individual titration may be more efficient but has not been investigated in clinical trials Ghrelin mimetic Ghrelin is a 28-amino-acid peptide that is produced by the P/D1 cells of the stomach, which stimulates GH secretion (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 studies and short-term human trials, clinical studies to investigate the use of ghrelin and GHS-R agonists for the treatment of anorexia and cachexia syndrome that is caused by multiple underlying diseases seems to be promising. Synthetic human ghrelin has been demonstrated to improve muscle wasting and functional capacity in patients with cardiopulmonary-associated cachexia [92]. The single-dose intravenous administration of ghrelin to cancer patients with cachexia has not demonstrated univocal efficacy in increasing food intake. In a study that was conducted by Strasser et al. [93], a total of 21 adult cancer patients were randomized to receive ghrelin on days 1 and 8 and a placebo on days 4 and 11, or vice versa. The patients were given the following intravenous doses over a 60-min period before lunch: 10 patients received 2 mg kg -1 (lower-dose) ghrelin and 11 patients received 8 mg kg -1 (upper-dose) ghrelin. Nutritional intake and eating-related symptoms were not significantly different between the ghrelin and the placebo arms. Ghrelin was well tolerated and safe. The results on the safety, tolerance, and patient preference of treatment showed no differences between the lower- and upper-dose groups. It is worth of note that levels of acyl-ghrelin are 50% higher in cancer patients with cachexia when compared to those without cachexia and 80% higher than in non-cancer patients [94]. These elevated levels of ghrelin may impact the ability of ghrelin analogues to improve appetite in cachectic cancer patients. Neary et al. [95] performed an acute, randomized, placebocontrolled, crossover clinical trial to determine whether ghrelin (5 pmol/kg/min for 180 min i.c.) stimulates appetite in cancer patients with anorexia. A marked increase in energy intake was observed with a ghrelin infusion compared with a saline control, and all of the patients reported a food intake increase. The meal appreciation score increased by 28.8% with the ghrelin treatment. No side effects were observed. The prolonged administration of a GSH-receptor agonist has been tested by Garcia et al. [96] in a randomized, placebo-controlled trial in 81 patients with cancer at different sites (predominantly lung cancer). The GHS-R agonist (RC-1291, an orally active small molecule) was administered over a 12-week period: an improvement of total body mass and LBM was observed. More recently, Anamorelin, an oral mimetic of ghrelin, has been demonstrated to increase body weight and anabolic hormone levels in healthy volunteers. This drug was also investigated to treat anorexia and cachexia syndrome in a population of 16 patients with different cancers, and it significantly increased body weight and improved patient-reported symptoms, including appetite, compared with the placebo [97]. However, these studies were small Phase I and Phase II trials; therefore, their results should be considered with caution. Significant questions remain to be answered before ghrelin can be widely used, such as whether the safety and efficacy of the GHS-R agonists are maintained during longterm use in humans. Additional controlled randomized studies are warranted before the use of ghrelin can be translated into clinical practice. 2.4 Nutritional supplements/nutraceuticals Antioxidants As explained above, in the Introduction section, several mechanisms may lead to oxidative stress in cancer patients with anorexia and cachexia syndrome. First, the altered energy metabolism may account for symptoms, such as anorexia, nausea, and vomiting, that inhibit the normal supply of nutrients, such as glucose, proteins, and antioxidant vitamins, leading to the accumulation of ROS. The second mechanism is a nonspecific chronic activation of the immune system, which results in an excessive production of ROS. A third mechanism is the result of the use of antineoplastic drugs. Many of these drugs, particularly alkylating agents and cisplatin, can produce an excess of ROS and lead to oxidative stress. Because oxidative stress is involved in the pathogenesis of cachexia symptoms, specifically counteracting its effects is essential. Antioxidants are classified into i) exogenous that are derived from dietary sources, such as vitamins A, C, E, and polyphenols; and ii) endogenous that are found both in extracellular and intracellular environments and are arranged within the cell to provide maximum protection against ROS. Endogenous antioxidants include both enzymes, such as GPx, catalase, and SOD, and nonenzymatic defenses, such as glutathione, lipoic acid, reduced coenzyme Q10, melatonin, and plasma protein thiols. Increasing the circulating levels of antioxidants may help to prevent oxidative stress. Therefore, their supplementation either through increased consumption in the diet or from nutritional supplements has been tested in patients with anorexia and cachexia syndrome. The antioxidant agents that are most widely used include GSH, alpha-lipoic acid (ALA), cysteinecontaining compounds such as N-acetyl cysteine (NAC), and antioxidant vitamins [22]. In some studies,we demonstrated 8 Expert Opin. Pharmacother. [Early Online]

10 Current pharmacotherapy options for cancer anorexia and cachexia that the antioxidant agents ALA, carbocysteine lysine salt, and vitamins A, C and E, which were administered to advanced cancer patients alone or in combination, could reduce ROS levels and increase GPx activity while reducing the serum levels of proinflammatory cytokines [98]. Moreover, we demonstrated that ALA and NAC could correct in vitro the most significant functional defects of peripheral blood mononuclear cells that were isolated from advanced stage cancer patients, that is, the defective response to an anti-cd3 mab and the defective membrane expression of CD25 and CD95 as markers of lymphocytes activation [20]. Based on this rationale, we introduced these antioxidants in a combined dietary, nutritional and pharmacological approach with the aim to normalize the metabolic environment that is associated with cancer cachexia and improve the associated symptoms that affect the QL [29,99,100] n-3 Fatty acids The supplementation of n-3 polyunsaturated fatty acids has been demonstrated to inhibit IL-1 and TNF-a production through a blockade of the COX and lipo-oxygenase pathways. Eicosapentaenoic acid (EPA) is the main component of this family and is found in large quantities in fish oil. At doses of g daily, this agent has lowered the synthesis of proinflammatory cytokines in healthy volunteers [101]. In addition, EPA can downregulate the acute-phase protein response [102] as well as the effects of the proteolysis-inducing factor and the lipid-mobilizing factor [103]. Two studies by Wigmore et al. [104,105] reported the effects of n-3 fatty acid treatment in patients with pancreatic cancer who were losing weight. In the first study [104], oral supplementation with fish oil capsules for 3 months led to a significant median body weight gain of 0.3 kg/month compared with a previous body weight loss of 2.9 kg/month. Additionally, a significant reduction in acute-phase protein production was observed. In the second study [105], 4 weeks of treatment with EPA reduced the CRP levels through the suppression of IL-6 production. In a Phase III randomized controlled trial, Fearon et al. [106] compared a protein and energy dense supplement that was enriched with n-3 fatty acids and antioxidants with an isocaloric isonitrogenous control supplement to determine their effect on weight, LBM, dietary intake, and QL in 200 cachectic patients with advanced pancreatic cancer. The intentionto-treat group comparisons indicated that enrichment with n-3 fatty acids did not provide a therapeutic advantage at the mean dose that was given (1.5 g/day corresponding to 1.4 cans/day), and both supplements were equally effective at counteracting weight loss. A post hoc dose--response analysis found that when the n-3 fatty acid-enriched energy and protein-dense supplements were taken in a sufficient quantity (> 1.5 cans/day), these supplements resulted in a net gain of weight, LBM, and improved QL. The North Central Cancer Treatment Group and the National Cancer Institute in Canada conducted a clinical trial that compared an EPA supplement versus MA versus their combination in 421 patients with cancer-associated wasting. This study did not demonstrate an improvement in weight or appetite with the EPA supplement [107]. Based on these results, the Cochrane meta-analysis, which was published in 2007 [108], concluded that there were insufficient data to establish whether oral EPA was more effective than a placebo. Therefore, the use of EPA alone cannot be recommended for treatment of cancer-related anorexia and cachexia syndrome. Furthermore, this meta-analysis indicated that the comparison of EPA combined with a protein energy supplementation versus a protein energy supplementation without EPA in the presence of MA provided no evidence that the addition of EPA improves the symptoms that are associated with cachexia. Similarly, a recent systematic review that was performed by the European Palliative Care Research Collaboration found that although several small trials, which were unrandomized and without a control group, reported a good effect of n-3-fatty acids in patients with cancer-related cachexia, the results of larger randomized controlled trials did not support these positive results [109]. Recently, Murphy et al. [110] suggested several considerations for the design of future trials with EPA. First, offering patients a choice of supplementation format (capsules or liquid) or the use of EPAenriched parenteral or enteral nutrition may be effective at improving study compliance. Moreover, early intervention with EPA supplementation may be more effective and allows for the accrual of patients who likely have a better prospect of survival and for whom maintenance or muscle gain is more likely to occur Branched-chain amino acids Amino acids such as branched-chain amino acids (BCAAs) are essential for the maintenance of skeletal muscle mass. The anabolic properties of BCAAs have been known for many years; however, their molecular mechanisms have only recently been elucidated. Consistent experimental and clinical data indicate that BCAAs, particularly leucine and its metabolite b-hydroxy-b-methylbutyrate, are highly effective at preventing anorexia and cachexia syndrome by enhancing protein metabolism and promoting appetite and food intake [111]. Although the experimental data have been promising, the results in humans to date have been disappointing. A Phase III trial with over 400 advanced-stage cancer patients, who had up to 10% weight loss, randomized the patients to receive an amino acid compound that contained beta-hydroxyl beta-methyl butyrate, glutamine, and arginine (HMB/Arg/Gin) or a placebo (RTOG 0122) twice daily for 8 weeks. Using an intention-to-treat analysis, there were no significant differences in the LBM between the two arms [112]. Therefore, to date the use of BCAAs for cancer-related cachexia cannot be recommended in clinical practice L-carnitine Among the oral nutritional supplements, L-carnitine with its nutritional, antioxidant, and antimyopathic effects is one of Expert Opin. Pharmacother. [Early Online] 9