Medroxyprogesterone acetate in the management of cancer cachexia
Clelia Madeddu, Antonio Macciò, Filomena Panzone, Francesca Maria Tanca &
Giovanni Mantovani†
University of Cagliari, Department of Medical Oncology, Italy
Background: Medroxyprogesterone acetate (MPA) is a synthetic, orally active derivative of the natural steroid hormone progesterone, widely used in oncology both in the endocrine treatment of hormone-related cancers and as supportive therapy in the cachexia syndrome. Objective: The anticachectic mechanisms of medroxyprogesterone, beyond its endocrine activity, are described to explain its therapeutic efficacy in the treatment of cachexia. Methods: After reviewing its pathophysiology and preclinical studies, the main clinical trials on the use of medroxyprogesterone acetate in cancer cachexia, are reviewed. Results/conclusions: Progestagens, including MPA, are at present the only approved drugs in Europe for the clinical treatment of cancer- related anorexia/cachexia syndrome. Placebo-controlled trials on the effect of MPA on cachexia have generally reported an improvement of both anorexia and body weight as well as of quality-of-life parameters. However, the weight gain was due to increased body fat, while fat-free mass was not significantly influenced by MPA treatment. Moreover, very recently the combination of MPA with other new anticachectic agents has been suggested as a way of ameliorating their efficacy in the treatment of cachexia.
Keywords: cancer cachexia, lean body mass, medroxyprogesterone acetate, proinflammatory cytokines Expert Opin. Pharmacother. (2009) 10(8):1359-1366
1.Introduction
Medroxyprogesterone acetate (MPA; Provera, Pfizer) is a synthetic, orally active derivative of the natural steroid hormone, progesterone. It is widely used in oncology both in the endocrine treatment of hormone-related cancers, such as breast and endometrial cancer, and as supportive therapy in the cachexia syndrome. This review explains its mechanism of action and summarizes clinical experiences with MPA in the treatment of cachexia.
2.Overview
Cachexia is the most common feature of most chronic severe diseases, such as AIDS, chronic heart failure (CHF), chronic obstructive pulmonary disease (COPD) and mostly cancer [1]. It is a multifactorial syndrome characterized by tissue wasting, loss of body weight, particularly of lean body (muscle) mass (LBM) and, to a lesser extent adipose tissue, metabolic changes, fatigue, reduced performance status, very often accompanied by anorexia leading to a reduced food intake: this condition is called ‘cancer-related anorexia/cachexia syndrome’ (CACS).
Indeed, cachexia occurs in the majority of cancer patients before death and it is responsible by itself for the death of 22% of cancer patients. Among other chronic diseases, before the era of highly active antiretroviral therapy, estimates of prevalence of wasting as the first AIDS-defining diagnosis ranged up to 31% [2].
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Fatigue, as a result of muscle wasting, is an extremely common symptom in CACS and, in particular, it is observed in a high percentage of CHF patients [3].
Key features of CACS are increased resting energy expenditure (REE), abnormalities both in energy and carbohydrate, lipid and protein metabolism, increased levels of circulating factors produced by the host immune system in response to the tumor, such as proinflammatory cytokines, or by the tumor itself, such as proteolysis-inducing factor [4].
Although anorexia plays a very important role in the development of weight loss, it is not considered a constitutive feature of CACS: indeed, it has to be pointed out that, in many cases, even the use of high-energy, total parenteral nutri- tion does not prevent the loss of body weight [5]. It seems, therefore, quite evident that host metabolic disturbances (increased energy inefficiency, insulin resistance and abnormal carbohydrate metabolism, lipolysis and muscle wasting) are responsible for the development of cachexia [6].
3.Definition of cachexia
Cachexia has long been recognized as a syndrome associated with many chronic illnesses. However, there is no universally agreed upon definition. On 13 and 14 December 2006, scientists and clinicians met in Washington, DC, to reach a consensus on the definition of the constellation of abnor- malities that have been grouped under the name of cachexia. The definition that emerged was:
Cachexia is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. The prominent clinical feature of cachexia is weight loss in adults (corrected for fluid retention) or growth failure in children (excluding endocrine disorders). Anorexia, inflammation, insulin resistance and increased muscle protein breakdown are frequently associated with wasting disease. Wasting disease is distinct from starvation, age-related loss of muscle mass, primary depression, malabsorption and hyperthyroidism and is associated with increased morbidity.
The consensus panel also developed a set of diagnostic criteria to allow clinicians and researchers to make a definitive diagnosis of cachexia. The key component was at least a 5% loss of edema-free body weight during the previous 12 months or less, plus three of the following criteria:
4.Cytokine activity in cancer-related anorexia/cachexia syndrome: role of medroxyprogesterone acetate
Proinflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α) are the main actors in the pathophysiology of CACS [8]. High serum levels of these cytokines have been previously reported in cancer patients in advanced stages and particularly in cachectic patients [9,10]. Moreover, we have observed increased production of IL-1, IL-6 and TNF-α by phytohemoagglutinin (PHA)-stimulated cultured peripheral blood mononuclear cells (PBMCs) isolated from advanced cancer patients [11].
Chronic administration of these cytokines, either alone or in combination, is capable of reproducing the different features of CACS in vivo, whereas treatment with the specific antagonists can reverse their effects [12].
The main finding of these studies is that the single cytokines do not work alone but in concert with each other and different factors produced by the tumor [13].
4.1Interleukin-1
The role of IL-1 in the pathogenesis of CACS has been clearly elucidated. IL-1 exerts a specific effect on reducing food intake and influences meal size, duration and frequency [14]. IL-1 has an anorectic action by directly decreasing neuro- peptide Y (NPY) neurotransmission and secondarily by increas- ing corticotropin-releasing factor (CRF), which in turn acts on the satiety circuitry inhibiting food intake. In rat models, IL-1 has been demonstrated to inhibit serum levels of growth hormone (GH) by increasing CRF and somatostatin levels [15]: this in turn leads to reduced synthesis of the insulin-like growth factors (IGFs), thus influencing the muscle protein turnover and the autocrine and paracrine regulation of muscle mass proliferation [16]. Both in vitro and animal studies have shown that IGF-1 induces muscle glucose synthesis and amino acid uptake and inhibits protein catabolism. IL-1 also acts peripherally on pancreatic beta cells binding its specific receptors influencing insulin synthesis and release [17].
4.2Tumor necrosis factor-a
TNF-α has been shown to promote lipolysis and inhibit lipogenesis and plays a key role in the depletion of adipose tissue mass seen in cachexia. It has been suggested that an
•decreased muscle strength elevation in plasma levels of TNF-α is responsible for the
•fatigue metabolic alterations in adipose tissue seen in cachexia [18].
•anorexia Studies using mammary adipose tissue from human subjects
•low fat-free mass index have shown that TNF-α inhibits lipoproteinlipase (LPL)
•abnormal biochemistry: i) increased inflammatory markers activity by downregulating its protein expression [19]. Indeed,
C-reactive protein (CRP) > 5.0 mg/l), IL-6 > 4.0 pg/ml; ii) anemia (hemoglobin < 12 g/dl); iii) low serum albumin (< 3.2 g/dl). In cases where a history of weight loss cannot be documented, a body mass index (BMI) of < 20.0 kg/m2 was considered sufficient to establish a diagnosis of cachexia [7]. increased TNF-α mRNA levels are correlated with decreased LPL activity in human subcutaneous adipose tissue [20]. In addition, TNF-α has been shown to reduce the expression of free fatty acid (FFA) transporters in adipose tissue and thus hinder the synthesis and entry of FFA into the adipocyte, curtailing an increase in the intracellular triglyceride pool 1360 Expert Opin. Pharmacother. (2009) 10(8) size. Studies have also indicated that TNF-α may decrease the expression of enzymes involved in lipogenesis. Specifically, it has been suggested that acetyl-CoA carboxylase as well as fatty acid synthase and Acyl-CoA synthase are down regulated by TNF-α [21]. TNF-α has been found to promote lipolysis: however, the mechanisms by which this is achieved are unclear. TNF-α administration also induces increase of cortisol, glucagon and insulin levels and these effects seem to be medi- ated by IL-1; the concomitant administration of recombinant IGF-1 reduces the percentage of protein loss by 15% with an associated improvement of glucose metabolism. Extensive research has highlighted several potential mechanisms by which TNF-α induces insulin resistance. These include: accelerated lipolysis and a concomitant increase in circulating FFA concentrations, downregulation of glucose transporter (GLUT)-4 synthesis, downregulation of insulin receptor, insulin receptor substrate-1 (IRS-1) synthesis and increased Ser/Thr phosphorylation of IRS-1 [22]. 4.3Interleukin-6 IL-6 is another proinflammatory cytokine with cachectic effects. In an experimental animal model, Strassmann et al. [23] demonstrated that the presence of tumor in mouse models was associated with early CACS and production of IL-6, dosable in the serum. Serum IL-6 levels correlated with the severity of CACS. Moreover, the administration of anti-IL-6 antibody inhibits the comparison of CACS symptoms. In vitro studies have shown that IL-6 induces, similarly to IL-1, the hypothalamic release of CRF. Moreover, IL-6 acts on beta pancreatic cells similarly to IL-1. 4.4Medroxyprogesterone acetate and cytokine synthesis In the light of the mechanisms described above, proinflam- matory cytokines IL-1, TNF-α and IL-6 clearly play a central role in the pathogenesis of metabolic derangements associated with CACS. It may be hypothesized that, during the initial phases of the neoplastic disease, the synthesis of proinflam- matory cytokines leads to an efficient antineoplastic effect. However, their chronic activity leads to severe alterations of cell metabolism, with deleterious effects on body composition, nutritional status and immune system efficiency [13]. MPA has been shown to improve appetite and body weight, regardless of tumor response, in the treatment of disseminated breast cancer [24]. This led to the hypothesis that synthetic progestagens could also stimulate weight gain in patients with nonhormone-sensitive tumors. The main mechanisms involved in the antineoplastic activity of MPA are known, whilst its anticachectic action has not been completely established yet. It may be attributed to glucocorticoid-like activity making this drug similar to corticosteroids. More- over, there is evidence that MPA may stimulate appetite via neuropeptide Y in the CNS. Furthermore, its anticachectic action seems to be mediated mainly by their ability to downregulate the synthesis and release of proinflammatory cytokines, as shown by experimental and clinical studies, including our own [11,25,26]. 5.Medroxyprogesterone acetate 5.1Chemistry and mechanism of action The chemical name for MPA is pregn-4-ene-3, 20-dione, 17-(acetyloxy)-6-methyl-, (6α)-. The structural formula is shown in Figure 1. MPA has slight androgenic action and exerts glucocorticoid activity when given at high doses [27]. The proposed mechanism of action of progestagen MPA in CACS has not been com- pletely established. It may be attributed to glucocorticoid-like activity, making this drug similar to corticosteroids. More- over, there is evidence that MPA may stimulate appetite via neuropeptide Y in the CNS (ventromedial hypothalamus) [28]. Furthermore, it acts, at least in part, by downregulating the synthesis and release of proinflammatory cytokines, as shown by experimental and clinical studies, including our own [25,26]. The strongest evidence supporting this finding comes from one of our studies [26], which addressed whether MPA, at doses pharmacologically active in vitro (0.1, 0.2 and 0.4 μg/ml), was able to influence the production and/or release in culture of cytokines and serotonin (5-HT) by PHA-stimulated PBMC of patients with advanced stage cancer. PHA-stimulated PBMC cultures from cancer patients revealed significantly higher levels of proinflammatory cytokines in comparison to controls. The addition into culture of 0.2 μg/ml MPA significantly reduced the PBMC production of IL-1, IL-6, TNF-α and 5-HT but not IL-2. The concentration of MPA used in our study can be achieved in vivo following very high-dose MPA administration (1500 – 2000 mg/day p.o.): this dose is used for endocrine therapy of hormone-related cancers and, to a lesser extent, as supportive care for CACS. The study showed that the in vitro production of IL-1, IL-6, TNF-α and 5-HT by PHA-stimulated PBMC of cancer patients is significantly reduced in the presence of MPA. Our results also showed that MPA was unable to interfere with both the activity of IL-2 on lymphocytes and with IL-2R expression by these cells [26]. Moreover, we demonstrated that MPA was able to inhibit 5-HT production and release by cancer-patient PBMCs. It can be hypothesized, therefore, that, along with cytokines, high levels of 5-HT may be produced in advanced-stage cancer patients as a consequence of chronic aspecific activation of the immune system, thus playing a role in the onset of CACS [13]. 5.2Pharmacokinetics and metabolism After oral intake medroxyprogesterone acetate does not undergo any first pass effect. The bioavailability is nearly 100%. The most important metabolic steps are hydroxylation reactions [29]. 5.2.1Absorption No specific investigation on the absolute bioavailability of MPA in humans has been conducted. MPA is rapidly absorbed from the gastrointestinal tract, and maximum MPA Expert Opin. Pharmacother. (2009) 10(8) 1361 into medium and induces cachexia when injected into CO female nude mice. MPA (10 – 1000 nM) dose dependently decreased basal IL-6 secretion into medium, and also sup- OCOCH3 pressed TNF-α-induced IL-6 secretion. Both basal and H TNF-α-induced IL-6 mRNA levels were dose dependently lowered by MPA. Moreover, intramuscular injections of MPA (100 mg/kg twice a week) into nude mice bearing H H KPL-4 transplanted tumors significantly decreased serum O H IL-6 levels without affecting tumor growth and preserved the body weight of recipient mice [32]. Accordingly, MPA significantly inhibits TNF-stimulated IL-6 production in mouse fibroblast (L929sA) cells and, in addition, IL-6 and Figure 1. Structural formula of medroxyprogesterone acetate. C24H34O4 Molecular Weight: 386.53 concentrations are obtained between 2 and 4 h after oral administration. Administration of MPA with food increases its bioavailability. A 10-mg dose of MPA, taken immediately before or after a meal, increases MPA Cmax (50 – 70%) and area under plasma concentration curves (AUC; 18 – 33%). The half-life of MPA does not change with food. 5.2.2Distribution MPA is approximately 90% protein bound, primarily to albumin; no MPA binding occurs with sex hormone binding globulin (SHBG) and corticosteroid binding globulin (CBG). 5.2.3Metabolism Following oral dosing, MPA is extensively metabolized in the liver via hydroxylation, with subsequent conjugation and elimination in the urine. 5.2.4Excretion Most MPA metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates. 6.Preclinical studies Several experimental studies on animal models of cancer cachexia have shown the ability of MPA to reduce the systemic inflammatory response and to reverse the cachexia syndrome. In mice bearing LP07 lung adenocarcinoma, which present some characteristics similar to those shown in patients with several malignant diseases and develop paraneoplastic syndromes such as cachexia, leukocytosis, and hypercalcemia, partly due to a systemic inflammatory response, MPA both alone and in combination with an anti-inflammatory drug (i.e., indo- methacin) was able to abolish paraneoplastic syndromes, leukocytosis and cachexia and to reduce circulating levels of IL-6 known to regulate cachexia and inflammation [30]. It has been suggested that MPA decreases serum IL-6 levels and thus may preserve body weight and subjective wellbeing in advanced cancer patients [31]. Therefore, the effects of MPA on IL-6 secretion were studied both in vitro and in vivo also in a human breast cancer cell line, KPL-4, which secretes IL-6 IL-8 promoter–reporter constructs at the transcriptional level, via interference with nuclear factor κB (NFκB) and activator protein-1 (AP-1) [33]. These findings indicate that suppression of proinflammatory cytokines secretion may, at least in part, cause the anticachectic effect of MPA. 7.Clinical efficacy Progestagens were the first agents used and are now the only approved treatment in Europe for patients with CACS. An extensive amount of literature is available both for megestrol acetate (MA) and MPA. Both MA and MPA are synthetic progestagens that were first used to treat hormone-sensitive tumors [34]. As a result of the observed body weight gain and appetite stimulation in a number of patients, several trials in the last two decades have addressed their use for the man- agement of CACS. The two drugs are equivalent in terms of effectiveness in the treatment of CACS and no difference exists between them. However, MA has been the drug most widely studied versus MPA for its effect on CACS, with eight randomized, double-blind, placebo-controlled trials [34]. Downer et al. [35] compared MPA (1000 mg twice daily p.o.) with placebo in 60 patients with advanced breast cancer. Twenty-one patients in the MPA group and 20 in the pla- cebo group received chemotherapy. Patients were treated for 6 weeks and were assessed at weeks 0, 3 and 6 for appetite, energy, mood and pain using visual analog scales. There was a significant improvement in appetite in the MPA group, whilst there was no significant improvement in appetite in the placebo group. Supporting this finding was the significant increase in serum thyroid binding prealbumin and retinol binding protein in the MPA group compared with placebo. There was no change in anthropometric measurements, body weight, performance status, energy, mood or pain in either group. These data indicate that there was a significant increase in appetite in anorexic patients with advanced cancer treated with MPA which was shown by increases in rapid turnover proteins reported to reflect nutritional status. How- ever, this apparent increase in appetite did not result in improved body weight, performance status, energy levels, mood or relief of pain. Later, Simons et al. [36] in a placebo-controlled study used oral medroxyprogesterone 1000 mg/day administered for 1362 Expert Opin. Pharmacother. (2009) 10(8) 12 weeks in 44 patients with nonhormone-sensitive cancer with weight loss and hypermetabolism, and reported a significant improvement of appetite, energy intake and body weight in comparison with placebo. Moreover, a prospective clinical study showed the ability of MPA to influence the quality of life of cancer patients undergoing different chemotherapeutic regimens and/or radio- therapy for different tumor types [37]. A series of 279 cancer patients undergoing either chemotherapy and/or radiotherapy treatment for different tumor types was randomly allocated to receive either MPA or no treatment. The effect of MPA oral suspension at the daily dose of 1000 mg for 12 weeks (group A) or no treatment (group B) was explored. An increase of body weight in group A patients and improvement in performance status was observed. The outcome of the present study strongly demonstrates that therapy with MPA plays a fundamental role in ameliorating the complex symptomatology of cancer patients in intermediate or advanced stage of the disease undergoing casual treatment with chemotherapy and/or radiotherapy. More recently, some studies have shown the efficacy of a combined approach including MPA for the treatment of cachexia. In 2004, Cerchietti et al. [38] demonstrated that a combined treatment approach with MPA (500 mg twice daily) plus celecoxib (200 mg twice daily) plus oral food supple- mentation administered for 6 weeks was able to counteract body weight loss and improve significantly nausea, early satiety, fatigue, appetite and performance status in a popula- tion of 15 patients with advanced lung adenocarcinoma. Moreover, our open Phase II study demonstrated the efficacy and safety of an integrated treatment based on MPA plus a pharmaconutritional support, antioxidants and celecoxib in a population of advanced neoplastic patients with CACS [39]. The treatment consisted of diet with high polyphenols content (400 mg), antioxidant treatment (300 mg/d alpha- lipoic acid + 2.7 g/d carbocysteine lysine salt + 400 mg/d vitamin E + 30,000 IU/d vitamin A + 500 mg/d vitamin C), and pharmaconutritional support enriched with two cans per day (n-3)-PUFA (eicosapentaenoic acid and docosahexaenoic acid), 500 mg/d MPA, and 200 mg/d selective cyclooxygenase-2 inhibitor celecoxib. The treatment duration was 4 months. From July 2002 to January 2005, 44 patients were enrolled. Of these, 39 completed the treatment and were assessable. Body weight increased significantly from baseline as did LBM and appetite. There was an important decrease of proinflammatory cytokines IL-6 and TNF-α, and a negative relationship worthy of note was only found between LBM and IL-6 changes. As for quality-of-life evaluation, there was a marked improvement in the European Organization for Research and Treatment of Cancer QLQ-C30, Euro QL5- D(VAS), and multidimensional fatigue symptom inventory short form scores. At the end of the study, 22 of the 39 patients were ‘responders’ or ‘high responders’. The minimum required was 21; therefore, the treatment was effective and more importantly was shown to be safe. On the basis of these results we started a Phase III randomized clinical trial to establish which was the most effective and safest treatment of CACS and oxidative stress in improving identified primary end points: increase of LBM, decrease of REE, increase of total daily physical activity, decrease of IL-6 and TNF-α, and improvement of fatigue assessed by the Multidimensional Fatigue Symptom Inventory – Short Form (MFSI-SF). All patients were given as basic treatment polyphenols plus antioxidant agents alpha-lipoic acid, carbocysteine, and vitamins A, C and E, all orally. Patients were then randomized to one of the follow- ing five arms: i) MPA/MA; ii) pharmacologic nutritional support containing eicosapentaenoic acid; iii) L-carnitine; iv) thalidomide; or v) MPA/MA plus pharmacologic nutri- tional support plus L-carnitine plus thalidomide. Treatment duration was 4 months. The sample included 475 patients. An interim analysis on 125 patients was published [4] and showed an improvement of at least one primary end point in arms 3, 4, and 5, whereas arm 2 showed a significant worsening of LBM, REE and MFSI-SF. Analysis of variance comparing the change of primary end points between arms showed a significant improvement of REE in favor of arm 5 versus arm 2 and a significant improvement of MFSI-SF in favor of arms 1, 3 and 5 versus arm 2. A significant inferiority of arm 2 versus arms 3, 4 and 5 for the primary end points LBM, REE and MFSI-SF was observed on the basis of a t-test for changes. As for safety, no severe side effects were observed. The interim results obtained so far seem to suggest that the most effective treatment for CACS and oxidative stress should be a combination regimen. The study is still in progress. 8.Safety and tolerability Synthetic progestagen treatment is generally well tolerated in advanced-stage cancer patients. The most frequent adverse events are the development of peripheral edema and an increased incidence of thromboembolic complications, mainly deep vein thrombosis of lower limbs, although the latter occurs at relatively high synthetic progestagen dose and is infrequently severe [40]. Other adverse events might be related to the glucocorticoid-like activity: indeed, metabolic syndromes such as diabetes mellitus and Cushing’s syndrome have been reported only occasionally. Other corticosteroid- related toxicities, such as myopathy, striae, opportunistic infections, femoral head necrosis or peptic ulcer disease, are extremely rare. However, it is unlikely that patients on MPA have to withdraw the drug because of adverse events. Most published studies using megestrol or medroxypro- gesterone in patients with CACS referred to tablets rather than the oral suspension formulation. However, oncologists are increasingly using megestrol or medroxyprogesterone oral suspensions in their patients with malignancies because of improved compliance and decreased cost [41]. A very recent new formulation, ‘nano crystal oral suspension’ of MA, was Expert Opin. Pharmacother. (2009) 10(8) 1363 developed to optimize drug delivery. It was approved by the FDA for the treatment of cachectic AIDS patients [42]. 8.1Bone metabolism Results from estrogen/progestin interventions trials and from widespread clinical practice in postmenopausal women indicate no additional effect of MPA on an estrogen-induced increase in bone mass. Vice versa, there is also evidence that long-term use of long-acting injectable contraceptive depot MPA is asso- ciated with lower bone mineral density levels [43]. Different types of progestins may have different effects on bone meta bolism. Progestins with no significant affinity to the glucocorti- coid receptor have beneficial effects on bone density, whereas progestins with significant affinity to glucocorticoid receptor do not have a significant effect on bone density [44-46]. 9.Conclusions Progestagens, including MPA, are the only approved drugs in Europe for clinical treatment of CACS. Their anticachectic effect is mainly mediated by their influence on the synthesis and release of several procachectic cytokines, in particular IL-6, TNF-α, IL-1 and serotonin. Placebo-controlled trials on the effect of MPA on cachexia generally reported an improvement of both anorexia and body weight as well as of quality-of-life parameters. However, authors who analyzed body weight composition demonstrated that the bulk of the body weight gain was due to increased body fat, while fat-free mass was not significantly influenced by MPA treatment [36]. Finally, as for safety, all reported data indicate that MPA is usually well tolerated and serious adverse events are not fre- quent in clinical practice. The only important selection to be made before MPA administration is a careful medical history collection and the assessment of thromboembolic risk of individual patients. 10.Expert opinion Synthetic progestagens MPA and MA are at present the So far, according to the guidelines of ASCO, ESMO and AIOM, progestagens, such as MPA, should be considered the treatment of choice for cancer cachexia and a dosage of 1000 mg/day orally of MPA is recommended. On the basis of our clinical experience we suggest a dosage of 500 mg/day, especially when used in combination with other anticachectic drugs. However, as CACS is a multifactorial syndrome, the logical rationale is that only a multitargeted approach may be effective. Indeed, patients on total parenteral nutrition are still subject to significant body wasting, emphasizing the role of the metabolic abnormalities in cachexia. Therefore, any therapeutic approach based on increasing food intake should be combined with a pharmacological strategy to counteract metabolic changes in a complex setting in which the pharmaco-nutritional approach may have the central role. Timing has to be considered carefully when designing the therapeutic plan: it is to be taken into consideration when treating cancer patients that any nutritional/metabolic/ pharmacological support should be started early in the course of the disease, before severe weight loss occurs. Another important issue associated with the design of the ideal therapeutic approach is that no definite mediators of cachexia have been identified yet. Implementing a single targeted approach is quite difficult since the setting of clinic, metabolic and quality-of-life effects mediated by each potential target (i.e., TNF-α, IL-6, IFN-γ, PIF) for CACS has not been completely ascertained. Bearing this in mind, it is obvious that a better understanding of the mechanisms involved in the signaling cascade triggered by these mediators may be crucial in the design of the therapeutic strategy. Until now, MPA has been considered a standard option in the treatment of CACS. However, limitations in the knowledge of its mechanisms of action and definition of its efficacy outcomes in clinical trials published so far (i.e., weight gain, increase of LBM, improvement of quality of life) do not allow it to be deemed the most effective therapeutic option for cachexia. Some possible scenarios may be suggested to improve its efficacy: only approved drugs for CACS in Europe. So far, more than 15 randomized controlled studies have demonstrated that progestagens significantly improve appetite, food intake, body weight and sometimes nausea and emesis, whereas their effect on quality of life showed some discrepancies. Moreover, the role of MPA in the treatment of cachexia has been the subject of critical reviews with some doubt arising as to its efficacy [47,48]. Nevertheless, the efficacy criteria were assessed mainly on body weight increase and appetite stimulation. Therefore, on the basis of new insights on the • • • a biological characterization of cachectic patient based on the identification of specific factors to be considered as predictive markers of response an earlier and more accurate diagnosis of cachexia in order to start drug interventions early in the course of the disease, before severe weight loss occurs a review of clinical efficacy outcomes, focusing mainly on health-related quality-of-life improvement. In conclusion, since CACS is a multifactorial process, it is complex pathogenesis of CACS, these outcome parameters are probably not the most clinically significant. At present, the leading researchers in the field believe that the most appropriate clinical outcome parameters are improvement of LBM, decrease of REE and fatigue and correction of chronic inflammatory status. unlikely that MPA alone may counteract the complex processes involved in cachexia. Accordingly, very recent studies have indicated that the combination of MPA with other new anticachectic agents may be a more effective a way of treating cachexia [4,38,39]. Future treatment of CACS should no doubt combine different pharmacological approaches to 1364 Expert Opin. Pharmacother. (2009) 10(8) reverse efficiently the many different clinical features described above. Defining this combination of drugs with nutritional support and behavioral interventions will be an exciting challenge for researchers in the coming years. Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript. 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Am J Physiol Endocrinol Metab 2001;280:E745-51 21.Sethi JK, Hotamisligil GS. The role of TNF alpha in adipocyte metabolism. Semin Cell Dev Biol 1999;10:19-29 22.Moller DE. Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab 2000;11:212-17 23.Strassmann G, Fong M, Kenney JS, Jacob CO. Evidence for the involvement of interleukin 6 in experimental cancer cachexia. J Clin Invest 1992;89:1681-4 24.Tominaga T, Abe O, Ohshima A, et al. Comparison of chemotherapy with or without medroxyprogesterone acetate for advanced or recurrent breast cancer. Eur J Cancer 1994;30A:959-64 25.Mantovani G, Macciò A, Bianchi A, et al. Megestrol acetate in neoplastic anorexia/cachexia: clinical evaluation and comparison with cytokine levels in patients with head and neck carcinoma treated with neoadjuvant chemotherapy. Int J Clin Lab Res 1995;25:135-41 •• The first clinical study showing a correlation between the clinical efficacy of a progestagen (megestrol acetate) and the decrease of serum levels of proinflammatory cytokines. 26.Mantovani G, Macciò A, Esu S, et al. Medroxyprogesterone acetate reduces the in vitro production of cytokines and serotonin involved in anorexia/cachexia and emesis by peripheral blood mononuclear cells of cancer patients. Eur J Cancer 1997;33:602-7 •• The first laboratory study showing that the administration in-vitro of medroxiprogesterone acetate induced a Expert Opin. Pharmacother. (2009) 10(8) 1365 downregulation of the production/release of proinflammatory cytokines. 27.Sitruk-Ware R. Pharmacological profile of progestins. Maturitas 2004;47:277-83 28.McCarthy HD, Crowder RE, Dryden S, Williams G. Megestrol acetate stimulates food and water intake in the rat: effects on regional hypothalamic neuropeptide Y concentrations. Eur J Pharmacol 1994;265:99-102 29.Schindler AE, Campagnoli C, Druckmann R, et al. Classification and pharmacology of progestins. Maturitas 2003;46(Suppl 1):7-16 30.Diament MJ, Peluffo GD, Stillitani I, et al. Inhibition of tumor progression and paraneoplastic syndrome development in a murine lung adenocarcinoma by medroxyprogesterone acetate and indomethacin. Cancer Invest 2006;24:126-31 31.Yamashita JI, Ogawa M. Medroxyprogesterone acetate and cancer cachexia: interleukin-6 involvement. Breast Cancer 2000;7:130-5 32.Kurebayashi J, Yamamoto S, Otsuki T, Sonoo H. Medroxyprogesterone acetate inhibits interleukin 6 secretion from KPL-4 human breast cancer cells both in vitro and in vivo: a possible mechanism of the anticachectic effect. Br J Cancer 1999;79:631-6 33.Koubovec D, Berghe WV, Vermeulen L, et al. Medroxyprogesterone acetate downregulates cytokine gene expression in mouse fibroblast cells. Mol Cell Endocrinol 2004;221:75-85 34.Mantovani G, Macciò A, Massa E, Madeddu C. Managing cancer-related anorexia/cachexia. Drugs 2001;61:499-514 35.Downer S, Joel S, Allbright A, et al. A double blind placebo controlled trial of medroxyprogesterone acetate (MPA) in cancer cachexia. Br J Cancer 1993;67:1102-5 36.Simons JP, Schols AM, Hoefnagels JM, et al. Effects of medroxyprogesterone acetate on food intake, body composition, and resting energy expenditure in patients with advanced, nonhormone-sensitive cancer: a randomized, placebo-controlled trial. Cancer 1998;82:553-60 •• Probably the most significant randomized clinical trial on medroxi progesteron acetate in cancer cachexia. 37.Neri B, Garosi VL, Intini C. Effect of medroxyprogesterone acetate on the quality of life of the oncologic patient: a multicentric cooperative study. Anticancer Drugs 1997;8:459-65 38.Cerchietti LC, Navigante AH, Peluffo GD, et al. Effects of celecoxib, medroxyprogesterone, and dietary intervention on systemic syndromes in patients with advanced lung adenocarcinoma: a pilot study. J Pain Symptom Manage 2004;27:85-95 •• This is a very interesting study because it was one of the first to use a combined treatment approach against cancer cachexia. 39.Mantovani G, Macciò A, Madeddu C, et al. A phase II study with antioxidants, both in the diet and supplemented, pharmaconutritional support, progestagen, and anti-cyclooxygenase-2 showing efficacy and safety in patients with cancer-related anorexia/cachexia and oxidative stress. Cancer Epidemiol Biomarkers Prev 2006;15:1030-4 •• This was the first phase II study of a multi-targeted combined treatment approach which was shown to be effective in cancer cachexia by assessing several clinical, nutritional, functional, laboratory and quality of life parameters. 40.Mantovani G. The current management of cancer cachexia. Milan: Springer-Verlag, 2006 41.Ottery FD, Walsh D, Strawford A. Pharmacologic management of a norexia/cachexia. Semin Oncol 1998;25:35-44 42.Femia RA, Goyette RE. The science of megestrol acetate delivery: potential to improve outcomes in cachexia. BioDrugs 2005;19:179-87 43.Ishida Y, Mine T, Taguchi T. Effect of progestins with different glucocorticoid activity on bone metabolism. Clin Endocrinol (Oxf) 2008;68:423-8 44.Ishida Y, Ishida Y, Heersche JN. Pharmacologic doses of medroxyprogesterone may cause bone loss through glucocorticoid activity: an hypothesis. Osteoporos Int 2002;13:601-5 45.Kontula K, Paavonen T, Luukkainen T, Andersson LC. Binding of progestins to the glucocorticoid receptor. Correlation to their glucocorticoid-like effects on in vitro functions of human mononuclear leukocytes. Biochem Pharmacol 1983;32:1511-18 46.Selman PJ, Wolfswinkel J, Mol JA. Binding specificity of medroxyprogesterone acetate and proligestone for the progesterone and glucocorticoid receptor in the dog. Steroids 1996;61:133-7 47.Gagnon B, Bruera E. A review of the drug treatment of cachexia associated with cancer. Drugs 1998;55:675-88 48.Maltoni M, Nanni O, Scarpi E, et al. High-dose progestins for the treatment of cancer anorexia-cachexia syndrome: a systematic review of randomised clinical trials. Ann Oncol 2001;12:289-300 • This is a very interesting, albeit not very recent, review on high-dose progestins for the treatment of cancer anorexia-cachexia syndrome. Affiliation Clelia Madeddu MD, Antonio Macciò MD, Filomena Panzone MD, Francesca Maria Tanca MD & Giovanni Mantovani† MD †Author for correspondence University of Cagliari, Department of Medical Oncology, SS 554, km 4.500, 09042 Monserrato (Cagliari), Italy Tel: +39 070 5109 6253; Fax: +39 070 5109 6253; E-mail: [email protected] 1366 Expert Opin. Pharmacother. (2009) 10(8)NSC-26386