Purpose. A phase III, randomized study was carried out to establish the most effective and safest treatment to improve the primary endpoints of cancer cachexia-lean body mass (LBM), resting energy expenditure (REE), and fatigue-and relevant secondary endpoints: appetite, quality of life, grip strength, Glasgow Prognostic Score (GPS) and proinflammatory cytokines.Patients and Methods. Three hundred thirty-two assessable patients with cancer-related anorexia/cachexia syndrome were randomly assigned to one of five treatment arms: arm 1, medroxyprogesterone (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); and arm 5, a combination of the above. Treatment duration was 4 months.Results. Analysis of variance showed a significant difference between treatment arms. A post hoc analysis showed the superiority of arm 5 over the others for all primary endpoints. An analysis of changes from baseline showed that LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) significantly increased in arm 5. REE decreased significantly and fatigue improved significantly in arm 5. Appetite increased significantly in arm 5; interleukin (IL)-6 decreased significantly in arm 5 and arm 4; GPS and Eastern Cooperative Oncology Group performance status (ECOG PS) score decreased significantly in arm 5, arm 4, and arm 3. Toxicity was quite negligible, and was comparable between arms. Conclusion. The most effective treatment in terms of all three primary efficacy endpoints and the secondary endpoints appetite, IL-6, GPS, and ECOG PS score was the combination regimen that included all selected agents. The Oncologist 2010;15:200 -211

Highlights This ESMO Clinical Practice Guideline provides key recommendations for managing cancer-related cachexia. It covers screening, assessment and multimodal management of cancer cachexia. All recommendations were compiled by a multidisciplinary group of experts. Recommendations are based on available scientific data and the author's expert opinion.

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ABSTRACTfore, essential to analyze all these factors that cause anemia, particularly before beginning any form of therapy that may worsen anemia.The aim of this work was to document the prevalence of anemia in a large cohort of patients with solid tumors before any exposure to antineoplastic treatment, and to assess the possible correlation between Hb levels and the commonly used indices of inflammation, malnutrition, and metabolic stress. We hypothesized that inflammation and malnutrition are independent predictors of the development and severity of anemia and that a better knowledge of CRA may enable its more adequate treatment. MethodsThis study was a prospective, observational trial performed in accordance with the Helsinki declaration after approval by the Local Institutional Ethics Committee. Between May 2011 and January 2014, 888 consecutive patients with histologically confirmed solid cancer at different sites referred to the Departments of Obstetrics and Gynecology, Sirai Hospital, Carbonia, Medical Oncology at "N.S. Bonaria" Hospital, San Gavino, "Nuova Casa di Cura", Decimomannu, and "A. Businco" Hospital, Cagliari, Italy, were enrolled. Table 1 reports the participants' clinical characteristics. Patients were assessed at diagnosis before receiving any cancer treatment. Exclusion criteria were: evidence of infections, chronic inflammatory disease, active bleeding, hemolysis, renal insufficiency, or hypothyroidism; known history of hematologic disorders (including hemoglobinopathies), family history of thalassemia or hemocromatosis; treatment with EPO, i.v. iron or blood transfusion in the preceding 12 weeks; current iron, vitamin B12 or folate supplementation.Anemia was defined according to our laboratory populationbased normal ranges as Hb <13.0 g/dL for males and <12.0 g/dL for females. Karnofsky PS was categorized into four prognostic classes. 17 Blood samples were obtained at 8 a.m. after overnight fasting since serum hepcidin and iron levels show similar circadian changes. In accordance with Ganz et al., 18 the 8 a.m. fasting hepcidin concentrations were more consistent than those at other times of the day. After centrifugation of the blood samples, serum was stored at -80°C until analysis.In all patients Hb levels and parameters of chronic inflammation [CRP, fibrinogen, IL-6, IL-1β, tumor necrosis factor-α (TNFα)], iron metabolism (iron, ferritin, transferrin, hepcidin), EPO, nutritional status (albumin, leptin, cholesterol, HDL, LDL, triglycerides) and oxidative stress [ROS, glutathione peroxidase (GPx), superoxide dismutase (SOD)] were measured. The formula for expected EPO was: 2.5 x (140-Hb g/L). 19 Since leptin is highly dependent on body mass index (BMI), the leptin/BMI ratio was reported. The modified Glasgow prognostic score (mGPS) was calculated as follows: 2, both elevated CRP (≥10 mg/L) and low albumin (<3.5 g/dL); 1, elevated CRP only; 0, normal CRP (<10 mg/L). 20 Laboratory assaysRoutine analyses of Hb, CRP, fibrinogen, serum iron, transferrin, ferritin, triglycerides, cholesterol...

Cancer-related anorexia/cachexia (CAC) is a complex phenomenon in which metabolic abnormalities, proinflammatory cytokines produced by the host immune system, circulating tumour-derived catabolic factors, decreased food intake, and probably additional unknown factors, all play different roles. This review examines the mechanisms of CAC and its management. All the potential modalities of intervention from nutritional to pharmacological approaches are included with a clear distinction between unproven, investigational and well established treatments. Among the latter, the progestogens are currently considered the most effective and safest drugs for the management of CAC. Agents currently under investigation for CAC include thalidomide, pentoxifylline and melatonin, which most probably act on cytokine release, and clenbuterol, which acts on muscle mass and to antagonise protein wasting. Our personal experience with the synthetic progestogens megestrol and medroxyprogesterone supports their use as first-line agents. In addition, our work on the potential role of antioxidant agents in counteracting the oxidative stress, which appears to be involved in CAC, shows them to be promising agents when used in combination chemotherapy regimens either alone or with other 'biologics'. There is an ongoing need for quality of life questionnaires which specifically address the most significant symptoms present in patients with CAC.

In advanced cancer patients, the oxidative stress could take place either at the onset of disease or as a function of disease progression. To test this hypothesis, the following parameters were investigated: the erythrocyte activity of the enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), the serum activity of glutathione reductase (GR) and the serum total antioxidant status (TAS). The total antioxidant capacity of plasma LMWA was evaluated by the cyclic voltammetry methodology. We further determined the serum levels of proinflammatory cytokines (IL-6 and TNF␣), IL-2, leptin and C-reactive protein (CRP). All of these parameters have been correlated with the most important clinical indices of patients such as Stage of disease, ECOG PS and clinical response. Eighty-two advanced stage cancer patients and 36 healthy individuals used as controls were included in the study. Our findings show that SOD activity was significantly higher in cancer patients than in controls and GPx activity was significantly lower in cancer patients than in controls. Serum values of IL-6, TNF␣ and CRP were significantly higher in patients than in controls. Serum leptin values of cancer patients were significantly lower than controls. SOD activity increased significantly from Stage II/ECOG 0-1 to Stage IV/ECOG 0 -1, whereas it decreased significantly in Stage IV/ECOG 3. GPx activity decreased significantly in Stage IV/ECOG 2-3. An inverse correlation between ECOG PS and serum leptin levels was found. Serum levels of IL-2 decreased from Stage II/ECOG 0 -1 to Stage IV/ECOG 2-3. A direct correlation between Stage/ECOG PS and serum levels of both IL-6 and CRP was observed. Cisplatin administration induced a significant increase of GPx after 24 hr. In conclusion, this is the first study that shows that several "biological" parameters of cancer patients such as antioxidant enzyme activity, cytokines, leptin and CRP strictly correlate with the most important clinical parameters of disease such as Stage and ECOG PS.

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Leptin is a recently identified hormone produced by the adipocyte ob gene which acts as a negative feedback signal critical to the normal control of food intake and body weight. A number of proinflammatory cytokines, such as interleukin (IL) 1alpha, IL-6, tumor necrosis factor (TNF) alpha and interferon (IFN) gamma, have been proposed as mediators of cancer cachexia. These data suggest that abnormalities in leptin production/release or in its feedback mechanism play a role in cancer patients. To elucidate this we studied the relationship between total serum leptin and serum cytokines IL-1alpha, IL-6, TNFalpha as well as the production of leptin and cytokines by peripheral blood mononuclear cells (PBMC) isolated from cancer patients. Sixteen advanced cancer patients (mainly stage IV) with tumors at different sites were included in the study. The serum levels of leptin in cancer patients were significantly lower than those of healthy individuals at all times (7 a.m., noon, 3 p.m.). No significant differences were found in circadian rhythm between patients and controls. Serum levels of IL-1alpha, IL-6, and TNFalpha were significantly higher in cancer patients than in healthy individuals. An inverse correlation between serum levels of leptin and IL-6 was found in cancer patients. The production in culture of leptin by unstimulated PBMCs and those stimulated by phytohemagglutinin M or by phorbol myristate acetate isolated from cancer patients was very low; no differences were observed in comparison with leptin production by PBMCs from healthy individuals.