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LA CACHESSIA NEOPLASTICA Prof. Giovanni Mantovani Cattedra di Oncologia Medica Università degli Studi di Cagliari

LA CACHESSIA NEOPLASTICA Prof. Giovanni Mantovani Cattedra di Oncologia Medica Università degli Studi di Cagliari. nausea/vomiting. weight loss . anorexia. depletion of both fat and muscle tissue . SYMPTOMS OF CANCER-RELATED CACHEXIA. anemia. immunodepression. fatigue.

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LA CACHESSIA NEOPLASTICA Prof. Giovanni Mantovani Cattedra di Oncologia Medica Università degli Studi di Cagliari

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  1. LA CACHESSIA NEOPLASTICA Prof. Giovanni Mantovani Cattedra di Oncologia Medica Università degli Studi di Cagliari

  2. nausea/vomiting • weight loss • anorexia • depletion of both fat and muscle tissue SYMPTOMS OF CANCER-RELATED CACHEXIA • anemia • immunodepression • fatigue • resistance to antineoplastic treatments and enhancement of their side effects

  3. INCIDENCE OF CANCER CACHEXIA/ANOREXIA SYNDROME  Incidence of weight loss in cancers of different sites (LavianoA, et al. Nature Clinical Practice Oncology (2005) 2, 158-165) Approximately 2/3 of patients who die with advanced cancer suffer from cancer cachexia 20% of cancer patients die from effects of malnutrition rather than from direct effects of malignancy Marion M. Support Line. 1998;20:3 Ottery FD. Cancer Pract. 1994;2:123 DeWys WD, et al. Am J Med. 1980;69:491

  4. PATHOGENESIS OF CACS Cancer-induced cachexia is invariably associated with the presence and growth of the tumor. The main factors leading to CACS anorexia decreased food intake metabolic changes (cytokines) increased REE. In addition, the competition for nutrients between tumor and host leads to an accelerated starvation state characterised by severe metabolic disturbances and hypermetabolism resulting in an increased energetic inefficiency

  5. METABOLIC CHANGES:CACHEXIA VS. STARVATION Adapted from Kotler DP. 2000. Ann Intern Med. 133:622

  6. CHANGES OF ENERGY METABOLISM • In cancer patients in advanced stage of disease, a characteristic deregulation of energy metabolism is frequently observed: •  increased energy expendituredue to tumor growth and activation of the immune system •  intake of energetic substrates (especially glucose) due to symptoms such as anorexia, nausea and vomiting • cytokine-induced metabolic alterations (insuline resistance, etc)

  7. CHANGES OF GLUCOSE METABOLISM IN CANCER CACHEXIA  PROTEIN AND LIPID STORES GLYCEROL + FREE FATTY ACIDS a)  GLUCONEOGENESIS  CORI CYCLE b) hyperglicaemia c) IMPAIRED GLUCOSE TOLERANCE hypoglicaemia d) INSULIN RESISTANCE

  8. CHANGES OF PROTEIN METABOLISM IN CANCER CACHEXIA muscle and liver sinthesis of albumin, etc and  liver synthesis of acute phase proteins (APP=C Reactive Protein and Fibrinogen)  serum levels of Proteolysis Inducing Factor (PIF)  selective muscle wasting

  9. CHANGES OF LIPID METABOLISM IN CANCER CACHEXIA • Lipolysis (fatty acids beta oxidation)  Lipogenesis  Free fatty acids turnover (FFA)  synthesis of free fatty acids (FFA)  lipoproteinlipase activity  Hypertrigliceridaemia

  10. HYPERMETABOLISM In cancer cachexia the decreased caloric intake is not accompanied by a drop in energy expenditure. Hyltander et al, in a wide population study, have showed that cancer patients have a higher resting energy expenditure as compared with normal controls. Whole body protein turnover APPR Resting Energy Expenditure Glucose production and turnover Protein catabolism Protein synthesis Lipogenesis lipolysis Argiles JM, Med Res Rev, 1999

  11. CATABOLIC MEDIATORS IN CANCER BOTH TUMOUR-DERIVED AND HUMORAL (CYTOKINES) FACTORS ARE INVOLVED IN MEDIATING ANOREXIA AND METABOLIC CHANGES, CHARACTERISTIC OF THE CACHECTIC STATE. HUMORAL TUMOR-DERIVED ANTI- CACHECTIC CYTOKINES IL-4, IL-10, IL-15, sTNFR, sIL-6R PRO CACHECTIC CYTOKINES TNF, IL-6, IL-1,IFN-g PIF, LMF, ETC.. ANOREXIA METABOLIC ALTERATIONS CACHEXIA

  12. TUMOR MONOCYTES/ MACROPHAGES LYMPHOCYTES CYTOKINES (IL-1, IL-6, TNFa) GLUCOSE METABOLISM CENTRAL NERVOUS SYSTEM LIPID METABOLISM  CRF AND SOMATOSTATINE GH ANOREXIA IGF-1 PROTEOLYSIS NAUSEA AND VOMITING DAMAGE ON PANCREATIC b CELLS HYPOINSULINEMIA IMPAIRED GLUCOSE METABOLISM HYPO/HYPERGLICAEMIA LIPOPROTEINLIPASE LYPOLISIS HYPERTRIGLICERIDEMIA  ADIPOCYTE SIZE  FAT TISSUE

  13. MUSCLE WASTE AND ACUTE-PHASE RESPONSE IL-6, TNF, IL-1, IFN-g PROTEINS  AA ACUTE PHASE PROTEINS AA  PROTEIN DEGRADATION THE MOST PARADIGMATIC METABOLIC DERANGEMENTS INDUCED BY THE TUMOR ARE THE ACTIVATION OF PROTEOLYSIS IN SKELETAL MUSCLE AND THE REDISTRIBUTION OF PROTEIN SYNTHESIS IN THE LIVER ( SYNTHESIS OF ALBUMIN, ETC AND  CRP, ETC). THESE ALTERATIONS CAN BE INDUCED BY DIFFERENT CYTOKINES From Tisdale “Cachexia in Medicine” 2004

  14. HYPOTHALAMIC NEUROPEPTIDE CIRCUITRY IN CACS ANOREXIGENIC NEUROPEPTIDES OREXIGENIC NEUROPEPTIDES P H Y S I O L O G Y NEUROTENSIN MCH CART/GLP-I OREXIN/GALANIN LEPTIN  MELANOCORTIN AGRP CRF NPY - + GHRELIN   SEROTONIN IL-1, IL-6, TNF-a, IFN-g C A C S  Leptin;  ghrelin  TRYPTOPHAN DECREASED FOOD INTAKE INCREASED RESTING ENERGY EXPENDITURE

  15. PHYSIOLOGY OF CENTRAL EFFECT OF LEPTIN IN REGULATING NEUROENDOCRINE FUNCTION AND ENERGY HOMEOSTASIS food intake food intake energy expenditure energy expenditure

  16. LEVELS OF C-REACTIVE PROTEIN, FIBRINOGEN, PROINFLAMMATORY CYTOKINES AND LEPTIN IN ADVANCED CANCER PATIENTS * * * * * * * p<0.005 in comparison to controls J Mol Med 2000; 78: 554-561

  17. SERUM LEPTIN LEVELS IN CANCER PATIENTS ACCORDING TO STAGE leptin (ng/ml) * * p=0.009 Mann-Whitney test: patients versus controls J Mol Med 2001; 79: 406-414

  18. SERUM LEVELS OF LEPTIN AND PROINFLAMMATORY CYTOKINES IN CANCER PATIENTS ACCORDING TO PERFORMANCE STATUS Lowest ECOG PS (2 and 3) are associated with lowest levels of leptin and highest levels of proinflammatory cytokines (expecially IL-6). J Mol Med 2001;79:406-414

  19. CACS LOW LEPTIN LEVELS ___ Hyperphagia  REE Weight loss Anorexia  REE T-Lymphocytes Cytokines Tumor Macrophages IL-1, IL-,TNF ROS

  20. ACTIVATED IMMUNE SYSTEM 5-HT, CYTOKINES CRH Neuropeptide Y emesis Anorexia REDUCED FOOD INTAKE

  21. OXIDATIVE STRESS “Imbalance between oxidants and antioxidants in favor of oxidants” Enzymatic antioxidants: Glutathione Peroxidase, Superoxide Dismutase, Catalase Non enzymatic antioxidants: GSH, Lipoic Acid, Vit C, Vit E, Flavonoids, Carotenoids O2-  OH H2O2

  22. MECHANISMS LEADING TO OXIDATIVE STRESS IN CANCER PATIENTS • altered energy metabolism • reduced food intake • aspecific chronic activation of immune system (associated to an excessive production of proinflammatory cytokines) • use of antineoplastic drugs

  23. Impairment of Immune system Nausea/vomiting metabolic alterations Free radicals Reduced energy intake (especially glucose) Reduction of antioxidant defences (GSH) OXIDATIVE STRESS

  24. BLOOD LEVELS OF ROS, GPx AND SOD IN 60 CONTROLS AND 120 CANCER PATIENTS. The box plots in the figure represent columns of data as boxes whose extents indicate the 25th and the 75th percentile of the column. Capped bars indicate the min and the max value. p<0.001 versus controls (Student’s t- test) Mantovani G, et al. J Mol Med 2003

  25. ERYTHROCYTE ACTIVITY OF SOD AND GPx IN CANCER PATIENTS ACCORDING TO STAGE AND PERFORMANCE STATUS GPx U/L whole blood * Results are expressed as mean values. * p<0.05 as calculated with Student’s t-test in comparison to controls SOD U/ml whole blood * Mantovani G, et al. Int J Cancer, 2002

  26. MEGESTROL ACETATE IN NEOPLASTIC ANOREXIA/CACHEXIA: CLINICAL EVALUATION AND COMPARISON WITH CYTOKINE LEVELS IN PATIENTS WITH HEAD AND NECK CARCINOMA TREATED WITH NEOADJUVANT CHEMOTHERAPY. Mantovani G, et al. Int. J. Clin. Lab. Res. 25, 135-141, 1995 11 male patients were enrolled in the study and were treated with MA during neoadjuvant chemotherapy

  27. SERUM LEVELS OF IL-1a, IL-1b, IL-2, IL-6, TNFa AND sIL-2R IN CANCER PATIENTS BEFORE AND AFTER CHEMOTHERAPY + MA TREATMENT N.S N.S N.S N.S * * Results are expressed as mean values. *p<0.05 as calculated with Student’s t test in comparison to controls. N.S. non significant Mantovani G, et al. Int. J. Clin. Lab. Res., 1995

  28. MEDROXYPROGESTERONE ACETATE REDUCES THE IN VITRO PRODUCTION OF CYTOKINES AND SEROTONIN INVOLVED IN ANOREXIA/CACHEXIA AND EMESIS BY PBMC OF CANCER PATIENTS. Mantovani G, et al. Eur J Cancer 33, 602-607, 1997

  29. EFFECT OF MEDROXYPROGESTERONE ACETATE ON CYTOKINES AND 5-HT PRODUCTION BY PBMC OF ADVANCED CANCER PATIENTS * § * * § § * * § Results are expressed as mean values. *p<0.05, calculated with Student’s t test versus controls § p<0.05, calculated with Student’s t test versus PHA-stimulated patients PBMC Mantovani G, et al. Eur J Cancer, 1997

  30. CANCER-RELATED ANOREXIA/CACHEXIA SYNDROME AND OXIDATIVE STRESS: AN INNOVATIVE APPROACH BEYOND CURRENT TREATMENT Giovanni Mantovani, Clelia Madeddu, Antonio Macciò, Giulia Gramignano, Maria Rita Lusso, Elena Massa, Giorgio Astara and Roberto Serpe Department of Medical Oncology, University of Cagliari, Italy Cancer Epidemiol Biomarkers and Prev 2006; 15:1030-1034 Cancer Epidemiol Biomarkers and Prev 2004; 13:1651-1659

  31. AIM OF THE STUDY • CACS and Oxidative Stress (OS) play a key role in the progression and outcome of the neoplastic disease: their appearance and worsening are very important negative prognostic factors in the progression of cancer. • Aim of the study wasto test the EFFICACY AND SAFETY • of an integrated treatment based on diet, p.o. pharmaconutritional support, and drugs in a population of advanced cancer patients with CACS/OS. • The efficacy was assessed in terms of: • - clinical response • improvement of nutritional and functional variables • changes of laboratory variables (as indicators of CACS/OS) • and improvement of quality of life (QL). • The ultimate goal of our study should be that of translating the results obtained on CACS/OS symptoms found in advanced cancer patients into a prevention trial in a population of individuals at risk of developing CACS/OS.

  32. STUDY DESIGN- PHASE II STUDY The trial design was: AN OPEN NON RANDOMIZED PHASE II STUDY On the basis of the Simon two-stage design for phase II studies, considering as P0 (i.e. non effective treatment) a total response  40% of patients, and as P1 (i.e. effective treatment) a total response  60% of patients, the treatment has to be considered effective if at least 18/34 patients demonstrate a response in the first stage, while in the second stage 21/39 patients should demonstrate a response. Mantovani G, et al Cancer Epidemiol, Biomarkers and Prev, 2004, 13:1651-9 and 2006,15:1030-4

  33. PATIENT ELIGIBILITY CRITERIA: • 18 to 80 years old • hystologically confirmed tumors of any site especially cancers inducing early CACS (head and neck and gastrointestinal cancer) • patients with the following nutritional characteristics: • 1) patients who had lost at least 5% of ideal or pre-illness body weight in the last 3 months (clinical CACS); • 2) and/or with abnormal values of proinflammatory cytokines, ROS and antioxidant enzymes predictive of the onset of CACS • patients treated with either antineoplastic therapy with curative or palliative intent or supportive care • patients with a life expectancy > 4 months. Mantovani G, et al Cancer Epidemiol, Biomarkers and Prev, 2004, 13:1651-9 and 2006,15:1030-4

  34. PATIENT EXCLUSION CRITERIA: • pregnancy • significant comorbidities • Impaired food intake due to mechanical obstruction • medical treatments inducing significant changes of patient metabolism or body weight such as enteral or parenteral nutrition, corticosteroids, insulin, or any other drug potentially capable of influencing body weight. Mantovani G, et al Cancer Epidemiol, Biomarkers and Prev, 2004, 13:1651-9 and 2006,15:1030-4

  35. TREATMENT PLAN On the basis of several of our previously published studies and our clinical experience we have developed an innovative approach which consists of an integrated nutritional and pharmacological treatment: • 1. diet with high poliphenols content (400 mg) obtained by alimentary sources (onions, apples, oranges, red wine, or green tea) or supplemented by tablets per os; • 2.pharmaco-nutritional support enriched with n-3 PUFA containing EPA and DHA; • 3. oral progestagen:medroxyprogesterone acetate 500 mg/day; • 4. antioxidant treatment with alpha lipoic acid 300 mg/day + carboxycysteine lysine salt 2.7 g/day + vitamin E 400 mg/day + vitamin A 30000 IU + vitamin C 500 mg/day. • Selective COX-2 inhibitor: Celecoxib 200 mg/day orally • The planned treatment duration is 16 weeks. Mantovani G, et al Cancer Epidemiol, Biomarkers and Prev, 2004, 13:1651-9 and 2006,15:1030-4

  36. RATIONALE FOR SELECTED AGENTS 1. The polyphenols, in particular quercetin have been included for their high activity as antioxidants. 2. The oral dietary supplement has the objective to integrate the energetic/proteic intake with the supplementation of n-3 PUFA, which are able to inhibit cytokine production (TNFa). 3. The treatment with medroxyprogesterone acetate has the objective to inhibit the cytokine production and to act positively on patients cenestesis: our previous experimental and clinical experience with MPA supports this choice. 4. The selected antioxidant treatment has been demonstrated effective in reducing blood levels of ROS and increasing blood levels of physiological antioxidant enzymes in a series of our published papers. 5. The COX-2 selective inhibitor Celecoxib has been chosen for its ability, demonstrated both in experimental and in clinical studies, to inhibit cancer-related inflammatory mediators (PGE2), angiogenesis and therefore cancer progression as well as CACS causal factors.

  37. EFFICACY VARIABLES: • The following CLINICAL VARIABLES have been evaluated and the following changes were to be considered as significant for response: • Objective clinical response before and after treatment: improvement or disease stability • Performance status according to ECOG scale before and after treatment: improvement of 1 unit Mantovani G, et al Cancer Epidemiol, Biomarkers and Prev, 2004, 13:1651-9 and 2006,15:1030-4

  38. EFFICACY VARIABLES: The following NUTRITIONAL/FUNCTIONALvariables have been evaluated and the following changes were to be considered as significant for response: • Body Weight: increase of at least 5% • Lean Body Mass (LBM) by BIA: • increase of at least 10% • Appetite evaluated by analogue visual scale (VAS): an increase of at least 2 units; • grip strenght by dinamometer: • an increase of at least 30% • REE by indirect calorimetry: a decrease of at least 10%

  39. EFFICACY VARIABLES: The following LABORATORY variables have been evaluated and the following changes were to be considered as significant for response: by ELISA ASSAY • serum levels of proinflammatory cytokines (IL-6 and TNF a): a decrease of at least 25% in comparison to baseline values; • serum leptin levels: an increase of at least 100% in comparison to baseline values ; • blood levels of reactive oxygen species (ROS): a decrease of at least 80-100 Fort U in comparison to baseline values; • erythrocyte levels of glutathione peroxidase (GPx): an increase of at least 2000 Units (50%) in comparison to baseline.

  40. EFFICACY VARIABLES: The following QUALITY OF LIFEvariables have been evaluated and the following changes were to be considered as significant for response: • EORTC QLQ-C30: an increase of at least 25% of the score • EQ-5D INDEX and VAS: an increase of at least 25% of the score • Multidimensional Fatigue Symptom Inventory-Short Form is a 30-item questionnaire evaluating the principal manifestations of fatigue: a decrease of at least 25% of the score

  41. PATIENT CHARACTERISTICS No. % Patients evaluable 39 M/F: 23/16 Mean age 58.9 y, range 42-78 Mean weight 55.8 kgs, range 36-76 Body mass index (kg/m2) <18.5 9 23.1 18.5-25 25 64.1 >25 5 12.8 Stage IIIA 1 2.6 IV 38 97.4 Performance Status (ECOG) ECOG 0 2 5.1 ECOG 1 27 69.2 ECOG 2 10 25.7 Mantovani G, et al Cancer Epidemiol, Biomarkers and Prev, 2004, 13:1651-9 and 2006,15:1030-4

  42. PATIENT CHARACTERISTICS: TUMOR SITES Mantovani G, et al Cancer Epidemiol, Biomarkers and Prev, 2004, 13:1651-9 and 2006,15:1030-4

  43. BODY WEIGHT AND LEAN BODY MASS (LBM) CHANGE AFTER 1, 2 AND 4 MONTHS OF TREATMENT COMPARED TO BASELINE 39 patients were evaluable after 1 , 2 and 4 months of treatment kg p=0.001 p=0.031 p=0.036 p=0.024 p=0.045 N.S. p=0.011 N.S. N.S. Bars represent the mean increase in comparison to baseline (0). Significance was evaluated by Student’ s t -test for paired data. N.S., not significant Mantovani G, et al Cancer Epidemiol, Biomarkers and Prev, 2004, 13:1651-9 and 2006,15:1030-4

  44. PROINFLAMMATORY CYTOKINES AND LEPTIN BEFORE AND AFTER 1, 2 AND 4 MONTHS OF TREATMENT 39 patients were evaluable after 1 , 2 and 4 months of treatment pg/ml ng/ml N.S. pg/ml p=0.021 p=0.011 P<0.0001 p=0.0006 p=0.025 p=0.016 p=0.01 p=0.016 Results are expressed as mean values. Significance was calculated by Student’ t test for paired data. N.S. not significant Mantovani G, et al Cancer Epidemiol, Biomarkers and Prev, 2004, 13:1651-9 and 2006,15:1030-4

  45. BLOOD LEVELS OF REACTIVE OXYGEN SPECIES (ROS) AND GLUTATHIONE PEROXIDASE (GPx) BEFORE AND AFTER 1, 2 AND 4 MONTHS OF TREATMENT 39 patients were evaluable after 1 , 2 and 4 months of treatment Fort U U/l N.S. N.S. N.S N.S. N.S p=0.033 Results are expressed as mean values. Significance was calculated by Student’ t test for paired data. N.S. not significant Mantovani G, et al Cancer Epidemiol, Biomarkers and Prev, 2004, 13:1651-9 and 2006,15:1030-4

  46. Change of Resting Energy Expenditure in 3 ouf of 5 patients studied with indirect calorimetry before and after treatment REE values Bars represent the observed minus expected values of REE Mantovani G, et al Cancer Epidemiol, Biomarkers and Prev, 2004, 13:1651-9 and 2006,15:1030-4

  47. EVALUATION OF APPETITE AND QUALITY OF LIFE AFTER 1 MONTH, 2 AND 4 MONTHS OF TREATMENT Questionnaire baseline 1 month 2 months 4 months VAS-APPETITE 5.5± 2.5 6.6 ± 2.2* 6.8 ± 1.9* 7.0 ± 1.6* EORTC-QLQ C30 66 ± 16.4 72.4 ± 15.6* 71.8± 14.6* 70.9 ± 14.6* EQ-5D index 0.50 ± 0.4 0.58 ± 0.4 0.56 ± 0.4 0.59 ± 0.4 EQ-5D vas 49.4 ± 21.4 58.9 ± 22.7* 58.6± 20.6* 58.7± 19.4 * MSFI-SF 20.1 ± 22.1 14.4 ±20.3 11.8 ± 17.2* 10.8 ± 14.4* Results are espressed as mean score ± SD. Significance was calculated in comparison to baseline by Student’s t-test for paired data. * p<0.05 Mantovani G, et al Cancer Epidemiol, Biomarkers and Prev, 2004, 13:1651-9 and 2006,15:1030-4

  48. CORRELATION BETWEEN LBM CHANGES AND CHANGES OF CLINICAL, NUTRITIONAL/FUNCTIONAL, LABORATORY AND QUALITY OF LIFE VARIABLES Spearman’s rp CLINICAL ECOG PS -0.09 0.568 NUTRITIONAL/FUNCTIONAL APPETITE 0.08 0.664 GRIP STRENGHT 0.01 0.949 LABORATORY IL-6 -0.40 0.013 TNFa -0.17 0.321 LEPTIN +0.26 0.121 ROS 0.11 0.529 GPx 0.05 0.747 QL QUESTIONNAIRES EORTC QLQ C30 0.17 0.303 EQ-5D INDEX 0.02 0.913 EQ-5D VAS 0.28 0.097 MSFI-SF 0.21 0.271

  49. ASSESSMENT OF “RESPONDERS” AND “NON RESPONDERS” THE CONCLUSIVE ANALYSIS ON 39 PATIENTS WHO HAVE COMPLETED THE TREATMENT SHOWED 17 PATIENTS “RESPONDERS” AND 5 “HIGH RESPONDERS” THE 22/39 “RESPONDERS” PATIENTS DEMONSTRATE THE EFFICACY OF TREATMENT. THE MINIMUM REQUIRED ACCORDING TO THE SIMON’S DESIGN WAS 21/39“RESPONDERS”. Mantovani G, et al Cancer Epidemiol, Biomarkers and Prev, 2004, 13:1651-9 and 2006,15:1030-4

  50. CONCLUSIONS • The treatment has demonstrated to be EFFECTIVEas for: • - increase of body weight • - increase of lean body mass • decrease of proinflammatory cytokines • improvement of quality of life parameters • amelioration of fatigue symptom • The treatment has demonstrated to be • SAFEwith good compliance of patients. Mantovani G, et al Cancer Epidemiol, Biomarkers and Prev, 2004, 13:1651-9 and 2006,15:1030-4

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