LA CACHESSIA NEOPLASTICA

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 (Laviano A, 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. 1998203 Ottery FD.
Cancer Pract. 19942123 DeWys WD, et al. Am J
Med. 198069491
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 CHANGESCACHEXIA VS. STARVATION
Cachexia Starvation
Body Weight /
Body Cell Mass (Lean Body Mass)
Body Fat
Caloric Intake
Total Energy Expenditure (TEE)
Resting EE (REE)
Protein Synthesis
Protein Degradation
Proteolysis-Inducing Factor (PIF) YES NO
Adapted from Kotler DP. 2000. Ann Intern Med.
133622
6
CHANGES OF ENERGY METABOLISM

• In cancer patients in advanced stage of disease,
  a characteristic deregulation of energy
  metabolism is frequently observed
• ? increased energy expenditure due 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 (APPC
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 IMP
AIRED 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






plt0.005 in comparison to controls
J Mol Med 2000 78 554-561
17
SERUM LEPTIN LEVELS IN CANCER PATIENTS ACCORDING
TO STAGE
leptin (ng/ml)

p0.009 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 200179406-414
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
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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
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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. plt0.001
versus controls (Students 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. plt0.05
as calculated with Students 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
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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. plt0.05 as
calculated with Students 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
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EFFECT OF MEDROXYPROGESTERONE ACETATE ON
CYTOKINES AND 5-HT PRODUCTION BY PBMC OF ADVANCED
CANCER PATIENTS









Results are expressed as mean values. plt0.05,
calculated with Students t test versus controls
plt0.05, calculated with Students 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
151030-1034
Cancer Epidemiol Biomarkers and Prev 2004
131651-1659
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 was to 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.

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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, 131651-9 and 2006,151030-4
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 gt 4 months.

Mantovani G, et al Cancer Epidemiol, Biomarkers
and Prev, 2004, 131651-9 and 2006,151030-4
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, 131651-9 and 2006,151030-4
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, 131651-9 and 2006,151030-4
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, 131651-9 and 2006,151030-4
38
EFFICACY VARIABLES The following
NUTRITIONAL/FUNCTIONAL variables 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 LIFE
variables 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)
• lt18.5 9 23.1
• 18.5-25 25 64.1
• gt25 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, 131651-9 and 2006,151030-4
42
PATIENT CHARACTERISTICS TUMOR SITES
Mantovani G, et al Cancer Epidemiol, Biomarkers
and Prev, 2004, 131651-9 and 2006,151030-4
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
p0.001
p0.031
p0.036
p0.024
p0.045
N.S.
p0.011
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, 131651-9 and 2006,151030-4
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
p0.021
p0.011
Plt0.0001
p0.0006
p0.025
p0.01
p0.016
p0.016
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, 131651-9 and 2006,151030-4
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
p0.033
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, 131651-9 and 2006,151030-4
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, 131651-9 and 2006,151030-4
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 Students t-test for paired data.
plt0.05
Mantovani G, et al Cancer Epidemiol, Biomarkers
and Prev, 2004, 131651-9 and 2006,151030-4
48
CORRELATION BETWEEN LBM CHANGES AND CHANGES
OF CLINICAL, NUTRITIONAL/FUNCTIONAL, LABORATORY
AND QUALITY OF LIFE VARIABLES
Spearmans r p 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 SIMONS DESIGN WAS 21/39RESPONDERS.
Mantovani G, et al Cancer Epidemiol, Biomarkers
and Prev, 2004, 131651-9 and 2006,151030-4
50
CONCLUSIONS

• The treatment has demonstrated to be EFFECTIVE as
  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
• SAFE with good compliance of patients.

Mantovani G, et al Cancer Epidemiol, Biomarkers
and Prev, 2004, 131651-9 and 2006,151030-4
51
STUDIO CLINICO RANDOMIZZATO DI FASE III PER
VALUTARE L'EFFICACIA E LA TOLLERABILITÀ DI UN
TRATTAMENTO INTEGRATO (DIETETICO,
FARMACO-NUTRIZIONALE E FARMACOLOGICO) IN PAZIENTI
NEOPLASTICI CON CACS E STRESS OSSIDATIVO.
A phase III randomised study has started in
February 2005 as a multicenter trial. AIM OF
THE STUDY to demonstrate which is/are the most
effective treatment or treatments for CACS in
terms of amelioration of some key of CACS, i.e.
LBM, resting energy expenditure, daily physical
activity, proinflammatory cytokines and quality
of life parameters.
52

• 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 gt 4 months.

53

• PATIENT EXCLUSION CRITERIA
• pregnancy
• significant comorbidities
• Impaired food intake due to mechanical
  obstruction
• controindications to use of MPA such as positive
  history of thromboembolic event and deep venous
  thrombosis
• medical treatments inducing significant changes
  of patient metabolism or body weight, such as
  enteral or parenteral nutrition, corticosteroids,
  insulin, etc..

54
TREATMENT PLAN
Patients will be randomised to the following 5
arms of treatment. Poliphenols (300 mg/day)
antioxidants agents (alpha lipoic acid 300 mg/day
carbocysteine 2.7 g/day vitamin E 400 mg/day
vitamin A 30000 IU Vitamin C 500 mg/day) are
the basic treatment. The following components
all orally are added to each arm Arm 1.
Medroxyprogesterone acetate (MPA) 500 mg/day.
Arm 2. Pharmaco-nutritional support containing
EPA, 2-3 briks/day Arm 3. L-carnitine 4
g/day. Arm 4. Thalidomide 200 mg/day Arm 5. MPA
Pharmaco-nutritional support L-carnitine
Thalidomide The planned treatment duration is
16 weeks.
55
(No Transcript)
56

• Fatigue is a multidimensional symptom that is
  described in terms of perceived energy, mental
  capacity, and psychological status it can impair
  daily functioning and lead to negative effects on
  quality of life.
• AIM OF THE STUDY to test the efficacy and safety
  of LC supplementation in a population of patients
  who had advanced cancer and developed fatigue,
  high blood levels of reactive oxygen species, or
  both.
• OUTCOME MEASURES
• fatigue and quality of life
• nutritional status
• laboratory variables levels of reactive oxygen
  species,glutathione peroxidase, and
  proinflammatory cytokines
• TREATMENT PLAN
• L-Carnitine was administered orally at 6 g/day
  for 4 weeks.

57
RESULTS
From March to July 2004, 12 patients who had
advanced tumors (50 at stage IV) at different
sites were enrolled (M/F ratio 210, mean age 60
y, range 4273).
APPETITE (VAS)
MFSI-SF
LEAN BODY MASS
EQ-5D VAS
58
KEY VARIABLES Nutritional/Functional - lean
body mass - grip strenght - resting
energy expenditure - total daily physical
activity and related energy
expenditure Laboratory - Proinflammatory
cytokines IL-6 and TNF a Quality of Life -
fatigue assessed by Multidimensional Fatigue
Symptom Inventory Short Form (MFSI-SF)
59
STATISTICAL ANALYSIS
Hypothesizing a difference between arms of 20,
considering an alpha type error of 0.05 and a
beta type error of 0.20, 95 patients will be
enrolled for each arm for a total of 475
patients. The efficacy of each arm versus the
other ones will be made comparing the arms by the
ANOVA t-test for repeated measures (or the
Kruskall-Wallis test for non parametric
variables) for the "key variables". Moreover,
the benefit obtained by the patients enrolled in
each arm following the treatment will be
evaluated using the paired Student's t test or
Wilcoxon Signed Rank test when appropriate
(pre-treatment vs post-treatment values).
Survival (overall survival and progression-free
survival) will be evaluated starting from the
date of enrollment in the study using the
Kaplan-Meier method.
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PATIENT CHARACTERISTICS

• No.
• Patients enrolled at October 2006 111
• M/F 45/36
• Mean age 61 y, range 35-81
• Mean weight 58.0 kgs, range 38-62
• Body mass index (kg/m2)
• lt18.5 13 11.7
• 18.5-25 88 79.3
• gt25 10 9.0
• Stage
• III 6 5.4
• IV 105 94.6
• Performance Status (ECOG)
• ECOG 0 3 2.7
• ECOG 1 57 51.4
• ECOG 2 49 44.1

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PATIENT CHARACTERISTICS TUMOR SITES
62
RANDOMIZATION
63
CHANGES OF BODY COMPOSITION DURING TREATMENT AN
EXAMPLE
FAT MASS 0.8 KG
BODY CELL MASS2.5 KG
64
CHANGES OF PHASE ANGLE DURING TREATMENT AN
EXAMPLE
Phase angle at the end of treatment 3.9
Phase angle at baseline 3.1
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CHANGE OF TOTAL DAILY PHYSICAL ACTIVITY AND
RELATED ENERGY EXPENDITURE
BASELINE Total energy expenditure (TEE)1677 Kcal
Step count 1273 Physical activity 6 minutes
AFTER 2 MONTHS OF TREATMENT Total energy
expenditure (TEE)1677 Kcal Step count
1273 Physical activity 6 minutes
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PARTICIPATING CENTERS

• Center already included in the study
• Oncologia Medica 1 Policlinico Universitario,
  Cagliari (Prof. Mantovani)
• Oncologia Medica 2 Policlinico Universitario,
  Cagliari (Prof. Massidda)
• Oncologia Medica 2, Ospedale Businco, Cagliari
  (Dott. Floris)
• O. Oncologia Clinica, Azienda Ospedaliera
  Universitaria, Ferrara (Dott. Lelli)
• - Dipartimento di Gastroenterologia, Università
  degli Studi di Bari (Dott. Guglielmi)

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Thank you for your attentionand interest!