Download Diapositiva 1

LA CACHESSIA NEOPLASTICA
Prof. Giovanni Mantovani
Cattedra di Oncologia Medica
Università degli Studi di Cagliari
 nausea/vomiting
 anorexia
 anemia
 weight loss
 depletion of both fat
and muscle tissue
SYMPTOMS OF
CANCER-RELATED
CACHEXIA
 immunodepression
 fatigue
 resistance to antineoplastic treatments
and enhancement of their side effects
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. 1998;20:3
Ottery FD. Cancer Pract. 1994;2:123
DeWys WD, et al. Am J Med. 1980;69:491
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.
Neoplastic Cachexia Syndrome
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
METABOLIC CHANGES:
CACHEXIA VS. STARVATION
Cachexia
Body Weight
Starvation
–/
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
Adapted from Kotler DP. 2000. Ann Intern Med. 133:622
NO
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)
CHANGES OF GLUCOSE METABOLISM IN
CANCER CACHEXIA
 PROTEIN AND LIPID
STORES
GLYCEROL +
FREE FATTY
ACIDS
 GLUCONEOGENESIS
a)
 CORI CYCLE
b)
hyperglicaemia
c)
IMPAIRED GLUCOSE TOLERANCE
d)
INSULIN RESISTANCE
hypoglicaemia
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
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
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
Glucose production
and turnover
 Lipogenesis
 lipolysis
Resting
Energy
Expenditure
Protein
catabolism
Protein
synthesis
Argiles JM, Med Res Rev, 1999
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
PRO CACHECTIC
CYTOKINES
ANTI- CACHECTIC
CYTOKINES
TNF, IL-6, IL-1,IFN-g
IL-4, IL-10, IL-15,
sTNFR, sIL-6R
PIF, LMF, ETC..
ANOREXIA
METABOLIC
ALTERATIONS
CACHEXIA
TUMOR
LYMPHOCYTES
MONOCYTES/
MACROPHAGES
CYTOKINES (IL-1, IL-6, TNFa)
CENTRAL NERVOUS
SYSTEM
 CRF AND
SOMATOSTATINE
LIPID
METABOLISM
GLUCOSE
METABOLISM
DAMAGE ON
 LIPOPROTEINLIPASE
PANCREATIC b CELLS
 IGF-1
LYPOLISIS
HYPERTRIGLICERIDEMIA
HYPOINSULINEMIA
PROTEOLYSIS
 ADIPOCYTE SIZE
IMPAIRED GLUCOSE
METABOLISM
NAUSEA AND VOMITING
 FAT TISSUE
HYPO/HYPERGLICAEMIA
 GH  ANOREXIA
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
HYPOTHALAMIC NEUROPEPTIDE CIRCUITRY IN CACS
ANOREXIGENIC
NEUROPEPTIDES
P
H
Y
S
I
O
L
O
G
Y
OREXIGENIC NEUROPEPTIDES
NEUROTENSIN
MCH
CART/GLP-I
 LEPTIN 
OREXIN/GALANIN
MELANOCORTIN
AGRP
CRF
NPY
+
 GHRELIN 
C
A
C
S
IL-1, IL-6,
TNF-a, IFN-g
 Leptin;  ghrelin
 SEROTONIN
 TRYPTOPHAN
DECREASED FOOD INTAKE
INCREASED RESTING ENERGY EXPENDITURE
PHYSIOLOGY OF CENTRAL EFFECT OF LEPTIN IN
REGULATING NEUROENDOCRINE FUNCTION AND ENERGY
HOMEOSTASIS
food intake
energy expenditure
food intake
energy expenditure
LEVELS OF C-REACTIVE PROTEIN, FIBRINOGEN,
PROINFLAMMATORY CYTOKINES AND LEPTIN IN ADVANCED
CANCER PATIENTS
50
*
40
*
30
20
*
*
*
controls
*
10
cancer patients
0
CRP
Fbg
IL-6
TNF
IL-1
leptin
alpha
* p<0.005 in comparison to controls
J Mol Med 2000; 78: 554-561
SERUM LEPTIN LEVELS IN CANCER PATIENTS
ACCORDING TO STAGE
80
leptin (ng/ml)
70
60
50
40
30
*
20
10
0
Controls
stage I-II
stage III-IV
* p=0.009 Mann-Whitney test: patients versus controls
J Mol Med 2001; 79: 406-414
SERUM LEVELS OF LEPTIN AND PROINFLAMMATORY
CYTOKINES IN CANCER PATIENTS ACCORDING TO
PERFORMANCE STATUS
60
50
40
leptin
30
TNF alpha
20
IL-6
10
0
controls
ECOG 0
ECOG 1
ECOG 2
ECOG 3
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
CACS
LOW LEPTIN LEVELS
___
Hyperphagia
 REE
Weight loss
Anorexia
 REE
Tumor
T-Lymphocytes
Macrophages
Cytokines
IL-1, IL-,TNFa
ROS
ACTIVATED
IMMUNE SYSTEM
5-HT, CYTOKINES
CRH
Neuropeptide Y
emesis
Anorexia
REDUCED FOOD INTAKE
OXIDATIVE STRESS
“Imbalance between oxidants and antioxidants
in favor of oxidants”
Enzymatic antioxidants:
O2 - 
OH
H2O2
Glutathione Peroxidase,
Superoxide Dismutase, Catalase
Non enzymatic antioxidants:
GSH, Lipoic Acid, Vit C, Vit E,
Flavonoids, Carotenoids
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
Nausea/vomiting
metabolic alterations
Reduced energy intake
Impairment of
Immune system
Free radicals
(especially glucose)
Reduction of
antioxidant defences
(GSH)
OXIDATIVE
STRESS
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
ERYTHROCYTE ACTIVITY OF SOD AND GPx IN CANCER
PATIENTS ACCORDING TO STAGE AND PERFORMANCE STATUS
GPx
U/L whole
blood
12000
10000
8000
*
6000
4000
Results are expressed as
mean values.
2000
0
Controls
Stage II Stage III Stage IV
Stage IV
ECG 0/1
ECOG 2/3
SOD
100
90
80
* p<0.05 as calculated with
Student’s t-test in
comparison to controls
U/ml whole
blood
70
60
50
*
40
30
20
10
0
Controls
Stage II Stage III Stage IV
Stage IV
ECOG 0/1 ECOG 2/3
Mantovani G, et al. Int J Cancer, 2002
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
SERUM LEVELS OF IL-1a, IL-1b, IL-2, IL-6, TNFa AND sIL2R IN CANCER PATIENTS BEFORE AND AFTER
CHEMOTHERAPY + MA TREATMENT
60
50
N.S
40
30
20
10
0
*
N.S
N.S
N.S
before treatment
after treatment
*
IL-1
IL-1
alpha
beta
IL-2
IL-6
TNF
sIL-
alpha
2R
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
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
EFFECT OF MEDROXYPROGESTERONE ACETATE ON CYTOKINES
AND 5-HT PRODUCTION BY PBMC OF ADVANCED CANCER
PATIENTS
Cytokines (pg/mL); 5-HT (nM/mL)
7000
*
6000
§
5000
4000
3000
Controls PHA-stimulated
PBMC
*
*
§
§
Patients PHA-stimulated
PBMC
*
2000
*
1000
§
Patients PHA+MPA (0,2
microg/mL) stimulated
PBMC
0
IL-1 beta
IL-6
TNF
alpha
IL-2
5-HT
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
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
2004; 13:1651-1659
Cancer Epidemiol Biomarkers and Prev
2006; 15:1030-1034
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.
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
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
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
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.
5. 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
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.
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,
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;
 REE by indirect calorimetry: a
decrease of at least 10%
 grip strenght by dinamometer:
an increase of at least 30%
EFFICACY VARIABLES:
The following LABORATORY variables have been evaluated and
the following changes were to be considered as significant for
response:
 serum levels of proinflammatory
by ELISA ASSAY
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.
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
PATIENT CHARACTERISTICS
Patients evaluable
No.
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
18.5-25
>25
9
25
5
23.1
64.1
12.8
Stage
IIIA
IV
1
38
2.6
97.4
Performance Status (ECOG)
ECOG 0
ECOG 1
ECOG 2
2
27
10
5.1
69.2
25.7
Mantovani G, et al Cancer Epidemiol, Biomarkers and Prev,
2004, 13:1651-9 and 2006,15:1030-4
PATIENT CHARACTERISTICS: TUMOR SITES
kidney
uterine sarcoma
pancreas
stomach
ovary
breast
lung
head and neck
0
5
10
15
20
number of patients
Mantovani G, et al Cancer Epidemiol, Biomarkers and Prev,
2004, 13:1651-9 and 2006,15:1030-4
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
8
7
6
kg
5
4
weight
3
LBM
2
1
p=0.001
N.S.
N.S.
p=0.036
p=0.045
N.S.
p=0.031
p=0.024
p=0.011
dry LBM
0
-1
1 month
2 months
4 months
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
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
25
N.S.
20
pg/ml
p=0.021
p=0.011
15
10
ng/ml
p=0.0006
p=0.01
p=0.016
P<0.0001
p=0.025
p=0.016
baseline
1 month
2 months
4 months
5
0
IL-6
TNF alfa
Leptin
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
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
550
500
10000
Fort U
N.S
p=0.033
450
N.S
9000
U/l
N.S.
7000
350
6000
300
5000
250
4000
GPx
ROS
1 month
2 months
N.S.
8000
400
baseline
N.S.
4 months
baseline
1 month
2 months
4 months
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
Change of Resting Energy Expenditure in 3 ouf of 5 patients
studied with indirect calorimetry before and after treatment
REE values
30
25
20
15
10
5
0
-5
-10
-15
PT
MG
CG
Baseline
2 months
Patients
Bars represent the observed minus expected values of REE
4 months
Mantovani G, et al Cancer Epidemiol, Biomarkers and Prev,
2004, 13:1651-9 and 2006,15:1030-4
EVALUATION OF APPETITE AND QUALITY OF LIFE AFTER 1
MONTH, 2 AND 4 MONTHS OF TREATMENT
Questionnaire
baseline
1 month
VAS-APPETITE
5.5± 2.5
6.6 ± 2.2*
EORTC-QLQ C30
66 ± 16.4 72.4 ± 15.6*
EQ-5D index
0.50 ± 0.4
EQ-5D vas
49.4 ± 21.4 58.9 ± 22.7*
MSFI-SF
20.1 ± 22.1
0.58 ± 0.4
14.4 ±20.3
2 months
4 months
6.8 ± 1.9*
7.0 ± 1.6*
71.8± 14.6*
70.9 ± 14.6*
0.56 ± 0.4
0.59 ± 0.4
58.6± 20.6*
58.7± 19.4 *
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
CORRELATION BETWEEN LBM CHANGES AND CHANGES OF
CLINICAL, NUTRITIONAL/FUNCTIONAL, LABORATORY AND
QUALITY OF LIFE VARIABLES
CLINICAL
ECOG PS
NUTRITIONAL/FUNCTIONAL
APPETITE
GRIP STRENGHT
LABORATORY
IL-6
TNFa
LEPTIN
ROS
GPx
QL QUESTIONNAIRES
EORTC QLQ C30
EQ-5D INDEX
EQ-5D VAS
MSFI-SF
Spearman’s r
p
-0.09
0.568
0.08
0.01
0.664
0.949
-0.40
-0.17
+0.26
0.11
0.05
0.013
0.321
0.121
0.529
0.747
0.17
0.02
0.28
0.21
0.303
0.913
0.097
0.271
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
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,
STUDIO CLINICO RANDOMIZZATO DI FASE III PER
VALUTARE L'EFFICACIA E LA TOLLERABILITÀ DI UN
TRATTAMENTO INTEGRATO (DIETETICO, FARMACONUTRIZIONALE 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.
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.
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..
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.
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.
RESULTS
From March to July 2004, 12 patients who had advanced tumors
(50% at stage IV) at different sites were enrolled
(M/F ratio 2:10, mean age 60 y, range 42–73).
APPETITE (VAS)
MFSI-SF
7
30
6
25
5
20
4
15
3
10
2
5
1
0
t0
t1
t2
0
t0
t1
t2
LEAN BODY MASS
EQ-5D VAS
41
80
40
60
39
40
38
20
37
36
0
t0
t1
t2
t0
t1
t2
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)
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.
PATIENT CHARACTERISTICS
Patients enrolled at October 2006
No.
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)
<18.5
18.5-25
>25
13
88
10
11.7
79.3
9.0
Stage
III
IV
6
105
5.4
94.6
Performance Status (ECOG)
ECOG 0
ECOG 1
ECOG 2
ECOG 3
3
57
49
2
2.7
51.4
44.1
1.8
PATIENT CHARACTERISTICS: TUMOR SITES
melanoma
oesophagus
peritoneal
prostate
thymoma
neuroendocrine
LNH
kidney
bladder
biliary duct
uterus
lung
head and neck
stomach
ovary
colorectal
breast
pancreas
0
number of patients
5
10
15
20
RANDOMIZATION
ARM 5
ARM 4
ARM 3
ARM 2
ARM 1
0
number of patients
5
10
15
20
25
30
CHANGES OF BODY COMPOSITION DURING TREATMENT:
AN EXAMPLE
FAT MASS: +0.8 KG
BODY CELL MASS:+2.5 KG
CHANGES OF PHASE ANGLE DURING TREATMENT:
AN EXAMPLE
Phase angle at the
end of treatment: 3.9
Phase angle at baseline: 3.1
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
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)
Thank you for your attention
and interest!