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Scuola Mediterranea di Oncologia Chronomodulated
Infusions of Chemotherapeutic Drugs in CRC
Roma 2.2.2007

• Dott. Carlo Garufi
• Oncologia Medica C
• Istituto Regina Elena, Roma

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Chronobiology

• Chronobiology is the study of the temporal
  relationships of biological phenomena
• Biological rhythms have been demonstrated
• For most physiological, biochemical and
  behavioral processes
• From single cell organisms to man
• All Eukaryotes and some Eubacteria
• With several rhythm periods
• High frequency (FSH, LH, heart rate)
• Circadian (24 hour period)
• Menstrual cycle
• Annual variations

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The SCN The Pacemaker for the Circadian Rhythms
in Metabolic / Physiological Processes and Sleep
/ Activity
Suprachiasmatic nuclei (SCN)
Pineal gland Circadian melatonin secretion
Light via retina Synchronizes rhythm to the 24
hour day
Signaling to all organs Autonomic nervous
system Endocrine system
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The Mammalian Molecular ClockTranscriptional /
Translational Feedback Loops of 9 Clock Genes
Clock-Controlled-Genes control biological
rhythms
Negative feedback loop
Cell Cycle
Apoptosis
Clock Controlled Genes
Angiogenesis
Gene expression
Activation loop
Positive feedback loop
Nature Review Neuroscience2003
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Circadian Clock Gene Expression in rodent SCN
and Peripheral Tissues
Dunlap, J.C Cell vol 96, 271-90, 1999
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Impact of Chronotherapy in the Management of
Colorectal Cancer

• Clinical development of oxaliplatin
• Role of dose-intensity in advanced disease
• Neoadjuvant treatment of liver metastases
• Long term survival in the metastatic setting

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Steps for Development of Chronotherapy Studies in
Colorectal Cancer

• Validation of a best timing for a single drug or
  for a combination in the animal model (toxicity,
  activity, chronopharmaco-kinetics)
• Transfer of this model in cancer patients,
  validation in phase II and then phase III trials

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Relevant rhythms in humans
Mouse ?Man Rest-activity cycle
Units
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Monotherapy with chronomodulated 5-fluorouracil
and leucovorin
Garufi et al., EJC 1997
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First line chronomodulated 5-FU-LV-l-OHP in
patients with metastatic colorectal cancer
5 days q 3 weeks (FFL5-16)
5-FU 700 mg/m²/d
Oxaliplatin 25 mg/m²/d
Leucovorin 300 mg/m²/d
Delivery rate (arb. un.)
Phase II ORR 58
4 A.M.
4 P.M.
Lévi et al., Cancer 1992
Time (clock hours)
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Chronotherapeutic development
5-FU, leucovorin, oxaliplatin Colorectal cancers
(1988-2005)
Experimental Chronotherapeutics
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How to Demonstrate the Efficacy of Chronotherapy
in Clinical Trials?

• Proof of Principle Trials crono versus flat
• Trials of Comparison with Standard Therapies
  EORTC 05963
• Best Time Finding Studies EORTC 05011

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First line 5-FU-LV-l-OHP
Constant rate
278 patients with metastatic colorectal cancer
5-FU 600 - 700 mg/m²/d
LV 300 mg/m²/d
Oxaliplatin 20-25 mg/m²/d
Chronotherapy
Each course 5 days on, 16 days off
0400
1600
Time (clock hours)
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Flat vs chrono FFL
Chrono ()
p
Flat ()
Hospitalization for toxicity
31
10
0.001
76
Severe mucositis
14
0.0001
Functional impairment
31
16
0.01
lt 0.001
ORR 95 CI
30
51
9.3mo 7.5 11.1
L.R., 0.18 Wilco., 0.09 Multiv.0.04
Median PFS
7.2 mo 5.6 - 8.8
L.R., 0.78 Wilco., 0.37
Median Survival
16.7 /- 2.9
16.2/- 2.1
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Tolerability of 5-FU-LV-l-OHP according to
delivery schedule
Grade 2-3 sensory neuropathy
Grade 3-4 mucositis
p lt 0.001
p lt 0.01
Constant
Constant
Chrono
Chrono
1
12
1
12
6
6
Number of courses
Lancet 1997 Lancet Oncology 2001
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Messages from chrono versus flat trial

• Chronotherapy
• reduces toxicity
• increases response rate and Progression-Free
  Survival
• does not increase survival

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ChronoFLO4 vs FOLFOX2 (EORTC 05963)
Hypothesis endpoints

• Primary endpoint survival
• Hypothesis 10 difference in 2 year
  survival
• 430 events
• N of patients 282 per arm (?5 ß20)

• Secondary endpoints
• Response rate, Progression-free survival,
  Toxicities

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Chrono FFL4/10 vs FOLFOX2 Treatment delivery
schedules
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05963 TRIAL
Chrono FFL4/10 vs FOLFOX2 Design
Phase III , advanced or metastatic colorectal
cancer, PS lt 3, measurable disease, no prior
chemotherapy for mets

• performance status 0-1 vs 2
• center N 36 in 10 countries
• Liver involvement none vs lt 25 vs 25

Stratification
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ChronoFLO4 vs FOLFOX2 (EORTC 05963)
Overall Survival by treatment arm
Survival (intent to treat)

100
Median survival 95 CL, months FOLFOX2
18.7 17.7 21.0 ChronoFLO4
19.6 18.2 21.2
90
80
70
60
Logrank test, p0.549
50
40
30
20
ChronoFLO4
FOLFOX2
10
(months)
0
0
6
12
18
24
30
36
42
48
54
60
66
O
N
Number of patients at risk
Treatment
229
282
254
204
150
102
63
35
21
10
6
5
FOLFOX-2
221
282
248
200
155
100
65
42
29
19
7
0
Chrono FLO4
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ChronoFLO4 vs FOLFOX2 (EORTC 05963)
Overall survival Gender x Treatment(226 females
/338 males)
Giacchetti et al, JCO 2006
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ChronoFLO4 vs FOLFOX2 (EORTC 05963)

100
Overall Survival by gender
90
Log Rank, P 0.0053 (df3)
80
70
60
Survival ()
50
40
30
20
10
(months)
0
0
7
14
21
28
35
42
49
56
63
O
N
Number of patients at risk
Treatment sex
87
112
100
75
50
29
14
7
4
3
Female/FOLFOX-2
142
170
147
107
70
41
24
14
5
3
Male/FOLFOX-2
100
114
97
67
35
20
13
9
4
0
Female/ChronoFLO4
121
168
141
120
87
56
31
20
13
4
Male/ChronoFLO4
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ChronoFLO4 vs FOLFOX2 (EORTC 05963)

Overall Survival in 226 women with metastatic
colorectal cancer
100
Endpoint FOLFOX2 ChronoFLO4
90
MST (months) 19.1 17.624.1 16.3 14.119.6
80
2-yr survival () 40.8 31.649.9 27.1 18.835.4
70
60
Survival ()
Log Rank, P 0.0269
50
40
30
20
FOLFOX2
10
ChronoFLO4
0
0
7
14
21
28
35
42
49
56
63
Time (months)
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ChronoFLO4 vs FOLFOX2 (EORTC 05963)

Overall Survival in 338 men with metastatic
colorectal cancer
100
Endpoint FOLFOX2 ChronoFLO4
90
MST (months) 18.3 16.8 20.5 21.4 19.3 24.6
80
70
2-yr survival () 34.3 27.2 41.5 43.6 36.151.1
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Survival ()
Log Rank, p 0.0183
50
40
30
ChronoFLO4
20
10
FOLFOX2
0
0
7
14
21
28
35
42
49
56
63
Time (months)
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ChronoFLO4 vs FOLFOX2 (EORTC 05963)
Relative dose intensities (dose given dose
planned over total treatment duration)
Dose intensities were reduced in women vs men
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ChronoFLO4 vs FOLFOX2 (EORTC 05963)
Gender x treatment
Patients ()
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Hypotheses
ChronoFLO4 vs FOLFOX2 (EORTC 05963)

• Schedule duration 2 days better than 4 in
  women? Recovery duration 12 days better than 10
  in women
• High dose intensity chemotherapy alters the
  circadian timing system
• Colorectal cancers in women differ from CRC in
  men
• Optimal circadian time different in females vs
  males

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Message from 05963 Trial

• Chronotherapy
• shows a different pattern of toxicity
• Survival not increased in the entire population
  but only in a subgroup (male patients)

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Impact of Chronotherapy in the Management of
Colorectal Cancer

• Clinical development of oxaliplatin
• Role of dose-intensity in advanced disease
• Neoadjuvant treatment of liver metastases
• Long term survival in the metastatic setting

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Role of oxaliplatin
Trial
phase
Drugs
Pts
Main
results
I
L-OHP
25
ltlt neurotox
JNCI 90
ltlt neutropenia
II
L-OHP
30
RR 10
EJC 93
?
II
35
RR 23
FF
FFL
Drugs
Anti-cancer
2000
III
FF L-OHP
200
RR 16
vs 53
JCO 2000
PFS 0.04
No
difference OS
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Impact of Chronotherapy in the Management of
Colorectal Cancer

• Clinical development of oxaliplatin
• Role of dose-intensity in advanced disease
• Neoadjuvant treatment of liver metastases
• Long term survival in the metastatic setting

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Dose intensity and response rate
70
FU-LV-l-OHP
Chrono 4-10
r 0.95 p 0.001
60
50
Chrono 5-16
Objective responses ()
40
Chrono 4-10
30
Flat 5-16
FU-LV
20
Chrono 5-16
0
0
800
1000
1200
1400
1600
1800
5-FU dose intensity (mg/m²/week)
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Impact of Chronotherapy in the Management of
Colorectal Cancer

• Clinical development of oxaliplatin
• Role of dose-intensity in advanced disease
• Neoadjuvant treatment of liver metastases
• Long term survival in the metastatic setting

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Response rate and surgery of metastases (First
line 5-FU, LV and l-OHP)
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93-94
Chrono 4-10
30
90-93
94-96
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Complete resection of metastases ()
Chrono 5-16
90-93
10
Flat 5-16
r 0.96 p 0.0007
0
0
30
40
50
70
60
Objective responses ()
Secondary surgery of metastases major
prognostic factor of survival
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Impact of Chronotherapy in the Management of
Colorectal Cancer

• Clinical development of oxaliplatin
• Role of dose-intensity in advanced disease
• Neoadjuvant treatment of liver metastases
• Long term survival in the metastatic setting

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Chronotherapy Studies with CPT-11
CPT-11? ASCO 99
CPT-11 bolus vs chrono Giacchetti et al ECCO 01
CPT-11 FF 5-16 Garufi et al Cancer 01
CPT-11 bolus FFL crono Garufi et al BJC 03
CPT-11 crono vs standard FF 4-10 Garufi et al
EJC 05
EORTC 05011 CPT-11? FFL?
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Study 05011
EORTC CHRONOTHERAPY GROUP

• Time finding study of chronomodulated
• irinotecan, 5-fluorouracil, leucovorin and
  oxaliplatin
• as first or second chemotherapy line
• against metastatic colorectal cancer

Coordinator C.Garufi, Rome
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EORTC study 05011 Colorectal
Trial Design
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Table 1. Patient enrolled in two consecutive
EORTC Chronotherapy Group Trials at IRE
05963 05011
N of patients 59 () 54 ()
Gender F/M 28 (47)/31(53) F/M 19(35)/35(65)
Median age (years) 60 (27-82) 58 (29-76)
WHO PS 0 1 2 42(72) 9(15) 8 (13) 39(75) 11(19) 3(6)
Primary Tumor site Colon Rectum 42 (71) 17 (29) 45 (83) 9 (17)
Metastases Synchronous Metacronous 41 (69) 18 (31) 49 (91) 5 (9)
Site of metastases Liver Lung Nodes Peritoneum 52 (88) 11 (18) 3 (5) 9 (15) 46 (85) 7 (13) 3 (6) 4 (7)
Liver involvement lt25 gt25 multiple diffuse hilar extraepatic 18(30) 34(57) 39(66) 11(18) 9(15) 14 (26) 32(60) 28 (51) 6 (11) 12 (22)
N of organs involved 1 gt2 31 (53) 28 (47) 39 (72) 15 (28)
CEA CA 19-9 295 693,7 701 2432,7 597 1298,1 672 1707,9

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Table 2. Patients with liver metastases
05963 05011
Liver only 30/52 34/46
N of patients submitted to surgery 7 (13.4) c.i 4.2-22.7 14 (30.4) c.i 17-43.7
N of courses of chemotherapy before surgery 16 (10-29) 9 (6-13)
Median time before surgery (days) 283 (66-484) 240 (162-342)
Median time from last course to surgery (days) 49 (37-170) 38 (24-135)
Median time from surgery to postop chemotherapy (days) na 41 (16-106)
Median time of chemo post-surgery (months) na 6 (1-16)
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Table 4. Surgery
05963 05011
R0 5 14
R1 1 0
Exploratory Laparotomy 1 0
Wedge resections 1 7
Anatomic resections 3 2
Right hepatectomy 2 1
Two-stage hepatectomy - 4
Re-hepatectomy - 3
Postoperative mortality 0 0
Mortalitylt 60 days 0 0
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TTP overall group
TTP pts with liver metastases
20.0 (0-78) months
Median Follow-up
16.0 (0-38) months
10.0 (7,9-12,0) months
05963
9.0 (7,4-10,5) months
P 0.05
P 0.007
05011
13.0 (6,7-19,2) months
15.0 (8,3-21,7) months
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Cetuximab CPT-11/OXA/FA/FU cronomodulato
(IRE)
CPT11 (130 mg/mq, g.1)/5FU (600 mg/mq/die gg.
1-4)/FA (150 mg/mq/die gg. 1-4)/L-OHP (20
mq/mq/die gg. 1-4) Cetuximab for 4-6 cycles
Patient with non-resectable colorectal liver
metastases
Evaluation for surgery
Non-resectable
Resectable
Chemo Cetuximab for 4-6 cycles
Continue until PD
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Patients will be considered non-resectable
according to these criteria (IRE)

• Size
• Multinodular
• Ilar location
• Extraepatic disease
• Patients with gt3 metastases who receive
  chemotherapy in order to stabilize liver disease
  before surgery
• Patients who present with huge resectable liver
  metastases at the time of resection of the
  primary tumor and need extended liver surgery

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Which choice for patients with clinical complete
response ?
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DOA

• DOA born on 01/06/1945
• 22/10/04 right emicolectomy. Hist ADC G2
  pT3N1M1 for a huge liver metastases.
• 30.11.04 FOLFIRI x 14 c
• with reduction lt 25
• 20.05.05 FOLFOX2 x 5 c

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• 04.04.06 left liver hypertrophy

• 01.09.05 Cetuximab CPT11- FFL
• 02.04.06 portal embolization
• 04.05.06 extended right hepatectomy
• with only necrosis in the resected specimen

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REST/ACTIVITY RHYTHM THE ACTIGRAPH
Piezo-electric accelerometer Number of wrist
accel./minute Allows continuous recording,
over a long time
period. Parameters 24-h pattern and alternance
of rest and activity.
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Correlation Rest/activity and Cortisol
rhythms, TGF-? and cytokines, and symptoms.
Individual patient circadian rhythm assessment by actigraphy. Cortisol Ratio (Slope) Serum TGF-? Serum IL-6 Symptoms
Robust Rhythm (autocorrelation gt0.47) 1.72 (Steep) Low Low Less fatigue, appetite loss.
Dampened Rhythm (autocorrelation lt0.35) 1.60 (Flat) High High More fatigue and appetite loss.
p lt 0.05
Clin Cancer Res 2005 11(5)1757-1764
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Independent prognostic value of the rest/activity
circadian rhythm on overall survival (OS) in
patients (pts) with metastatic colorectal cancer
(MCC) receiving first line chemotherapy with
5-fluorouracil, leucovorin and oxaliplatin a
companion study to EORTC 05963. C. Garufi et al.
ASCO 2005
The data confirmed the strong and indipendent
prognostic value of the RAR for the survival of
MCC patients in a multicentre randomized trial
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Quality of life (QoL) correlates with the
rest/activity circadian rhythm (RAR) in patients
(pts) with metastatic colorectal cancer (MCC) on
first line chemotherapy with 5-fluorouracil,
leucovorin and oxaliplatin an international
multicenter study (EORTC 05963). P.F.
Innominato et al. ASCO 2005
The correlation between RAR and Global QoL and
symptom scores as fatigue and anorexia was
confirmed for the first time in a multicenter
setting
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Approccio integrato sulla Qualità di Vita presso
lIRE

• Qualità di vita durante la cronoterapia
• Qualità di vita e sopravvivenza
• Efficacia dellintervento psicologico

Pugliese P et al. Health and Quality of Life
Outcomes, 2006
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Studi di Cronotherapia presso lIRE
5FU/FA? Garufi et al EJC 97
5FU/FA FFL Garufi et al Anticancer
Drugs 01
CPT-11 FF 5-16 Garufi et al Cancer 01
CPT-11 bolus FFL crono Garufi et al BJC 03
CPT-11 crono vs standard FF 4-10 Garufi et al
EJC 06
EORTC 05011 CPT-11? FFL?
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Quality of life during chronotherapy 123
Patients (QLQ C30)
plt 0.05
WEEKS OF ASSESSMENT
Wilcolxon test
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Qualità di vita durante cronoterapia

• La lunghezza del trattamento ha un effetto
  negativo sulla qualità di vita dopo 4 mesi di
  terapia

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Analisi Univariata e Multivariata sec Cox per la
Sopravvivenza
Variables Hazard ratio (HR) 95 Confidence Interval P-value
UNIVARIATE UNIVARIATE UNIVARIATE UNIVARIATE
Sex 0.677 0.462-0.991 0.04
Performance Status 0.277 0.163-0.469 lt0.0001
Age n.s.
Site of primary tumor n.s
Number site involved 0.605 0.402-0.911 0.01
Qol parameters
Physical Functionig 0.988 0.979-0.996 0.004
Emotional Functioning 0.99 0.982-0.998 0.01
Social Functioning 0.992 0.923-1.000 0.04
Fatigue 1.014 1.007-1.021 lt0.0001
Pain 1.011 1.004-1.018 0.002
Nausea/vomiting n.s.
Appetite Loss 1.007 1.000-1.014 0.04
Costipation n.s.
Diarrhoea n.s.
Global QoL 0.978 0.970-0.986 lt0.0001
MULTIVARIATE MULTIVARIATE MULTIVARIATE MULTIVARIATE
Performance Status 0.387 0.221-0.677 lt0.0001
Global QoL 0.977 0.969-0.986 lt0.0001
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The ErbB Family and Ligands
EGF TGF-? Amphiregulin ?-cellulin HB-EGF Epireguli
n
HB-EGF Heregulins ?-cellulin
No KnownLigands
Heregulins
Extracellular
Tyrosine Kinase Domain
Intracellular
ErbB-1HER1 EGFR
ErbB-2 HER2 neu
ErbB-3 HER3
ErbB-4 HER4
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EGFR-mediated regulation of activity
Kramer A, et al., Science 2001
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Transgenic TGF-a mice

• Significant loss of activity.
• NO difference in phase in DD.
• These results are consistent with hypothalamic
  modulation since the clock is intact.

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TGF-alpha Wild type
Rest Activity
Rest Activity
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Summary of preclinical model

• TGF-a (EGFR ligands), PK2 (VEGF), and CLC (IL-6)
  are inhibitory when infused into the 3rd
  ventricle.
• Peripheral production of TGF-? produces loss of
  activity.
• Is TGF-a responsible for fatigue and related
  symptoms in cancer patients?

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(Cleeland, et al, 2004)
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IDEAL IIResponse Symptom Improvement
Response Rate (PR)
Symptom Improvement Rate
Patients ()
43
9
12
35
ZD1839250 mg
ZD1839500 mg
ZD1839250 mg
ZD1839500 mg
70
IDEAL IITime to Symptom Improvement
Percent
40
30
Median 2 weeks
20
10
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Time to Improvement (Weeks)
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Ideal2 Cella, et al., JCO 232946, 2005
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Progetto Ritmi e QoL

• Valutare in pazienti operati con tumore della
  mammella, del colon e del polmone ritmi
  circadiani con lactigraph, ritmo del cortisolo.
• Correlare QoL con i parametri rilevati, PFS ed OS

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CHRONOBIOLOGY Conclusions

• Improvement in survival is a slow process
• Clinical Trials remain the cornerstone of
  clinical research in this field
• New perspectives come from molecular biology and
  must be introduced in clinical research