Title of Module/Lecture

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Maria Di Bartolomeo
Nordic Pharma
Please note, all disclosures are reported as submitted to ASCO, and
are always available at chicago2012.asco.org
Comparison of a sequential treatment
with irinotecan (CPT-11)
plus 5-fluorouracil (5-FU)/folinic acid (LV)
followed by docetaxel and cisplatin
versus a 5-FU/LV regimen
as postoperative treatment
for radically resected gastric cancer
E.Bajetta, I.Floriani, M.Di Bartolomeo, R.Labianca,
A.Santoro, R.Casaretti, E.Pasquini, F.Di Fabio, G.Pinotti,
P.Bidoli, G.Rosati, A.Mambrini, A.Ciarlo, S.Ricci,
L. Frassinetti, F.Di Costanzo, AM.Bochicchio
on behalf of ITACA-S group
PRESENTED BY MARIA DI BARTOLOMEO
• The
standard recommendation for resectable gastric
cancer was surgery (D1 dissection)
• Meta-analysis
of literature data showed a small but
significant benefit with chemotherapy1
• Large, patient-level meta-analysis2 confirmed that 5-FUbased chemotherapy is associated with a statistically
significant benefit:
•
OS
HR 0.82
(95% CI 0.76-0.90; P< .001)
DFS
HR 0.82
(95% CI 0.75-0.90; P< .001)
Our choice of 5-FU/LV regimen as control arm was
based on the results of meta-analysis of randomized
clinical trials
(1 Mari, Ann Oncol,2000; 2GASTRIC, JAMA 2010)
ITACA-S
Bajetta,
Cascinu,
Di Costanzo,
De Vita,
Ann Oncol, 2002
JNCI, 2007
JNCI, 2008
Ann Oncol, 2007
Stage
T3-4/N+
T3-4/N+
T3-4/N+
I-IIIB
Pts
137/137
196/201
128/130
112/113
EAPFU/LV
PELFwk
PELF
ELFE
Follow-up
FU/LV
Follow-up
Follow-up
HR
0.93
0.95
0.90
0.91
5-y OS
control arm
49%
50%
48.7%
43.5%
Experimental
Arm
Control arm
ITACA-S
•
•
•
FOLFIRI -> less hematological, renal and neurological
toxicity and less stomatitis than cisplatin combinations
Docetaxel (TXT), CDDP and 5-FU regimen is active in
terms of objective response and OS, but several grade 3-4
AEs
Treatment sequence FOLFIRI TXT/CDDP
• Minimize AEs by considering each drug toxicity
profile
• Feasibility of the sequence was documented in the
ITMO trial2
• Could
more active drugs improve the benefit of FU/LV
chemotherapy in patients radically resected with extended
lymph nodes dissection?
(1 Di Bartolomeo, Oncology 2006;)
ITACA-S
Independent, not for profit,
multicenter, randomized,
superiority trial
Control arm
5-FU:400-600mg/m2d1,2-14
LV:100mg/m2d1,2-14
9 cycles
Adenocarcinoma
of the stomach or GEJ
Experimental arm
CPT-11:180mg/m2d1-14
5-FU:400/600mg/m2d1,2-14
LV:100mg/m2d1,2-14
TXT:75mg/m2d1-21
CDDP:75mg/m2d1-21
Q2wks, 4 administrations
4 cycles
Stratification for:
Center
Lymph-node involvement (N-/N+)
ITACA-S
3 cycles
• Histologically proven carcinoma of the stomach or
gastroesophageal junction
• Total/subtotal gastrectomy with at least D1
dissection (D2 recommended )
• pN+ or pT2b-3-4
• No previous radiation and/or chemotherapy
• Complete recovery from surgery. The first infusion
administered 3 to 8 weeks after surgery
ITACA-S
• Primary endpoint: Disease-Free Survival (DFS)
• 636 events (1100 patients) required:
• to detect a 20% relative reduction of recurrence/death
(HR 0.80)
• assuming 3-year DFS in control arm to be 50%
• to provide 80% power
• with 5% two-sided significance level
• Interim analyses for monitoring study conduction
ITACA-S
1106 Randomized
541 control arm
565 experimental arm
• 6 excluded for major violations:
• 3 control arm
• 3 experimental arm
1100 ITT population
538 control arm
562 experimental arm
• 6 crossed group
• 4 control-> experimental
• 2 experimental -> control
• 28 never started treatment:
• 16 control arm
• 12 experimental arm
1072 Safety population
520 control arm
552 experimental arm
ITACA-S
Total
(n.1100)
Experimental
arm (n.562)
Control
arm (n.538)
62 (24-77)
16
62 (30-76)
17
61 (24-77)
15
Sex %
Male
63
62
65
ECOG %
0
1
90
10
91
9
88
12
Histology (acc. Lauren) %
Diffuse
Intestinal
Mixed
Other classification (WHO)
40
35
11
14
40
36
10
14
40
35
11
14
Age (yrs) %
median (range)
> 70 yrs
ITACA-S
Characteristics
Total
(n.1100)
Experimental
arm (n.562)
Control
arm (n.538)
Node dissection %
D1
D2
D3
25
72
3
24
73
3
27
71
2
Examined node %
median
<15
15-24
> 25
27
11
33
56
27
12
33
55
26
11
32
57
Tumor site %
GE junction
Proximal
Distal
Multicenter
12
3
59
26
13
3
57
26
11
2
59
26
ITACA-S
Total
(n.1100)
Experimental
arm (n.562)
Control arm
(n.538)
Stage (UICC6th) %
Ib
II
IIIa
IIIb
IV
8
32
27
14
17
8
32
25
14
19
8
31
29
14
17
N (UICC7th) %
N0
N1(1-2)
N2 (3-6)
N3a (7-15)
N3b (>15)
9
19
26
30
16
10
19
26
28
17
8
20
26
32
14
ITACA-S
Experimental arm
Completed:
- per protocol:
- modified:
Discontinued:
76%
17%
59%
24%
- Adverse events
15%
- Death
1%
- Withdrawal
7%
- Progressive disease 1%
ITACA-S
Control arm
Completed:
- per protocol:
- modified:
Discontinued:
86%
36%
50%
14%
- Adverse events
6%
- Death
1%
- Withdrawal
4%
- Progressive disease 3%
Experimental
arm
Control
arm
76%
86%
Treatment
completed
9 cycles
86%
8 cycles
90%
7 cycles
76%
93%
6 cycles
83%
94%
5 cycles
89%
95%
4 cycles
92%
97%
3 cycles
94%
98%
2 cycles
97%
99%
1 cycle
100%
100%
CDDP +TXT
ITACA-S
FOLFIRI
50
48 *
46 *
45
40
percentage
35
30
25
20
17 *
15
10
0.9
5
leukopenia
neutropenia
control
*All p<0.001
ITACA-S
0.2
9
0.8
0
*
anemia
experimental
9
max hematological
18
16 *
16
14 *
percentage
14
10 *
12
10
8
4 *
6
4
2 *
2
diarrhoea
vomiting
stomatitis
control
*All p<0.001
ITACA-S
3
0.6
2
3
3
0
fever/infection
experimental
asthenia
median follow up: 48 mos (range IQ35.5-62.2)
Events
Overall
(n.1100)
Experimental
arm (n.562)
Control
arm (n.538)
Relapse/Deaths %
558 (51)
283 (50)
275 (51)
Deaths %
440 (40)
222 (39)
218 (40)
10
8
82
10
9
81
10
7
83
Relapse site**: %
locoregional
both
distant
**% calculated on the total of relapses
ITACA-S
Disease Free Survival
1,0
HR:0.98
95%CI: 0.83-1.16
p=0.83
Median DFS: 41.3 months
0,8
0,6
0,4
5-year DFS: 44.8%
0,2
0,0
Control
Experimental
0
Patients at risk
Control
538
Experimental 562
ITACA-S
10
418
438
Events
275
283
Totals
538
562
20
30
40
Months from randomization
328
347
273
270
194
201
50
60
127
129
71
74
1,0
HR:1.0
95%CI: 0.83-1.20
p=0.986
Median OS: 69.8 months
Overall Survival
0,8
0,6
5-year OS: 52.2%
0,4
0,2
Control
Experimental
0,0
0
10
Patients at risk
Control
538
Experimental 562
ITACA-S
Events
218
222
Totals
538
562
20
30
40
Months from randomization
50
60
477
401
321
222
149
79
492
404
328
230
149
81
Test
Test
for
for
interaction
interaction
p=0.371
p=0.371
p=0.602
p=0.733
p=0.928
ITACA-S
• ITACA-S
is the largest western trial to compare two
different types of adjuvant chemotherapy in gastric
cancer
• Patients received adequate surgery and D2 dissection
in more than 75%
• Sequential irinotecan/FU-CDDP/TXT is feasible in the
adjuvant setting. However it is:
- not more effective than FU/LV
- more toxic than FU/LV
• According to these results there is no indication to use
polychemotherapy regimen in adjuvant setting for any
stage of gastric cancer
ITACA-S
Sponsor
Steering committee
• Istituto
Farmacologico
Mario Negri
Milano
• E.Bajetta (PI),
B.Daniele, D.Nitti, R.
Labianca, A.Martoni,
E.Mini, F.Di Costanzo,
A,Falcone, D. Amadori,
G.Tortora, G.Comella
DSMC
• MG. Valsecchi,
M. Tonato,
E. Zucca
Financial Support by: Sanofi Aventis-Italy & Pfizer- Italy
ITACA-S
ITACA-S
ITMO
GISCAD
GONO
Bajetta, Milano
Pinotti, Varese
Rosati, Potenza
Bordonaro, Catania
Bochicchio, Rionero
Fazio, Milano
Marini, Brescia
Buscarino,Catania
Massidda, Cagliari
Isa, Gorgonzola
Bartolini, Sondrio
Reguzzoni, Busto Arsizio
Iop, Latisana
Villa, Milano
Ucci, Lecco
Tumolo, Pordenone
Frustaci, Aviano
Lombardo, Pescara
Sbalzarini, Casalpusterlengo
Verusio, Saronno
Bonetti, Legnago
Monfadini, Padova
Agostara, Palermo
Bonciarelli, Este
Marchetti, Roma
Zagonel, Roma
Cicero, Castrovillari
Mantovani, Cagliari
Duro, Como
Oliani, Montecchio Maggiore
Porcile, Alba
Bobbio Pallavicini, Crema
Gebbia, Palermo
Repetto, Roma
Labianca, Bergamo
Bidoli, Monza
Foa, Milano
Aitini, Mantova
Barni, Treviglio
Giordano, Como
Martignoni, Milano
Catalano, Pesaro
Zaniboni, Brescia
Aglietta, Candiolo
Piazza, Milano
Beretta, Brescia
Menichetti, Senigallia
Cortesi, Roma
Silva, Fabriano
Nardi, Reggio
Calabria
Cascinu, Ancona
Luporini, Milano
Ficarella, Urbino
Falcone, Livorno
Cantore, Carrara
Di Leo, Prato
Ricci, Pisa
Magnanini, Arezzo
Sozzi, Biella
Fea, Cuneo
Chiara, Genova
Alabiso, Novara
Fioretto, Antella
Decensi, Genova
Ciuffreda, Torino
Barsani, lucca
GOCCI
Fiorentini, Empoli
Mazzanti, Firenze
APRIC
GOIRC
Santoro, Rozzano
Boni, Reggio Emilia
Di Costanzo, Firenze
Cavanna, Piacenza
Mattioli, Fano
Pucci, Parma
Bravi, Città di Castello
Artioli, Carpi
Passalacqua, Cremona
Contu, Sassari
Rossetti, Marsciano
Montesarchio, Napoli
Daniele, Benevento
Genua, Ariano Irpino
GOAM
Martoni, Bologna
Brandes, Bologna
Lelli, Ferrara
SICOG
Casaretti, Napoli
Farris, Sassari
Filippelli, Paola
Graco, Lamezia Terme
Roselli , Roma
Natale, Penne
Buzzi, Terni
Tafuto, Pozzuoli
Masullo, Vallo della Lucania
IRST
Ravaioli, Rimini
Amadori, Forlì
Marangolo, Ravenna
Gambi, Faenza
Cruciani, Lugo
GIRCG
Nitti, Padova
Tiberio, Brescia
De Manzoni, Verona
ONCOTECH
De Placido, Napoli
Cartenì, Napoli
……..the patients and their families