Disclosure InformationRelationships Relevant to this Session
Maria Di Bartolomeo
Nordic Pharma
Please note, all disclosures are reported as submitted to ASCO, and are always available at chicago2012.asco.org
ITACA-SIntergroup Trial of Adjuvant Chemotherapy
in Adenocarcinoma of the Stomach
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 cancerE.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
PRESENTED BY MARIA DI BARTOLOMEO
on behalf of ITACA-S group
• 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-FU-based 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
Background
(1 Mari, Ann Oncol,2000; 2GASTRIC, JAMA 2010)
ITACA-S
Bajetta, Ann Oncol, 2002
Cascinu, JNCI, 2007
Di Costanzo,JNCI, 2008
De Vita,Ann Oncol, 2007
Stage T3-4/N+ T3-4/N+ T3-4/N+ I-IIIB
Pts 137/137 196/201 128/130 112/113
Experimental Arm EAPFU/LV PELFwk PELF ELFE
Control arm 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%
Italian contribution
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?
Rationale for Experimental arm
ITACA-S
(1 Di Bartolomeo, Oncology 2006;)
Study Design
Independent, not for profit,multicenter, randomized, superiority trial
Adenocarcinoma of the stomach or GEJ
Stratification for:CenterLymph-node involvement (N-/N+)
Q2wks, 4 administrations
Control arm
5-FU:400-600mg/m2d1,2-14LV:100mg/m2d1,2-14 9 cycles
ITACA-S
CPT-11:180mg/m2d1-14 5-FU:400/600mg/m2d1,2-14LV:100mg/m2d1,2-14
TXT:75mg/m2d1-21CDDP:75mg/m2d1-21
3 cycles
Experimental arm
4 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
Eligibility criteria
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
Statistical considerations
ITACA-S
• 6 excluded for major violations:• 3 control arm• 3 experimental arm
Recruitment1106 Randomized
541 control arm 565 experimental arm
1100 ITT population538 control arm
562 experimental arm
1072 Safety population520 control arm
552 experimental arm
• 28 never started treatment:• 16 control arm• 12 experimental arm
• 6 crossed group• 4 control-> experimental• 2 experimental -> control
ITACA-S
Feb/2005-Aug/2009
Total (n.1100)
Experimental arm (n.562)
Controlarm (n.538)
Age (yrs) % median (range) > 70 yrs
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 MixedOther classification (WHO)
40351114
40361014
40351114
Baseline characteristics
ITACA-S
Characteristics Total (n.1100)
Experimental arm (n.562)
Control arm (n.538)
Node dissection % D1 D2 D3
25723
24733
27712
Examined node % median <15 15-24 > 25
271133 56
27123355
26 11 3257
Tumor site % GE junction Proximal Distal Multicenter
12 3
59 26
13 3
57 26
11 2 59 26
Surgical report
ITACA-S
Total (n.1100)
Experimental arm (n.562)
Control arm(n.538)
Stage (UICC6th) %IbIIIIIaIIIbIV
832 271417
8
32251419
831291417
N (UICC7th) % N0 N1(1-2) N2 (3-6) N3a (7-15) N3b (>15)
919263016
1019262817
820263214
TNM stage
ITACA-S
Completed: 76%- per protocol: 17% - modified: 59%
Discontinued: 24% - Adverse events 15%- Death 1% - Withdrawal 7%- Progressive disease 1%
Completed: 86%- per protocol: 36% - modified: 50%
Discontinued: 14%- Adverse events 6%- Death 1%- Withdrawal 4%- Progressive disease 3%
Treatment compliance
ITACA-S
Experimental arm Control arm
Experimental arm
Control arm
Treatment completed 76% 86%
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%
Treatment received
FOLFIRI CDDP +TXT
ITACA-S
leukopenia neutropenia anemia max hematological0
5
10
15
20
25
30
35
40
45
50
0.89
0.29
17
46
0.9
48
control experimental
percen
tage
Grade 3-4 hematological toxicity
*All p<0.001
*
*
*
*
ITACA-S
diarrhoea vomiting stomatitis fever/infection asthenia0
2
4
6
8
10
12
14
16
18
3 3 20.6000000000000
033
10
16
4
2
14
control experimental
percen
tage
Grade 3-4 non hematological toxicity
*All p<0.001
*
*
*
*
*
ITACA-S
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)
Relapse site**: % locoregional both distant
108
82
109
81
107
83
Events and Relapses
median follow up: 48 mos (range IQ35.5-62.2)
**% calculated on the total of relapses
ITACA-S
Disease-free survival
HR:0.98 95%CI: 0.83-1.16
p=0.83Median DFS: 41.3 months
5-year DFS: 44.8%
ITACA-S
538 418 328 273 194 127 71
562 438 347 270 201 129 74
ControlExperimental
Dis
ease
Fre
e S
urvi
val
0 10 20 30 40 50 600,0
0,2
0,4
0,6
0,8
1,0
Months from randomizationPatients at risk
ExperimentalControl
Events
275
283
Totals
538
562
Overall survival
ITACA-S
538 477 401 321 222 149 79
562 492 404 328 230 149 81
Control
Experimental
Ove
rall
Sur
viva
l
0 10 20 30 40 50 600,0
0,2
0,4
0,6
0,8
1,0
Months from randomizationPatients at risk
ExperimentalControl
Events
218
222
Totals
538
562
HR:1.0 95%CI: 0.83-1.20
p=0.986Median OS: 69.8 months
5-year OS: 52.2%
Hazard Ratio for deaths
ITACA-S
p=0.371
Test for interaction
p=0.602
p=0.733
p=0.928
p=0.371
Test for interaction
• 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
Conclusions
ITACA-S
Sponsor •Istituto Farmacologico Mario Negri Milano
Steering committee
• 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
ITACA-S
Financial Support by: Sanofi Aventis-Italy & Pfizer- Italy
ITACA-S
Bajetta, MilanoPinotti, VareseRosati, PotenzaBordonaro, CataniaBochicchio, RioneroFazio, MilanoMarini, BresciaBuscarino,CataniaMassidda, CagliariIsa, Gorgonzola Bartolini, SondrioReguzzoni, Busto ArsizioIop, LatisanaVilla, MilanoUcci, LeccoTumolo, PordenoneFrustaci, AvianoLombardo, PescaraSbalzarini, CasalpusterlengoVerusio, SaronnoBonetti, LegnagoMonfadini, PadovaAgostara, PalermoBonciarelli, EsteMarchetti, RomaZagonel, RomaCicero, CastrovillariMantovani, CagliariDuro, ComoOliani, Montecchio MaggiorePorcile, AlbaBobbio Pallavicini, CremaGebbia, PalermoRepetto, Roma
Labianca, Bergamo Bidoli, MonzaFoa, MilanoAitini, MantovaBarni, TreviglioGiordano, ComoMartignoni, MilanoCatalano, PesaroZaniboni, BresciaAglietta, CandioloPiazza, MilanoBeretta, BresciaMenichetti, SenigalliaCortesi, RomaSilva, FabrianoNardi, Reggio CalabriaCascinu, AnconaLuporini, MilanoFicarella, Urbino
Falcone, Livorno Cantore, CarraraDi Leo, PratoRicci, PisaMagnanini, ArezzoSozzi, BiellaFea, CuneoChiara, GenovaAlabiso, NovaraFioretto, AntellaDecensi, GenovaCiuffreda, TorinoBarsani, lucca
Fiorentini, EmpoliMazzanti, Firenze
Montesarchio, NapoliDaniele, BeneventoGenua, Ariano Irpino
Martoni, BolognaBrandes, BolognaLelli, Ferrara
Nitti, PadovaTiberio, BresciaDe Manzoni, Verona
De Placido, NapoliCartenì, Napoli
ITMO GISCAD
GOIRC
GONO
ONCOTECH
APRIC
GOCCI
GIRCG
IRST
SICOG
GOAM
Thanks to:
Santoro, RozzanoBoni, Reggio EmiliaDi Costanzo, FirenzeCavanna, PiacenzaMattioli, FanoPucci, ParmaBravi, Città di CastelloArtioli, CarpiPassalacqua, CremonaContu, SassariRossetti, Marsciano
Fiorentini, EmpoliMazzanti, Firenze
Casaretti, NapoliFarris, SassariFilippelli, PaolaGraco, Lamezia TermeRoselli , RomaNatale, PenneBuzzi, TerniTafuto, PozzuoliMasullo, Vallo della Lucania
Ravaioli, RiminiAmadori, ForlìMarangolo, RavennaGambi, FaenzaCruciani, Lugo
……..the patients and their families