Carcinoma Gastrico Localmente
Avanzato:
Terapie Integrate
25 Febbraio 2012
CRO Aviano
Terapia Medica
Angela Buonadonna
Oncologia Medica B – CRO, Aviano
CARCINOMA GASTRICO
Adeguata Stadiazione Preoperatoria
SEDE
T
N
EGDS
EUS
EUS/TAC
M
TAC/Laparoscopia
Ca gastrico localmente avanzato
(T2 N1-2 M0 / T3-4 anyN M0)
Trattamento chirurgico R0
Sopravvivenza a 5 anni del 20-30%
a causa dell’alto tasso di recidiva locale o regionale
Risultati della chirurgia nel Carcinoma Gastrico
STADI I - IIIB (UICC)
pT1-2 N0 M0
pT3 N0 M0
pT1-3 N1 M0
pT1-3 N2 M0
SOPRAVVIVENZA A 5 ANNI
70% - 80%
40% - 50%
30% - 40%
30%
Nuove diagnosi
pT1-2 N0 M0 + EGC
pT3 N0 M0
pT1-3 N1 M0
pT1-3 N2 M0
20% - 30%
70% - 80%
Terapia del Carcinoma Gastrico
Risultati migliorabili con strategie integrate ?
CHEMIOTERAPIA +/- RADIOTERAPIA
ADIUVANTE
post - chirurgia
NEOADIUVANTE
pre - chirurgia
Micrometastasi
Resecabilità
Micrometastasi
SOPRAVVIVENZA
JAMA. 2010;303(17):1729-1737
CT Adiuvante: Studi Italiani di Fase III
Autore
Stadio
Bajetta,
2002
T3-4N+
Cascinu,
2007
T3-4 N+
Di Costanzo, De Vita,
2008
2007
T3-4 N+
I-IIIB
N. Pz
137/137
196/201
128/130
112/113
PELFwk
PELF
ELFE
FU/LV
Follow-up
Follow-up
18%/72%
30%/70%
8%/82%
13%/87%
0.93
0.95
0.90
0.91
Tratt
speriment EAPale
FU/LV
controllo
Follow-up
Local: III
sup
/medio,inf
HR
Adjuvant chemotherapy
Italian Intergroup ITACA-S1 Trial
pT2b-4 N0 and/or N+; at least D1 and 15 LN; 1100 pts
5FU/AF
R
5FU/CPT-11
5FU/CDDP/Docetaxel
Participants:
123 Italian Centers from 11 Multicenter groups
Patients recruited :
1106: 562 exp arm, 538 control arm (Febr 2005 – Aug 2009)
Pre-op CT improves
OS and PFS
Pre-op ECF
MRC Clinical Trials Unit
Extent of tumor
(gastric only)
T1/T2
T3/T4
Operable
Surgery alone
P value
37%
0.002
Magic Clinical Trial
52%
ECF
x3
49%
Surgery
63%
ECF x 3
Nodal status
Stage
(gastricII-III
only)
N0/N1
N2/N3
R0 resection rate
84%
Surgery
70%
16%
29%
79%
(169/219)
70%
(166/240)
0.01
0.03
Cunningham D, NEJM 2006
Pre-op CT improves
OS and PFS
HR 0.66; 95% CI 0.53-0.81
HR 0.75; 95% CI 0.60-0.93
Patterns of relapse
Recurrences
Preop-CT
(%)
S
(%)
Locoregional
only
11
18
Distant only
13
19
Both
18
26
Total
42
62
Cunningham D, NEJM 2006
Randomization
TRIAL
Pre-op CT improves OS and DFS
CT+S
S
FP (*) X 2/3 every 28 days
Within 4 weeks
4 - 6 weeks
Surgical results
Pathological results
Resection
Resection
CT+S
S
n = 110
n=
109
p
CT+S
n = 98
4 - 6 weeks
Tumor
stage (%)
Rb pts (%)
pT0
0 (0)
3 (3)
pT1-T2
27
(32)
38
(39)
58
(68)
57
(58)
pN-
17
(20)
32
(33)
pN+
68
(80)
66
(67)
FP x 3/4 or no treatment
Extent of
resection
Follow-up
pT3-T4
(*) FP = 5FU mg/m2 CI x 5 days – CDDP: 100
2
No mg/m at d1 or d2, 1-hr infusion
10 (9)
7 (6)
resection
R0
S
n = 85
81 (74)
95
(87)
p=0.04
P
0.16
Nodal
status (%)
Boige V,
0.054
2007
Pre-op CT improves OS and DFS
Overall survival
9703
TRIAL
Disease-free survival
Median follow-up: 5.7 years [2.4-10.4]
5-year OS: 24% (16-33%) vs 38% (28-47%)
5-year DFS: 21% (14-30%) vs 34% (26-44%)
Boige V,
2007
MAGIC Trial
Feasibility
CT
Pre-operative CT completed
88%
Post-operative CT started
All 6 cycles completed
55%
43%
Post-operative complications
Post-operative deaths (30 d)
46%
6%
SURG
46%
6%
Cunningham D et al. N Engl J Med 2006
Chemioterapia neo-adiuvante
Vantaggi
•Possibile Downstaging e trattamento precoce delle micrometastasi con aumento del
tasso di resecabilità con intento curativo
•Migliore compliance e tollerabilità della terapia rispetto ad una somministrazione
post-operatoria
•Test di chemiosensitività in vivo che facilita la scelta del trattamento più appropriato
per il periodo post-operatorio
Svantaggi
•Rischio di evoluzione della malattia nel ritardare l’atto chirurgico
•Potenziale aumento delle complicanze chirurgiche
•Potenziali complicanze associate alla chemioterapia
Perioperative CT - Ongoing Trials
MAGIC-B TRIAL
Stage II-IV(M0) Gastric/EG Adenocarcinoma
R
A
N
D
O
M

ECX x 3 -- Surgery – ECX x 3

ECX x 3 + BEV – Surgery – ECX x 3+ BEV
BEV x 6
35
SURGERY
66%
100%
R
Locally Advanced
EGJ-Stomach
34
DCF x 4
100%
DCF x 4
74%
34%
SURGERY
94%
Pre-op CT better tolerated than post-op
More pts able to receive treatment in the pre-op setting
AIOM, AIRO, SICO, SIAPEC, SIGE
Pratica Clinica
• T3 N0
no terapia
• T2/3/4 N+
terapia con 5FU, o ECF o
CDDP, de Gramont , MitC.
• Se chirurgia inadeguata (Lfn <15 LN, R1)
RT-CT
• Se chirurgia adeguata, ma elevato N-ratio
RT-CT
Ongoing Trials
Italy
ITACAS-2 Phase III Study
Periop vs post-op EOX and assessment of
benefit of a post-op RT/Cape
DOX Phase II randomised Study
Periop DOX vs Preop DOX
NEOX-RT Phase II Study
Preop EOX + RT/OX
Ongoing Trials
Italy
ITACAS-2 Phase III Study
Periop vs post-op EOX and assessment of
benefit of a post-op RT/Cape
DOX Phase II randomised Study
Periop DOX vs Preop DOX
NEOX-RT Phase II Study
Preop EOX + RT/OX
ITACA-S 2 - Intergruppo Nazionale Adiuvante Gastrico–2
ITACA-S 2
(Intergroup Trial in Adjuvant Chemotherapy for Adenocarcinoma of the Stomach):
Comparison of the efficacy of a peri-operative versus a post-operative
chemotherapy treatment in patients with operable gastric cancer and
assessment of the benefit of a post-operative chemo-radiotherapy
Patologia: carcinoma gastrico operabile
Sponsor: Istituto di Ricerche Farmacologiche “Mario Negri”
Supporto: AIFA (bandi 2008) pari a 920.000 euro
Principal Investigator: Francesco Di Costanzo
STUDIO ITACA-S 2
Primari:
Lo studio propone due diversi quesiti
utilizzando un disegno fattoriale
Quesito di timing: Valutare l’efficacia di una
chemioterapia peri-operatoria vs. una chemioterapia
post-operatoria indipendentemente dall’effettuazione o
meno della radioterapia post-chirurgica
Quesito di radioterapia: Valutare l’efficacia del
trattamento combinato di chemio-radioterapia
post-operatorio vs. nessun trattamento,
indipendentemente dal momento di effettuazione
della chemioterapia peri e post-operatoria
Obiettivi
Perioper. CT vs Postoperat CT
RT
No
RT
PRE CT +
RT
Post CT +
RT
PRE CT
Post CT
Studio Fattoriale
1. CHT peri-operatoria o CHT postoperatoria
2. RTX post-operatoria o nessun
trattamento radioterapico
SONO INDIPENDENTI, LA 2a
NON OBBLIGATORIA
Randomizzazioni
Primari:
Quesito di timing: Sopravvivenza globale (OS), definita come
intervallo di tempo dalla randomizzazione alla morte per ogni
causa
Quesito di radioterapia: Sopravvivenza libera da ricaduta
locale (L-RFS), definita come intervallo di tempo dalla
randomizzazione alla recidiva locale o morte
Indicatori
Secondari:
Sopravvivenza libera da malattia (DFS) definita
come intervallo di tempo dalla randomizzazione
alla comparsa dalla recidiva locale o regionale o
metastasi a distanza o secondo tumore primario o
morte per ogni causa, per entrambi i quesiti
Sopravvivenza globale (OS), solo per
il quesito di radioterapia
Tollerabilità dei trattamenti in termini di tossicità (scala
NCI – CTCAE, versione 3.0) e di reazioni avverse serie,
attese ed inattese
Indicatori
La scelta delle triplette per il trattamento chemioterapico è lasciata libera alla
decisione di ogni singolo sperimentatore. Devono essere le stesse per entrambi i
bracci di chemioterapia (peri o post-chirurgica)
•
EOX: epirubicina 40mg/m2 e.v. bolus giorno 1, oxaliplatino
80 mg/m2 e.v. infusione giorno 1 e capecitabina 750 mg/m2
bid p.o. giorni 1-14
•
ECF: epirubicina 50mg/m2 e.v. bolus giorno 1, cisplatino 60
mg/m2 i.v. infusione giorno 1 e fluorouracile 200 mg/m2 bid
i.v. giorni 1-21
CHEMIOTERAPIA
Pazienti con diagnosi istologica di ca. gastrico
operabile
ECOG-PS 0-1
Interessamento linfonodale o se N0 T3-T4a-T4b
Nessuna metastasi a distanza
Assenza di carcinosi endoperitoneale (solo quesito di
radioterapia)
 Nessuna precedente CHT e/o RTX
Principali criteri eligibilità
Quesito di Timing
1000 ai 1180 pazienti
Quesito di Radioterapia
420-520 pazienti
Dimensione campionaria
Ongoing Trials
Italy
ITACAS-2 Phase III Study
Periop vs post-op EOX and assessment of
benefit of a post-op RT/Cape
DOX Phase II randomised Study
Periop DOX vs Preop DOX
NEOX-RT Phase II Study
Preop EOX + RT/OX
A randomised phase II study
of pre-operative or peri-operative docetaxel,
oxaliplatin, capecitabine (DOX) regimen in
patients with
locally advanced resectable gastric cancer
Chief Investigators
Prof. Dino Amadori
Prof. Stefano Cascinu
Prof. Giovanni De Manzoni
Prof. Franco Roviello
Study Objectives
Primary
The percentage of patients receiving all the planned chemotherapeutic cycles.
•
•
•
•
•
•
•
•
•
•
•
•
Secondary
Downstaging according to Recist criteria
pT1-3 vs pT0.
Safety: number of patients with grade 3-4 toxicity
The role of PET Scan as predictor of response
Curative vs palliative surgery
TTP
OS
Diagnostic correlation between the various staging methods
Possible correlations between CT scan, CT/PET, laparoscopy;
Molecualr marker related to toxicity: DPYD, MTHFR, TS, XPD, ERCC1, XRCC1;
Molecular marker related to prognosis: TYMS, GSTP1, COX-2, RUNX3, methylation profile (Cox2,
hMLH1, MGMT);
Molecular marker related to therapy response: TYMS, DPYD, MTHFR, OPRT, ERCC1, XRCC1/2/3, GSTP1,
GSTM1, GSTT1, ABCB1, methylation profile (Cox2, hMLH1, MGMT), whole genome arrayCGH.
Study design
Multicenter, randomized, open label phase II study
DOX 2 cycles Surgery  DOX 2 cycles  Follow-up
Random
DOX 4 cycles  Surgery  Follow-up
Treatment Plan
Treatment will be administered for 4 and 2 cycles before surgery in arm A and B,
respectively, and in arm B for a further 2 cycles after surgery unless progression or
unacceptable toxicity occurs, or a patient refuses treatment. In such cases patients
will go off treatment. 3-6 weeks after the end of the fourth (arm A) or second (arm
B) preoperative cycle, patients will undergo surgery.
After surgery 3-6 weeks from surgery patients in arm B will receive 2 more cycles.
DOX:
Docetaxel 35 mg/m2 day 1 and 8
Oxaliplatin 80 mg/m2 day 1
Capecitabine 750 mg/m2 x 2 daily for 2 weeks
Cycles repeated every 3 weeks
Duration of study
Overall study duration: from 04/2010
Target recruitment period: 20 months
Ongoing Trials
Italy
ITACAS-2 Phase III Study
Periop vs post-op EOX and assessment of
benefit of a post-op RT/Cape
DOX Phase II randomised Study
Periop DOX vs Preop DOX
NEOX-RT Phase II Study
Preop EOX + RT/OX
NEOX-RT Study
NEOADJUVANT
EPIRUBICIN-OXALIPLATIN-XELODA AND
OXALIPLATIN-XELODA RADIOTHERAPY
IN LOCALLY ADVANCED, RESECTABLE, GASTRIC
CANCER
A PHASE II COLLABORATIVE STUDY
Actived March 2009
NEOX-RT Study - Investigator Board
Study Coordinator
Mario Lise
Centro di Riferimento Oncologico, Aviano
Chair Investigators
Surgeon
Domenico D’Ugo
Università Cattolica S.Cuore, Roma
Donato Nitti
Università di Padova
Francesco De Marchi
Centro di Riferimento Oncologico, Aviano
Alberto Marchet
Università di Padova, Padova
Radiation Oncologist
Antonino De Paoli
Centro di Riferimento Oncologico, Aviano
Vincenzo Valentini
Università Cattolica S.Cuore, Roma
Medical Oncologist
Carlo Barone
Università Cattolica S.Cuore, Roma
Data management
Clinical Trial Office
Centro di Riferimento Oncologico, Aviano
Sergio Frustaci
Centro di Riferimento Oncologico, Aviano
Carcinoma gastrico
Utilità di fattori prognostici o predittivi
•
•
•
•
•
•
Indici proliferativi
Apoptosi
Oncogeni (p53)
Angiogenesi
Timidilato sintetasi
Mismach Repair
Molecular markers with possible predictive value in gastric cancer
Summary data on TS, TP, DPD, OPRT and GADD45A
Molecular marker
regimens
Method
Mechanism of action
Predictive value
TS
PCR/IHC
Catalyzes conversion of dUMP to dTMP in
Chemotherapeutic
Negative
5-FU,
Positive
5-FU,
cis/oxaliplatin
the synthesis of nucleotides
TP
IHC/PCR
Catalyzes conversion of 5-FU to FdUMP,
capecitabine
which inibits thymidylate synthase
DPD
IHC/ELISA
Rate limiting enzyme of 5-FU
Negative
5-FU, capecitabine, UFT,
Positive
5-FU, S-1
S-1
catabolism
OPRT
PCR/ELISA
Catalyzes conversion of 5-FU
Molecular markers with possible predictive value in gastric cancer
Summary data on p53, GSTP, Bak, Survivin, Bcl-2, III beta-tubuline
Molecular marker
Method
Mechanism of action
regimens
Predictive value
Chemotherapeutic
p53
IHC
Regulation of apoptosis
GSTP
IHC/PCR
Protects cellular macromolecules from damage Negative
Bak
IHC
Proapoptotic function
Negative
Methotrexate, 5-FU
Survivin
PCR
Inhibition of apoptosis
Negative
Cisplatin
Bcl-2
IHC
Antiapoptotic function
Negative
5-FU, cisplatin
III beta-tubuline
IHC
Target of taxanes
Negative
Docetaxel
Negative 5-FU, cisplatin,EPIAdm, CPT11
CDDP, OXDDP, 5-
FU
Molecular markers with possible predictive value in gastric cancer
Summary data on Methylation of gene promoters/MSI, Her-2/Neu, MMPs
and COX-2
Molecular marker
Method
Methylation of gene
Mechanism of action
PCR
Predictive value
DNA repair and cell cycle control
Chemotherapeutic regimens
Positive
Cisplatin, 5-FU
promoters/MSI
Her-2/Neu
IHC/FISH
Proto-oncogene which encodes for a
Positive
5-FU,ADM, trastuzumab,Oxddp
tyrosine kinase growth factor receptor
MMPs
–
Degradation of extracellular matrix
–
5-FU, marimastat
COX-2
IHC
Biosynthesis of prostaglandins
–
Celecoxib
Studio di fase II CRO
DOC in Ca stomaco avanzato
Studio corollario:
Ricerca su tessuto paraffinato del tumore primitivo
di un panel di
molecular markers con possibile valore predittivo
• P53
• Bcl-2
• Methylation of gene
promoters/MSI
• Her-2/Neu
• COX-2
Selezione dei
pazienti per
terapie adiuvanti
e neoadiuvanti