Carcinoma Gastrico Localmente Avanzato:
Terapie Integrate
25 Febbraio 2012
CRO Aviano
Terapia Medica
Angela Buonadonna
Oncologia Medica B – CRO, Aviano
CARCINOMA GASTRICO
SEDE T N M
EGDS EUS EUS/TAC TAC/Laparoscopia
Adeguata Stadiazione Preoperatoria
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%
pT3 N0 M0pT1-3 N1 M0 pT1-3 N2 M0
pT1-2 N0 M0 + EGC
Nuove diagnosi
70% - 80%
20% - 30%
Terapia del Carcinoma Gastrico Risultati migliorabili con strategie integrate ?
ADIUVANTE post - chirurgia
NEOADIUVANTE pre - chirurgia
CHEMIOTERAPIA +/- RADIOTERAPIA
Micrometastasi MicrometastasiResecabilità
SOPRAVVIVENZA
JAMA. 2010;303(17):1729-1737
Autore Bajetta,
2002
Cascinu,
2007
Di Costanzo,
2008
De Vita,
2007
Stadio T3-4N+ T3-4 N+ T3-4 N+ I-IIIB
N. Pz 137/137 196/201 128/130 112/113
Tratt
speriment
ale
EAP-
FU/LV
PELFwk PELF ELFE
controllo Follow-up FU/LV Follow-up Follow-up
Local: III
sup
/medio,inf
18%/72% 30%/70% 8%/82% 13%/87%
HR 0.93 0.95 0.90 0.91
CT Adiuvante: Studi Italiani di Fase III
Adjuvant chemotherapy
Italian Intergroup ITACA-S1 Trial
pT2b-4 N0 and/or N+; at least D1 and 15 LN; 1100 pts
5FU/AF
5FU/CPT-115FU/CDDP/Docetaxel
Participants: 123 Italian Centers from 11 Multicenter groups
Patients recruited :1106: 562 exp arm, 538 control arm (Febr 2005 – Aug 2009)
R
Operable Stage II-III
ECF x 3
Surgery
ECF x 3 Surgery
MRC Clinical Trials Unit Magic Clinical Trial
Pre-op CT improves OS and PFS
Cunningham D, NEJM 2006
Pre-op ECF Surgery alone P value
Extent of tumor(gastric only)
T1/T2 52% 37% 0.002
T3/T4 49% 63%
Nodal status (gastric only)
N0/N1 84% 70% 0.01
N2/N3 16% 29%
R0 resection rate79%
(169/219)70%
(166/240)0.03
Cunningham D, NEJM 2006
HR 0.75; 95% CI 0.60-0.93HR 0.66; 95% CI 0.53-0.81
Pre-op CT improves OS and PFS
Patterns of relapse
6242Total
2618Both
1913Distant only
1811Locoregional
only
S
(%)
Preop-CT (%)
Recurrences
Pre-op CT improves OS and DFS
Boige V, 2007
Randomization
Follow-up
Resection
Within 4 weeks
FP x 3/4 or no treatment
4 - 6 weeks
Resection
4 - 6 weeks
FP (*) X 2/3 every 28 days
CT+S S
(*) FP = 5FU mg/m2 CI x 5 days – CDDP: 100mg/m2 at d1 or d2, 1-hr infusion
TRIAL
p=0.0495
(87)81 (74)R0
7 (6)10 (9)No
resection
Extent of resection
Rb pts (%)
p
CT+S
n = 109
S
n = 110
0.05466
(67)68
(80)pN+
32 (33)
17 (20)
pN-
Nodal status (%)
0.1657
(58)58
(68)pT3-T4
38 (39)
27 (32)
pT1-T2
3 (3)0 (0)pT0
Tumor stage (%)
PCT+S
n = 98
S
n = 85
Pathological resultsSurgical results
Pre-op CT improves OS and DFS
5-year DFS: 21% (14-30%) vs 34% (26-44%)
Median follow-up: 5.7 years [2.4-10.4]
Disease-free survival
Boige V, 2007
5-year OS: 24% (16-33%) vs 38% (28-47%)
Overall survival
9703 TRIAL
CT SURG
Pre-operative CT completed 88%
Post-operative CT started 55%
All 6 cycles completed 43%
Post-operative complications 46% 46%
Post-operative deaths (30 d) 6% 6%
Feasibility
MAGIC Trial
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 TrialsMAGIC-B TRIAL
Stage II-IV(M0) Gastric/EG Adenocarcinoma
ECX x 3 -- Surgery – ECX x 3
ECX x 3 + BEV – Surgery – ECX x 3+ BEV BEV x 6
R
A
N
D
O
M
DCF x 4 SURGERY
DCF x 4SURGERY
R 100%
74%100%
66% 34%
94%
Locally AdvancedEGJ-Stomach
35
34
Pre-op CT better tolerated than post-opMore 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 StudyPeriop 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 StudyPreop EOX + RT/OX
Ongoing Trials
Italy
ITACAS-2 Phase III StudyPeriop 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 StudyPreop EOX + RT/OX
ITACA-S 2 - Intergruppo Nazionale Adiuvante Gastrico–2
STUDIO ITACA-S 2
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
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
Obiettivi
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
Studio Fattoriale
Perioper. CT vs Postoperat CT
RT
No
RT
PRE CT +
RT
Post CT +
RT
PRE CT Post CT
Randomizzazioni
1. CHT peri-operatoria o CHT post-
operatoria
2. RTX post-operatoria o nessun
trattamento radioterapico
SONO INDIPENDENTI, LA 2a NON OBBLIGATORIA
Indicatori
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
Tollerabilità dei trattamenti in termini di tossicità (scala NCI – CTCAE, versione 3.0) e di reazioni avverse serie,
attese ed inattese
Sopravvivenza globale (OS), solo per
il quesito di radioterapia
CHEMIOTERAPIA
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 bidi.v. giorni 1-21
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
Dimensione campionaria
Quesito di Timing
1000 ai 1180 pazienti
420-520 pazienti
Quesito di Radioterapia
Ongoing Trials
ItalyITACAS-2 Phase III Study
Periop vs post-op EOX and assessment ofbenefit 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
PrimaryThe 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 PlanTreatment 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 8Oxaliplatin 80 mg/m2 day 1Capecitabine 750 mg/m2 x 2 daily for 2 weeks
Cycles repeated every 3 weeks
Duration of studyOverall study duration: from 04/2010Target recruitment period: 20 months
Ongoing Trials
ItalyITACAS-2 Phase III Study
Periop vs post-op EOX and assessment ofbenefit 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
Sergio Frustaci
Centro di Riferimento Oncologico, Aviano
Data management
Clinical Trial Office
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 Method Mechanism of action Predictive value Chemotherapeutic
regimens
TS PCR/IHC Catalyzes conversion of dUMP to dTMP in Negative 5-FU,
cis/oxaliplatin
the synthesis of nucleotides
TP IHC/PCR Catalyzes conversion of 5-FU to FdUMP, Positive 5-FU,
capecitabine
which inibits thymidylate synthase
DPD IHC/ELISA Rate limiting enzyme of 5-FU Negative 5-FU, capecitabine, UFT,
S-1
catabolism
OPRT PCR/ELISA Catalyzes conversion of 5-FU Positive 5-FU, S-1
GADD45A PCR DNA repair and cell cycle control Negative Cisplatin
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 Predictive value Chemotherapeutic
regimens
p53 IHC Regulation of apoptosis Negative 5-FU, cisplatin,EPIAdm, CPT11
GSTP IHC/PCR Protects cellular macromolecules from damage Negative CDDP, OXDDP, 5-
FU
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
Molecular marker Method Mechanism of action Predictive value Chemotherapeutic regimens
Methylation of gene PCR DNA repair and cell cycle control 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
Molecular markers with possible predictive value in gastric cancer
Summary data on Methylation of gene promoters/MSI, Her-2/Neu, MMPs
and COX-2
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