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