Società Triveneta di ChirurgiaAviano, 25 Febbraio 2012

Carcinoma Gastrico

Localmente Avanzato:Terapie

Integrate

Progetto NEOX-RT

Antonino De Paoli

UO Oncologia Radioterapica, CRO Aviano

Gastric Cancer - Current Issues

Changing epidemiology(diagnosis and treatment implications)

Curative surgery (mainstay of treatment)

Adjuvant chemotherapy(still controversial)

Adjuvant chemoradiation(possible benefit)

Perioperative chemotherapy(possible benefit)

Neo-adjuvant and adjuvant therapy for gastric cancer: different strategies

Post-operative

Chemoradiotherapy

(trend to preoperative CT-RT

in academic centers)

Peri-operative

Chemotherapy

(ECF- 5FU/cisplatin)

Post-operative

Chemotherapy

(S-1 or combination)

Postoperative CT

Ongoing Trials

US (Intergroup Trial)

Post-op 5FU/LV + RT/5FU vs ECF + RT/5FU(Does ECF improve efficacy of post-op CRT?)

EUPeriop ECX vs Periop ECX-BEV (MAGIC-B)

(Is there a role of biologics?)

Preop ECX-Surg-postop ECX vs RT/X-DDP (CRITICS)(What is the role of postop CT-RT?)

Preop ECX x3 vs ECX x2-RT/X+postop ECX (EORTC)(What is the role of preop CT-RT?)

JapanAdjuvant S1 vs Surgery alone

Cosa fare nella 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 (>25%) RT-CT

Cascinu S - IRST Meldola, 2010

Japanese Research Society for

Gastric Cancer

1 right paracardium

2 left paracardium

3 lesser curvature

4 greater curvature

5 suprapylorum

6 infrapylorum

7 left gastric artery

8 common hepatic artery

9 celiac artery

10 splenic hilum

11 proximal splenic artery

12 hepatoduodenal ligament (a,b,p)

13 posterior surface of the pancreatic head

14 superior mesenteric vessels

15 middle colic vessels

16 abdominal aorta

41

58

613

17

1011

14

12b+p

16b1

20

110

20

4

1011

14

6

111

12b+p5

4

3

1

5

812b+p

6

Macdonald

281 pts%

RT-CT compliance

Korean

544 pts%

64.0 75.0G3 Acute Tox

G4 Acute Tox

41.0

32.0

23.5

6.0

PostOp RT-CT Toxicity

Macdonald JS et al – NEJM -2001

Kim S et al – IJROBP – 2005

Mattiucci GCet al – ESTRO- 2010

Italian pool

348 pts%

96.0

14.2

CENTRI PARTECIPANTI

Trieste

Aviano

Padova

Firenze S.M. Annunziata

Firenze

Chieti

Ancona

Viterbo

Varese

Arezzo

Roma UCSC

Siena

Rionero in

Vulture

Barletta

S.G.Rotondo

Taranto

Perugia

MeldolaIvrea

AIRO-GI Working Group

Ongoing Trials

Italy

ITACAS-2 Phase III Study

Periop vs post-op EOX and assessment of

benefit of post-op RT/Cape

DOX Phase II randomised Study

Periop DOX vs Preop DOX

NEOX-RT Phase II Study

Preop EOX + RT/OX

Sponsor: Istituto di Ricerche Farmacologiche “Mario Negri”

Supported by: AIFA

Medical Oncology: Francesco Di Costanzo (P.Investigator)

Radiation Oncology: Vincenzo Valentini

Surgery: Donato Nitti

ITACA-S 2 (Intergroup Trial in Adjuvant Chemotherapy for Adenocarcinoma

of the Stomach 2):

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

STUDIO ITACA-S 2

MAGIC

ITACA-S1

CRITICS

INT-0116

Disegno dello Studio

Preoperative

Chemoradiotherapy

in Castric Cancer-

The MD Anderson

. experience

pCR: 23% - R0 Rate: 95%

Post Op Compl: 38%

Post Op Death: 2.8% Fujitani K et al Ann Surg Oncol 2007

Reed VK et al IJROBP 2008

Post-op mortality: 5.6% vs 5.9%

Post-op morbility: 46% vs 45%

Post-op hosp stay (med): 13 d vs 13 d

MAGIC data, NEJM 2006

Ajani JA et Al – JCO – 2005

Cunningham et Al - NEJM – 2006Sthal M et al- JCO-2009

The risk of tumour progression

Neoadjuv ChemoRT in Gastric Cancer

MDACC

9/41 (22%) not resected for PD at surgery

Magic trial

37/209 (18%) not resected for PD at surgery

German trial

12/119 (10%) not resected for PD at surgery

INT-0116

Valentini V et al, Tumori 2008

Magic

D2 = 10% D2 = 40%

The “L” shape survival curve of Gastric Cancer

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 StudyPatients with locally advanced uT3-4,N0 or any uT,N+M0(LPS)

potentially resectable, EGJ(II-III)-Gastric Cancer

Induction

chemotherapy EOX x 3 cycles (q 3weeks)

for 9 weeks

Patients with early metabolic

disease progression (CT-

PET) will undergo to

immediate surgery

Responding pts CT-PET evaluation after 2

cycles EOX

Objective Response

(Endoscopy/EUS)

after 9 weeks

Chemoradiotherapy

RT 45 Gy

+ Oxaliplatin-Xeloda

for 5 weeks

Restaging CT-PET

CT abdomen and chest

Objective Response

(Endoscopy/EUS)

after 4 weeks from CT-RT

Surgery Week 22

SURGERY +/- IORT

4-6 weeks after chemoradiotherapy

Path Response Rate

R0 Resection Rate

Treat Compliance

NEOX-RT Study

Pre-Op CT

EOX x 3

Pre-Op CT-RT

OX + 45Gy (+/-CB)

Surgery +/-IORT

D2 10 Gy

1 - 9 12 - 16 21 - 22

weeks

CT-PET CT-PET CT-PET

Tissue banking

Nutritional monitoring and support

Quality of Life

Epirubicin 50 mg/m2 d1 3D-CRT 45Gy/25fr +/- 10Gy/10fr, 2 weekly

Oxaliplatin 130mg/m2 d1 Oxaliplatin 30mg/m2, weekly

Xeloda 625mg/m2 bid d1-21 Xeloda 625mg/m2, bid, d1-35

Use the following general planning

guidelines for therapy

Prerequisite Step

N

Procedure

Presumed loco-regional

cancer

1 Clinical staging and Endoscopic Ultrasound,

CT-PET

Non-metastatic cancer 2 Laparoscopy and peritoneal staging

No peritoneal cancer and

eligibility criteria

fulfilled

3 Get consent, register and start preoperative

Chemotherapy

Completed preoperative

chemotherapy (if CT-

PET responsive)

4 Rest 2 weeks then start preoperative

Chemoradiotherapy

Completed preoperative

chemoradiotherapy

5 Rest 4-5 weeks then proceed with

preoperative work-up

Non-metastatic cancer 6 Attempt Surgery +/-IORT

Completed all therapy 7 Follow-up for 5 years or until death

NEOX-RT Study - Investigator

BoardStudy 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

NEOX-RT Centri Partecipanti

CRO-Aviano Onc Chir, OncMed, OncRad

Ospedale Pordenone I°Chir, II°Chir, Onc Med

Ospedale S.Vito Chir, Onc Med

Ospedale Spilimbergo Chir, Onc Med

Ospedale Portogruaro Chir, Onc Med

UniversitàPD-IOV II°Clin Chir, OncMed, RadOnc

UCSC Roma I°Clin Chir, OncMed,RadOnc

SFN Roma Chir, OncMed, RadOnc

Ospedale Trento I°Chir, II°Chir, OncMed, RadOnc

Statistical considerations and

Sample Size

Primary end-point: pCR (all entered patients)

Sample size: 49 patients

pCR difference 15% (p0=5%; p1=20%)

I° Step 21 patients; if >1pCR, II° Step 20 patients.

Overall 41 patients; if 85% path asssessed,

TOTAL 49 patients

Simon’s two stage design

NEOX-RT Accrual 3-09 to 2-012

Patients accrued: 18

Completed Preop Program: 13

Ongoing Preop Program: 3

Underwent to Surgery: 14 (2pCR)

1 patient had emergency operation (bleeding)

1 patient drop-out (refusal)

1 patient had postop complication (re-operation)CRO 2008