Cáncer gástrico y de la UEG localizados QT Peri-operatoria ......Cáncer Gástrico Grupo heterogéneo de enfermedades Adenocarcinoma de la UEG Adenoca. Gástrico - Proximal / Distal

Cáncer gástrico y de la UEG localizados QT Peri-operatoria o QT/RT adyuvante; ¿Alguna novedad?

Fernando Rivera Herrero Sv Oncología Médica HU M Valdecilla. Santander

Gastric adenoca 5y OS 25% 1

Stage

Resectable: Early disease (T1-2,N0 M0) 10% pts 5y OS: > 80% Resectable: Loc. Advanced (T3-4 or N+ M0) 40% pts 5y OS: 30% Unresectable Loc.Advanced 15% pts Median OS: 18 m Metastatic 35% pts Median OS: 11 m

Gastric adenocarcinoma

5y OS

1.- De Angelis R et al. EUROCARE-5. Lancet Oncol 2014; 15: 23–34

Patterns of initial recurrence in completely resected gastric adenocarcinoma (M. D´Angelica et al. Ann Surg 2004)

MSKCC

Relapse: 42%

1172 pts with resected (R0) gastric cancer

Initial relapse - loco-regional: 54% Only loco-regional 26% - peritoneal: 29% - distant metastases 51%

- La cirugía OPTIMA sigue siendo esencial - Tto complementario: Seguimos teniendo distintas opciones - Hemos avanzado poco en la personalización de los ttos - Y vamos lentísimos en la incorporación de nuevas dianas

Cáncer gástrico y de la UEG localizados: QT Peri-operatoria o QT/RT adyuvante;

¿Alguna novedad?

…pues realmente muy pocas…

Cáncer gástrico: Estadificación / Resecabilidad

TUMOR IRRESECABLE: Invasión de cabeza pancreática, hilio hepático, mesocolon transverso, arteria mesentérica, aorta TUMOR RESECABLE: Invasión de lobulo hepático izquierdo, colon transverso, cuerpo o cola pancreática, bazo



¿Alguna novedad?

Treatment options in Resectable Gastric Cancer

Gastric Cancer

- Postoperative Chemotherapy -Postoperative Chemo-Radiotherapy - Perioperative Chemotherapy


Gastric Cancer


GASTRIC “GLOBAL ADVANCED/ADJUVANT STOMACH TUMOR

RESEARCH THROUGH INTERNATIONAL COLLABORATION”

JAMA. 2010 MAY 5;303(17):1729-37

Meta-Analysis

17 phase III trials 3 838 pts Individual data

HR: 0,82 (0,76-0,90)

5y OS: 55% vs 49%

Sakuramoto S et al, NEJM-07

1059 PTS

R0 Resected Gastric adenocarc.

St II-IV, D2+ nodal dissection No Postop treatment

Postoperative S-1

(S1 80mg/m2/d,

d 1-28 each 42d, 1 year)

Postoperative Chemotherapy: S-1 Phase III ACTS-GC (Japan)

Primary endpoint: Sv

S1 No CT HR p

Sv (3y) 80% vs 70% 0.68 0.003

Postoperative Chemotherapy

1035 PTS

R0 resected Gastric cancer, D2

St II-IIIB Surgery Surgery XELOX

Primary endpoint: SLP

Phase III CLASSIC (Asia)

HR p .

SLP (5y) 73% 0.58 <0.0001 61%

Bang YJ et al. Lancet Oncol 2014

HR 0,58 (0,47 - 0,72) p 0,0001 HR 0,66 (0,53 – 0,85) p 0,0015

OS


Gastric Cancer


Postoperative Chemo-Radiotherapy

SWOG 9008/INT 0116

Macdonald et al, N Engl J Med 2001

566 PTS

R0, St.IB-IV (M0)

Gastric 80%

E-G Junction 20% No Postop treatment

CT/RT

FU-Lv x5 / (45 Gy)

Sv (3 y) 50% p=0.005 41%

Loc.Relap(3y) 19% p=0.005 29%

Dist.Relap(3y) 33% 18%

Survival

(MacDonald JS et al. ASCO-04)

INT 0116 Survival according to

Nodal Dissection

D<1 (54% of pts)

D1 (34% of pts)

D2+ (10% of pts)

INT 0116

Survival according to Histology

Intestinal (61% of pts) Diffuse (39% of pts)

Macdonald et al, ASCO 2004

Smalley et al , J Clin Oncol 2012


546 PTS

R0 resected Gastric C.

Surgery

ECFx2F/RTECFx2

Surgery FLx2F/RTFLx2

Primary endpoint: OS

P. III CALGB 80101(US-Intergroup)

- Survival (median/3y) 37m /50% HR 1,03 p 0,8 38m/52%

- DFS (median/3y) 30m /46% HR 1,03 p 0,8 28m/47%

- G 4 Tox 40% p<0,001 26% (Fuchs, ASCO 2011#4003)


- DFS (7y) 67% HR 0,74 p 0,09 73%

- LR relapse 13% p 0,03 7%

- OS (7y) 73% HR 1,13 p 0,52 75%

458 PTS

R0 resected Gastric cancer, D2

St II-IV SurgeryXP/RT Surgery XP

P. III ARTIST (Korea)

1º endpoint: DFS

Park SH et al, J Clin Onc 2015

OS

POSTOPERATIVE CHEMO-RADIOTHERAPY

P. III ARTIST (Korea) Park SH et al, J Clin Onc 2015

PIII ARTIST-2 Adj CT vs CT/RT in pN+ resected gastric cancer

Role of RT in diffuse?

Treatment options in Resectable -Esophageal Cancer

- EGJ Adenocarcinoma - Gastric Adenocarcinoma

Gastric Cancer

- Postoperative Chemotherapy ?? -Postoperative Chemo-Radiotherapy - Perioperative Chemotherapy

Perioperative Chemotherapy

MAGIC-1

Cunningham et al, N Engl J Med 2006

503 PTS

Resectable St. II-IV (M0)

Gastric 74%

E-G Junction 26% Surgery Perioperative CT

ECFx3Surg. ECFx3

(44% of pts)

Sv (3y) 43% p<0.05 32%

Loc Rel (3y): 29% p<0.05 44%

Dist Rel (3y): 31% p<0.05 45%

Survival

Boige V et al, ASCO-07 # 4510

224 PTS

Resectable adenocarcinoma

-Gastric (no EGJ) 25 %

-EGJ 64 %

-distal esophagous 11 %

PS 0 / 1 (75% / 25%)

Surgery

Perioperative CT

CFx2-3Surgery

(CF x4 postSx if OR or SD with pN+: 50% pts)

CFSur Sur HR p

Sv (5y) 38% vs 24% 0,66 0,01

DFS (5y) 34% vs 21% 0,65 0,003

Perioperative Chemotherapy Phase III FNLCC-ACCORD07-FFCD 9703

Primary endpoint: Sv

Should RT be added to perioperative CT?

788 PTS

Resectable Gastric Cancer St. II-IV (M0)

Primary end point: Survival

Perioperative CT

ECX x3Surg. ECX x3

Preop CT + Postop CT/RT

ECX x3Surg. RT/Xeloda

F. III CRITICS (Dutch)

OS (5 y) 40.8 m p 0,99 40.9 m

PFS (5 y) 38.5% p 0,99 39.5 %

Verheij et al, ASCO 2016. Abstr 4000

1º endpoint OS

PFS





Should RT be added to perioperative CT?

- The addition of RT to Perioperat CT remains “investigational” - Waiting for Subgroup analysis of CRITICS

752 PTS

Resectable Gastric Cancer T3-4 and/or N+ (M0)

Primary end point: Survival

Perioperative CT

ECF x3Surg. ECF x3

Preop CT/RT + Postop CT

ECF x2 RT/FuSurg. ECFx3

F. III TOP GEAR (International Intergroup)

Treatment options in Resectable Gastric Adenocarcinoma

Gastric Cancer

- Perioperative Chemotherapy - Postoperative Chemo-Radiotherapy - Postoperative Chemotherapy ??

Experimental option - Preoperative Chemo-Radiotherapy

F. II: QT QT/RT Cir (3 pasos)

en C. Gástrico Resecable Estudio NºPts Mort. R 0 Mort. pRC Sv 2a Régimen QT->QT/RT Cirug. (med)

-------------------------------------------------------------------------- Ajani (J Clin Oncol,04) 34 3% (Fb+Np) 0 70% 4% 30% 54% PFL->F/RT 33,7 m)

Ajani (RTOG) (1,5 a) (J Clin Oncol,06) 49 0 0 77% 0 26% 53% PFL->FTaxol/RT (23,2m) Ajani (J Clin Oncol,05) 41 0 2% (IAM) 78% 0 20% 68% PFTaxol->F/RT (no alc.)

TTD(Resecables) (IJRBO-09) 23 0 0 65% 6% 9% 35%

ICIC/RT (14,5 m)

Treatment options in Resectable EGJ Adenocarcinoma

- Preoperative Chemo-Radiotherapy - Perioperative Chemotherapy

Stahl et al. J Clin Oncol 2009; 27: 851-856

119 Pts in 5 y (planned 177)

Siewert I / II-III 55%/45%

ECOG 0/1 60%/40%

Weight loss >10% 16%

Preop CT/RT

PFLx2PE/RTCx

OS (3y) 27% HR 0.67 (0.41-1.07) p 0.07 47%

Local Control (3y) 59% HR 0,45 (0,19-1,05) p 0.06 76%

R0 69% p NS 72%

pCR 2% p 0.03 16%

Perioperative Mort. 4% p 0.26 10%

Resectable EGJ adenocarcinoma F. III POET (Preop CT vs Preop CT-RT)

Primary endpoint: OS

Preop. CT

PFLx3Cx

Resectable EGJ Adenoca Phase III POET

Sv

Control Local 27.7%

36%

Perioperative Chemotherapy in EGJ Adenoca

1.- Cunningham et al, N Engl J Med 2006

2.- Boige et al, ASCO 2007 # 4510

131 pts included with - Distal esophageal adenoca (73 pts) - EGJ adenoca (58 pts)

MAGIC 1

FNLCC 2 64% o pts (143 pts) included with - EGJ adenoca

EGJ Adenocarcinoma Siewert Clasification

«Esophageal» options? Preop CT/RT

«Gastric» options? Perioperative CT



¿Alguna novedad?

Cáncer Gástrico Grupo heterogéneo de enfermedades

Adenocarcinoma de la UEG

Adenoca. Gástrico - Proximal / Distal

- Occidentales / asiáticos

- Tipo histológico de Lauren: intestinal/ difuso

- Localización

Cáncer gástrico: Intestinal / Difuso (Tipos histológicos de Lauren)

Diferente patogenia

INT 0116

Survival according to Histology

Intestinal (61% of pts) Diffuse (39% of pts)

Macdonald et al, ASCO 2004

Smalley et al , J Clin Oncol 2012

POSTOPERATIVE CHEMO-RADIOTHERAPY

P. III ARTIST (Korea) Park SH et al, J Clin Onc 2015

PIII ARTIST-2 Adj CT vs CT/RT in pN+ resected gastric cancer

Role of RT in diffuse?

9%

20 %

21%

50%

Gastric Cancer: Comprehensive Molecular Characterization

9%

21%

20 %

50%

Preoperative Chemotherapy in GC

Early PET Response: MUNICON trial (Lordick, Lancet Oncol-07)

14 days

119 pts. uT3-4 Resectable Esoph/EGJ adenoca Preop CT

Early PET response (SUV decrease >35%)

49% of pts

R0: 96% vs 74%

pCR: 16% vs 0%

DFS

OS

268 Pts

EGJ Adenoca, Siewert I / II

Resectable T3-4 or N+

FDG-baseline uptake

Resectable EGJ adenocarcinoma IMAGE trial (EORTC 40081) (F Lordick, O Matzinger)

Primary endpoint: R0

Preoperative CT

EOX/EOF (CF +antiHER2 if HER2+)

PET day 14

PET response (>35%)

Preoperative CT

x 3

Surgery

Preop CT/RT

Doce/Cis/RT (45Gy)

No PET response

Surgery

Randomization

Surgery



¿Alguna novedad?

Cetuximab-CT/RT: No metastatic Esophageal Ca

…Two negative P III

258 PTS (P.III no initiated due to futility analysis)

Esophageal Ca (Epid/Aden)

St I-III

Cis-Cape/RT 4 courses, 3º-4º with 50Gy

Cetuxi+Cis-Cape/RT 4 courses, 3º-4º with 50Gy

P. II-III SCOPE 1 1

1º Endpoint P II: TTF (24 w) 66% 77% OS (median) 22,1m HR 1,53; p 0,03 25,4m More Toxicity in the Cetuximab arm

1.- Crosby T el al. Lancet Oncology 2013 ; 2.- Suntharalingam et al, ASCO-GI 2014

328 PTS

Esophageal Ca(Adenoc 62%)

St I-IVA

Cis-Paclitaxel/RT 50Gy

Cetuxi+Cis-Pacli/RT 50Gy

P.III RTOG 0436 2

1º Endpoint OS (12 m) 64% p 0,7 65% OS (24 m) 44% p 0,7 42% No differences between Ca epiderm and Adenoca

Primary Objetive: Overall Survival

UK MRC ST03 (MAGIC-B) Phase III trial:

ECX ± Beva (perioperative) in early stage GC

Gastric or GEJ Cancer

type III resectable

N=1063

ECX

3 cycles

ECX + Avastin

3 cycles

ECX

3 cycles

ECX + Avastin

3 cycles

Surgery

Avastin

6 cycles

Cunningham et al. , ECC-ESMO 2015

ECX ECX-Avastin

Primary objetive: OS (3 y) 48.9% HR 1.06 p<0.47 47.6%

PFS HR 1,02 p 0.76

Studies with trastuzumab in resectable Her2+ esophago-gastric adenocarcinoma

36 Pts

Resectable Her2 +,Gastric-EGJ Cancer

Primary endpoint: DFS

Perioperative Xelox-Trastuz.

Xelox-T x3Surg. Xelox-T x3Tx12

P. II NEOXH (Spain)

53 Pts

Resectable Her 2+, Gastric-EGJ Cancer Primary endpoint: pCR

Perioperative FLOT-Trastuz.

FLOT-T x4Surg. FLOT-T x4Tx9

P II AIO-STO 0310 (Germany)

(Hofheinz R et al, ASCO 2014, #4073) R0: 93% , pCR: 22%

(Rivera F et al, ASCO-GI 2015 #107) R0: 78% (MAGIC: 69%) pCR: 8% (MAGIC: 0%) 24 m PFS: 60% (MAGIC: 45%) 24 m OS: 75% (MAGIC: 50%)

USO EXPERIMENTAL/FUERA DE INDICACIÓN

USO EXPERIMENTAL/FUERA DE INDICACIÓN

Slide 30

Ongoing trials with Inmunotherapy in GC

Mensajes para llevarse a casa:

- Qt Perioperatoria (de momento sigue sin RT) - QT-RT Postoperatoria - Qt Postoperatoria?

- Qt-RT Preoperatoria

- La Cirugía sigue siendo la base del tto - MANEJO MULTIDISCIPLINAR

Muchas gracias

Documents

Cáncer gástrico y de la UEG localizados QT Peri-operatoria ......Cáncer Gástrico Grupo heterogéneo de enfermedades Adenocarcinoma de la UEG Adenoca. Gástrico - Proximal / Distal