cáncer gástrico y de la ueg localizados qt peri-operatoria ......cáncer gástrico grupo...

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

- 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?

Treatment options in Resectable Gastric Cancer

Gastric Cancer

- Postoperative Chemotherapy -Postoperative Chemo-Radiotherapy - Perioperative Chemotherapy

Treatment options in Resectable Gastric Cancer

Gastric Cancer

- Postoperative Chemotherapy -Postoperative Chemo-Radiotherapy - Perioperative Chemotherapy

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

Treatment options in Resectable Gastric Cancer

Gastric Cancer

- Postoperative Chemotherapy -Postoperative Chemo-Radiotherapy - Perioperative Chemotherapy

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

Postoperative Chemo-Radiotherapy

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)

Postoperative Chemo-Radiotherapy

- 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

Verheij et al, ASCO 2016. Abstr 4000

F. III CRITICS (Dutch)

Verheij et al, ASCO 2016. Abstr 4000

F. III CRITICS (Dutch)

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

- 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?

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

- 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?

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