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
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