Cáncer gástrico y de la UEG localizados QT Peri-operatoria o QT/RT adyuvante; Alguna novedad? Fernando Rivera Herrero Sv Oncología Médica HU M

Transcripción

1 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

2 Gastric adenocarcinoma Gastric adenoca 5y OS 25% 1 5y OS 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 1.- De Angelis R et al. EUROCARE-5. Lancet Oncol 2014; 15: 23 34

3 Patterns of initial recurrence in completely resected gastric adenocarcinoma (M. D Angelica et al. Ann Surg 2004) MSKCC 1172 pts with resected (R0) gastric cancer Initial relapse - loco-regional: 54% Only loco-regional 26% - peritoneal: 29% - distant metastases 51% Relapse: 42%

4 Cáncer gástrico y de la UEG localizados: QT Peri-operatoria o QT/RT adyuvante; Alguna novedad? pues realmente muy pocas - 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

5 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

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

7 Treatment options in Resectable Gastric Cancer Gastric Cancer - Postoperative Chemotherapy -Postoperative Chemo-Radiotherapy - Perioperative Chemotherapy

9 GASTRIC GLOBAL ADVANCED/ADJUVANT STOMACH TUMOR RESEARCH THROUGH INTERNATIONAL COLLABORATION JAMA MAY 5;303(17): Meta-Analysis 17 phase III trials pts Individual data 5y OS: 55% vs 49% HR: 0,82 (0,76-0,90)

10 Postoperative Chemotherapy: S-1 Phase III ACTS-GC (Japan) 1059 PTS R0 Resected Gastric adenocarc. St II-IV, D2+ nodal dissection Primary endpoint: Sv Postoperative S-1 ( S1 80mg/m2/d, d 1-28 each 42d, 1 year) No Postop treatment S1 No CT HR p Sv (3y) 80% vs 70% Sakuramoto S et al, NEJM-07

11 Postoperative Chemotherapy Phase III CLASSIC (Asia) Bang YJ et al. Lancet Oncol PTS R0 resected Gastric cancer, D2 St II-IIIB Surgery XELOX Surgery Primary endpoint: SLP HR p. SLP (5y) 73% 0.58 < % OS HR 0,58 (0,47-0,72) p 0,0001 HR 0,66 (0,53 0,85) p 0,0015

13 Postoperative Chemo-Radiotherapy SWOG 9008/INT PTS R0, St.IB-IV (M0) Gastric 80% E-G Junction 20% CT/RT FU-Lv x5 / (45 Gy) No Postop treatment Survival Sv (3 y) 50% p= % Loc.Relap(3y) 19% p= % Dist.Relap(3y) 33% 18% Macdonald et al, N Engl J Med 2001

14 D<1 (54% of pts) INT 0116 Survival according to Nodal Dissection D2+ (10% of pts) D1 (34% of pts) (MacDonald JS et al. ASCO-04)

15 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

16 Postoperative Chemo-Radiotherapy P. III CALGB 80101(US-Intergroup) 546 PTS R0 resected Gastric C. Primary endpoint: OS Surgery FLx2 F/RT FLx2 Surgery ECFx2 F/RT ECFx2 - 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)

17 Postoperative Chemo-Radiotherapy P. III ARTIST (Korea) 458 PTS R0 resected Gastric cancer, D2 St II-IV 1º endpoint: DFS Surgery XP Surgery XP/RT - 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% OS Park SH et al, J Clin Onc 2015

18 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?

19 Treatment options in Resectable -Esophageal Cancer - EGJ Adenocarcinoma - Gastric Adenocarcinoma Gastric Cancer - Postoperative Chemotherapy?? -Postoperative Chemo-Radiotherapy - Perioperative Chemotherapy

20 Perioperative Chemotherapy MAGIC PTS Resectable St. II-IV (M0) Gastric 74% E-G Junction 26% Survival Perioperative CT Surgery ECFx3 Surg. ECFx3 (44% of pts) Sv (3y) 43% p< % Loc Rel (3y): 29% p< % Dist Rel (3y): 31% p< % Cunningham et al, N Engl J Med 2006

21 Perioperative Chemotherapy Phase III FNLCC-ACCORD07-FFCD PTS Resectable adenocarcinoma -Gastric (no EGJ) 25 % -EGJ 64 % -distal esophagous 11 % PS 0 / 1 (75% / 25%) Perioperative CT CFx2-3 Surgery ( CF x4 postsx if OR or SD with pn+: 50% pts) Surgery Primary endpoint: Sv CF Sur Sur HR p Sv (5y) 38% vs 24% 0,66 0,01 DFS (5y) 34% vs 21% 0,65 0,003 Boige V et al, ASCO-07 # 4510

22 Should RT be added to perioperative CT? F. III CRITICS (Dutch) 788 PTS Resectable Gastric Cancer St. II-IV (M0) Primary end point: Survival 1º endpoint OS Perioperative CT ECX x3 Surg. ECX x3 Preop CT + Postop CT/RT ECX x3 Surg. RT/Xeloda OS (5 y) 40.8 m p 0, m PFS (5 y) 38.5% p 0, % PFS Verheij et al, ASCO Abstr 4000

23 F. III CRITICS (Dutch) Verheij et al, ASCO Abstr 4000

24 F. III CRITICS (Dutch) Verheij et al, ASCO Abstr 4000

25 Should RT be added to perioperative CT? - The addition of RT to Perioperat CT remains investigational - Waiting for Subgroup analysis of CRITICS F. III TOP GEAR (International Intergroup) 752 PTS Resectable Gastric Cancer T3-4 and/or N+ (M0) Primary end point: Survival Perioperative CT ECF x3 Surg. ECF x3 Preop CT/RT + Postop CT ECF x2 RT/Fu Surg. ECFx3

26 Treatment options in Resectable Gastric Adenocarcinoma Gastric Cancer - Perioperative Chemotherapy - Postoperative Chemo-Radiotherapy - Postoperative Chemotherapy?? Experimental option - Preoperative Chemo-Radiotherapy

27 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) % 0 26% 53% PFL->FTaxol/RT (23,2m) Ajani (J Clin Oncol,05) % (IAM) 78% 0 20% 68% PFTaxol->F/RT (no alc.) TTD(Resecables) (IJRBO-09) % 6% 9% 35% IC IC/RT (14,5 m)

28 Treatment options in Resectable EGJ Adenocarcinoma - Preoperative Chemo-Radiotherapy - Perioperative Chemotherapy

29 Resectable EGJ adenocarcinoma F. III POET (Preop CT vs Preop CT-RT) 119 Pts in 5 y (planned 177) Siewert I / II-III 55%/45% ECOG 0/1 60%/40% Weight loss >10% 16% Primary endpoint: OS Preop. CT PFLx3 Cx Preop CT/RT PFLx2 PE/RT Cx OS (3y) 27% HR 0.67 ( ) p % Local Control (3y) 59% HR 0,45 (0,19-1,05) p % R0 69% p NS 72% pcr 2% p % Perioperative Mort. 4% p % Stahl et al. J Clin Oncol 2009; 27:

30 Resectable EGJ Adenoca Phase III POET Sv 36% 27.7% Control Local

31 Perioperative Chemotherapy in EGJ Adenoca MAGIC pts included with - Distal esophageal adenoca (73 pts) - EGJ adenoca (58 pts) FNLCC 2 64% o pts (143 pts) included with - EGJ adenoca 1.- Cunningham et al, N Engl J Med Boige et al, ASCO 2007 # 4510

32 EGJ Adenocarcinoma Siewert Clasification «Esophageal» options? Preop CT/RT «Gastric» options? Perioperative CT

34 Cáncer Gástrico Grupo heterogéneo de enfermedades - Localización Adenocarcinoma de la UEG Adenoca. Gástrico - Proximal / Distal - Occidentales / asiáticos - Tipo histológico de Lauren: intestinal/ difuso

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

36 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

37 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?

38 9% 21% 20 % 50%

39 Gastric Cancer: Comprehensive Molecular Characterization 50% 9% 21% 20 %

40 Preoperative Chemotherapy in GC Early PET Response: MUNICON trial (Lordick, Lancet Oncol-07) 119 pts. ut3-4 Resectable Esoph/EGJ adenoca Preop CT Early PET response (SUV decrease >35%) 14 days 49% of pts DFS R0: 96% vs 74% OS pcr: 16% vs 0%

41 Resectable EGJ adenocarcinoma IMAGE trial (EORTC 40081) (F Lordick, O Matzinger) 268 Pts EGJ Adenoca, Siewert I / II Resectable T3-4 or N+ FDG-baseline uptake Primary endpoint: R0 Preoperative CT EOX/EOF (CF +antiher2 if HER2+) PET day 14 No PET response PET response (>35%) Randomization Preop CT/RT Surgery Doce/Cis/RT (45Gy) Surgery Preoperative CT x 3 Surgery

43 Cetuximab-CT/RT: No metastatic Esophageal Ca P. II-III SCOPE PTS (P.III no initiated due to futility analysis) Esophageal Ca (Epid/Aden) Two negative P III Cetuxi+Cis-Cape/RT 4 courses, 3º-4º with 50Gy Cis-Cape/RT 4 courses, 3º-4º with 50Gy St I-III 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 P.III RTOG PTS Esophageal Ca(Adenoc 62%) Cetuxi+Cis-Pacli/RT 50Gy Cis-Paclitaxel/RT St I-IVA 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 50Gy 1.- Crosby T el al. Lancet Oncology 2013 ; 2.- Suntharalingam et al, ASCO-GI 2014

44 UK MRC ST03 (MAGIC-B) Phase III trial: ECX ± Beva (perioperative) in early stage GC Primary Objetive: Overall Survival Gastric or GEJ Cancer type III resectable N=1063 ECX 3 cycles ECX + Avastin 3 cycles Surgery ECX 3 cycles ECX + Avastin 3 cycles Avastin 6 cycles ECX ECX-Avastin Primary objetive: OS (3 y) 48.9% HR 1.06 p< % PFS HR 1,02 p 0.76 Cunningham et al., ECC-ESMO 2015

45 Studies with trastuzumab in resectable Her2+ esophago-gastric adenocarcinoma P. II NEOXH (Spain) 36 Pts Resectable Her2 +,Gastric-EGJ Cancer Perioperative Xelox-Trastuz. Xelox-T x3 Surg. Xelox-T x3 Tx12 Primary endpoint: DFS (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%) P II AIO-STO 0310 (Germany) 53 Pts Resectable Her 2+, Gastric-EGJ Cancer Primary endpoint: pcr Perioperative FLOT-Trastuz. FLOT-T x4 Surg. FLOT-T x4 Tx9 (Hofheinz R et al, ASCO 2014, #4073) R0: 93%, pcr: 22% USO EXPERIMENTAL/FUERA DE INDICACIÓN

46 USO EXPERIMENTAL/FUERA DE INDICACIÓN

47 Ongoing trials with Inmunotherapy in GC Slide 30

48 Mensajes para llevarse a casa: - La Cirugía sigue siendo la base del tto - MANEJO MULTIDISCIPLINAR - Qt-RT Preoperatoria - Qt Perioperatoria (de momento sigue sin RT) - QT-RT Postoperatoria - Qt Postoperatoria?

49 Muchas gracias