Terapia Sistémica y Radioterapia en Cáncer Gástrico Resecable: Adyuvancia y neoadyuvancia
Prof. Dr. Paulo M. Hoff Centro de Oncologia
Surgery NOT Enough for Most Patients
The Problem
0%
25%
50%
75%
100%
IA IB IIA IIB IIIA IIIB IIIC IV
Survival (%)
3 years
5 years Just Stage I Pts have a higher than 50/50 chance to
reach 5yrs
More than 10,000 pts from 1973 to 2005
A quarter or less of Stage III pts
are alive in 3 yrs
SEER Data Base – Based on Seventh Edition AJCC Cancer Staging Manual
Adjuvant Chemoradiation
ITN 0116
Macdonald et al, NEJM, (345) 2001
556 Pts Aug, 1991 – Jul, 1998
3 to 6 weeks aAer Surgery PS 0-‐ 2 Gastric or GEJ IB to IVM0
5-FU 425mg/m2 LCV 20 mg/m2 D1-D5
28 days
Radiotherapy CCT 5-FU 420mg/m2 LCV 20 mg/m2
D1-D4 D34–D36
275 pts
Follow up 281 pts
Macdonald et al, NEJM, (345) 2001
OS 36 x 27 months 3yS 50 x 41% HR 1.35 (1.09 – 1.66, p=0.005)
OS - HR 1.32 (p=0.004) All subsets, except diffuse histology
ITN 0116
Macdonald et al, NEJM, (345) 2001
85% had node mestastasis
20% were from EGJ
Elderly pts were included 87 years old – oldest
10% had a D2 ressection
More than 50% had LESS than a D1 ressection
ITN 0116
CALGB 80101
Fucks et al ASCO Annual Meeting 2011
MacMagic x Macdonald
546 Pts
OS 36.6 X 37.8 months (p=0.8) More GIII-‐IV Toxic effects
Macdonald
ECF ECF
MAGIC TRIAL
Cunningham et al, NEJM, (355) 2006
503 Pts Jul, 1994 – Apr, 2002
Gastric, GEJ, lower esophagus ECOG-‐ PS 0 -‐ 1 II to IVM0 (1998 AJCC)
Surgery
Epirrubicin 50 mg/m2 Cisplatin 60 mg/m2 5-FU 200 mg/m2 Daily
D1 / 21d
250 pts
Surgery Only 253 pts
Cunningham et al, NEJM, (355) 2006
Smaller tumors 3 x 5 cm (p<0.001)
Less advanced nodal disease (p=0.01) Less considered non-‐cura^ve ressec^ons (21% x 30%)
Reduced Local and Distal Recurrence
5yS 36.3 x 20.3 % HR 0.74 (p=0.008)
MAGIC TRIAL
To be remembered
15% lower esophagus 12% EGJ 20% older than 70 yo
• 41% completed 6 cycles of Chemo
• 15% Progressed during First Phase • 55% re-‐started Chemo aAer Surgery
Cunningham et al, NEJM, (355) 2006
MAGIC TRIAL
FNCLCC - FFCD TRIAL
224 Pts Nov, 1995 – Dec, 2003
GEJ, gastric, lower esophagus ECOG-‐ PS 0 -‐ 1 II to IVM0 (1998 AJCC)
65% of pts had dysphagia
Cisplatin 100 mg/m2 D1 5-FU 800 mg/m2 D1-D5 28 days
113 pts
Surgery Only 111 pts
Ychou et al, JCO, (13) 2011
Ychou et al, JCO, (13) 2011
More R0 Ressec^on 84% x 74% (p<0.04)
Similar postopera^ve complica^ons
5yS 38 x 24 % HR 0.69 (0.50 – 0.95, p=0.02)
FNCLCC - FFCD TRIAL
Japonese Adjuvant Trial (ACTS-GT) – S1
Sakuramoto et al, NEJM, (357) 2007
1059 Pts Oct, 2001 – Dec, 2004
Stage II – IIIb All pts -‐ D2 Surgery EAST ASIAN
Follow up 530 pts
S-1 40mg/m2 4 weeks on 2 weeks off FOR ONE YEAR
529 pts
Sakuramoto et al, NEJM, (357) 2007
Most pa^ents N0 and N1 Lower impact on local recurrence 65% pts Completed Treatment
3 yr OS: 81.1 x 70.1% HR for death 0.68, p=0.003
Japonese Adjuvant Trial (ACTS-GT) – S1
OR 0.8 (0.66-0.97)
Earle and Maroun, EJC, (35) 1999
The Gastric 17 trial 3838 pts OR 0.82 (0.76-0.92)
THE GASTRIC JAMA, (303) 2010
Bang et al, Lancet, (379) 2011
1035 Pts Jun 2006 – Jun, 2009
II to IIIB ECOG-‐ PS 0 -‐ 1 South Korea, Taiwan and China Within 6 weeks aAer Surgery
Capecitabine 2000 mg/m2/d– D1 to D14 Oxaliplatin 130 mg/m2 - D1
D1 / 21d
Surgery Only 515 pts
520 pts
CLASSIC
Bang et al, Lancet, (379) 2011
3y DFS 74% x 59% HR 0.56 (0.44 – 0.72, p<0.001)
CLASSIC
Bang et al, Lancet, (379) 2011
CLASSIC
Only 2% were GEJ More than 90% were node posi^ve
Primary End Point : 3y DFS
67% Completed the Adjuvant Chemo
56% Toxicidade G III e GIV
Bang et al, Lancet, (379) 2011
CLASSIC
ARTIST
458 Pts Nov 2004 to April 2008
Only Gastric Cancer Most were Node posi^ve and Diffuse
> 80% completed Chemoradia^on Arm
Most of the pa^ents had Dose Modifica^on
6 cycles XP (cisplatin 60 mg/m2)
XP Cct Capecitabine 1700 mg/m2/d
XP
Lee et al, JCO, (30) 2012
3y DFS 78 x 74 % p= 0.86
p= 0.0365
All Patients Node Positive
Non pre-planned
Analysis
ARTIST
Lee et al, JCO, (30) 2012
NO DIFFERENCES in the pajern of RECURRENCE
Lee et al, JCO, (30) 2012
ARTIST
ToGA trial design
HER2-positive advanced GC
(n=584)
5-FU or capecitabinea + cisplatin
(n=290)
R
5-FU or capecitabinea + cisplatin
+ trastuzumab
(n=294) Stratification factors
− advanced vs metastatic
− GC vs GEJ
− measurable vs non-measurable
− ECOG PS 0-1 vs 2
− capecitabine vs 5-FU
3807 patients screened 810 HER2-positive (22.1%)
OS in IHC2+/FISH+ or IHC3+ (exploratory analysis)
1.0
0.8
0.6
0.4
0.2
0.0
36 34 32 30 28 26 24 22 20 18 16 14 12 10 8 6 4 2 0
Time (months)
11.8 16.0
FC + T FC
Events
120 136
HR
0.65
95% CI
0.51, 0.83
Median OS
16.0 11.8
Event
0.1
0.3
0.5
0.7
0.9
Conclusions
" Even D2 surgery seems to be insufficient for most gastric cancers
" Adjuvant chemoradiotherapy and peri-operative chemotherapy are equally acceptable options at this point in time (level I)
" Chemotherapy alone is an acceptable alternative for selected cases, particularly those who are N0, or when the available radiotherapy is not ideal
Recommended