This document summarizes research on adjuvant, neoadjuvant, and advanced gastric cancer treatment. It discusses several phase III trials investigating chemoradiotherapy and chemotherapy in the adjuvant setting. It also reviews studies of first-line and second-line chemotherapy regimens for advanced gastric cancer, including combinations containing docetaxel, oxaliplatin, and fluoropyrimidines. Targeted therapies such as trastuzumab, ramucirumab, and lapatinib are also summarized, with some shown to improve outcomes versus chemotherapy alone in biomarker-selected patients.

1. TERAPIA ADIUVANTE,
NEOADIUVANTE E DELLA
MALATTIA AVANZATA NEL
CARCINOMA GASTRICO
Sara Lonardi
Oncologia Medica 1
Istituto Oncologico Veneto
Padova

2. GC mortality in Italy
derived from population
based cancer registries
AIRTUM, 2013

3. Carcinoma gastrico: chemioradioterapia adiuvante
Macdonald, N Engl J Med 2001
556 resected stage
IB-IV M0 gastric
cancer
R
a
n
d
o
m
Observation
5FU/LV + RT

4. Carcinoma gastrico: chemioradioterapia adiuvante
Relapse-free Survival
by treatment arm
Overall Survival
by treatment arm
HR 1.35 (95% CI: 1.09-1.66)
P=0.005
mOS 36 vs 27 months
HR 1.52 (95% CI: 1.23-1.86)
P<0.001
mRFS 30 vs19 months
Macdonald, N Engl J Med 2001

5. Carcinoma gastrico: chemioradioterapia adiuvante
Major critic: surgery inadequate
Macdonald, N Engl J Med 2001

6. Carcinoma gastrico: chemioterapia adiuvante – nuovi studi
Reference Stage Treatment N of
patients
5-yr
survival
P
Bajetta, 2002 pT3-4/N+ EAP x 2 → 5FU x 2
Surgery alone
135
136
52
48
NS
Bouché, 2005 II-IV M0 PF x 5
Surgery alone
138
140
46.6
41.9
NS
Nitti, 2006 IB-IV M0 FAMTX or FEMTX x 6
Surgery alone
194
203
43
44
NS
De Vita, 2007 IB-IIIB ELFE x 6
Surgery alone
113
112
48
43.5
NS
Di Costanzo, 2008 IB- IV M0 PELF x 4
Surgery alone
130
128
47.6
48.7
NS
Cascinu, 2007 II-IV M0 PELFw x 8
5FU bolus x 6
201
196
52
50
NS

7. Carcinoma gastrico: chemioterapia adiuvante –metanalisi
Reference N. of
studies
N of
patients
HR 95% CI Reduction of
Mortality
Bajetta, 2008 15 3514 0.82 NR 7%
Boku, 2008 14 3293 0.81 0.73-0.89 7%
GASTRIC, 2010 16 3710 0.83 0.76-0.91 6.5%

8. Carcinoma gastrico: chemioterapia adiuvante –metanalisi
GASTRIC, JAMA 2010

9. Chemioterapia adiuvante: XELOX

10. Chemioterapia adiuvante: fattibilità

11. CT adiuvante e perioperatoria
studi di fase III
Autore Sakuramoto 2007
(ACTS-CG)
Cunningham 2006
(MAGIC)
Ychou 2011
(FNCLCC/FFCD)
Stato Giappone UK Francia
Stadio II/III II/III III
N. Pz 529/530 250/253 113/111
Strategia Adiuvante Perioperatoria Perioperatoria
Tratt sperimentale S1 post ECFx3 preop+post FPx3 preop+post
controllo Follow-up Follow-up Follow-up
Loc gastrico/AEG NA 74%/26% 25%/75%
HR 0.68 P=0.003 0.75P=0.009 0.69P=0.02
Braccio di controllo :chirurgia

12. 5-year OS in advanced GC (aGC):
a sad starting point!
What are the aims of CT in this setting?
• Symptomatic control
• Improve of QoL or avoid its
deterioration
• Delay tumor progression
• Prolong survival
95
85
70
50
20
2
0
20
40
60
80
100
%
Ia Ib II IIIa IIIb IV

13. Should pts with aGC receive CT?
Wagner AD, JCO 2006
Effect of combination vs BSC on overall survival

14. Glimelius B, Ann Oncol 1994
When should pts with aGC receive CT?

15. Should pts with aGC receive mono or poliCT?
Wagner AD, JCO 2006
Effect of combination vs single-agent CT on OS

16. Recent phase III trials in aGC
Non-inferior
Study N 1st EP CT scheme mOS
REAL-2 964 OS
ECF vs EOF vs
ECX vs EOX
9.9 vs 9.9 vs
9.3 vs 11.2
ML17032 316 PFS XP vs CF 10.5 vs 9.3
JCOG9912 704 OS S1 vs FU 11.5 vs 10.8
Superior
Study N 1st EP CT scheme mOS
V325 457 TTP DCF vs CF 9.2 vs 8.4
V306 333 TTP IF vs CF 9.0 vs 8.7
JCOG9912 704 OS IP vs FU 12.3 vs 10.8
SPIRITS 305 OS S1P vs S1 13 vs 11
TOP-002 326 OS IS1 vs S1 12.8 vs 10.5
FLAGS 1053 OS S1P vs CF 8.6 vs 7.9
START 639 OS DS1 vs S1 12.5 vs 10.8

17. Oxaliplatin is as effective than cisplatin
Cunningham D, NEJM 2008
Al Batran SE, JCO 2008

18. Oral fluoropyrimidines can replace 5-FU:
Capecitabine
Okines, Ann Oncol 2009
HR 0.87
(p=0.027)

19. DCF improves CT efficacy over CF
Van Cutsem E, JCO 2006
Best overall response rate
(A)TTP and (B) OS among pts treated with DCF or CF
BUT…

20. …Toxicity
Van Cutsem E, JCO 2006
Hematologic and nonhematologic toxicities

21. Alternative Docetaxel-containing regimen
Tebutt NC, Br J Cancer 2010

22. Total events
Heterogeneity: ChP = 10.76, df = 11 (P = 0.46); P = 0%
Test for overall effect: Z = 4.67 (P < 0.00001)
DCF regimens increase ORR compared with
non- docetaxel containing CT
Cheng XL, Plos One 2013
DCF Control Risk Ratio
Study or subrgroup Events Total Events Total Weight M-H, Fixed, 95% CI Year
Sadighi S, et al 18 44 17 42 10.5% 1.01 (0.61. 1.68) 2006
Chu JH, et al 9 20 3 20 1.8% 3.00 (0.95. 9.48) 2006
Van CE, et al 81 221 57 224 34.0% 1.44 (1.08. 1.91) 2006
Roth AD, et al 15 41 10 40 6.1% 1.46 (0.75. 2.86) 2007
Li XQ, et al 22 30 19 30 11.4% 1.16 (0.82. 1.64) 2007
Zhang FL, et al 12 25 5 25 3.0% 2.40 (0.99. 5.81) 2007
Wu GC, et al 21 32 10 26 5.5% 1.71 (0.99. 2.95) 2008
Hou AJ, et al 10 19 3 17 1.9% 2.98 (0.98. 9.07) 2009
Shen YC, et al 11 24 9 24 5.4% 1.22 (0.62. 2.40) 2009
Zhao F, et al 16 31 15 32 8.9% 1.10 (0.67. 2.40) 2009
Liang B, et al 11 30 8 28 5.0% 1.28 (0.61. 2.72) 2010
Gao H, et al 18 32 9 32 5.4% 2.00 (1.06. 3.76) 2010
Total (95% CI) 549 540 100.0% 1.45 (1.24, 1.69)
165244
Risk Ratio
M-H, Fixed, 95% CI
20.5 0.7 1 1.5
Favours DCFFavours Control
Forest plot of overall response rate

23. Overall Response Rate of triplet CT
Data from randomized trials
EOX
Overall Response Rate
ECX
ECF
DCF
48%
46%
45%
35%

24. Time (months)
294
290
277
266
246
223
209
185
173
143
147
117
113
90
90
64
71
47
56
32
43
24
30
16
21
14
13
7
12
6
6
5
4
0
1
0
0
0
No.
at risk
11.1 13.8
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Event
FC + T
FC
Events
167
182
HR
0.74
95% CI
0.60, 0.91
p value
0.0046
Median
OS
13.8
11.1
ToGA primary end point: OS
Bang, Lancet 2010
Targeting HER-2
ToGA Trial: OS

25. 1.0
0.8
0.6
0.4
0.2
0.0
363432302826242220181614121086420
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
 4.2
0.1
0.3
0.5
0.7
0.9
Months
11
3
218
198
4
0
5
3
12
4
20
11
228
218
196
170
170
141
142
112
122
96
100
75
84
53
65
39
51
28
1
0
0
0
39
20
28
13
No.
at risk
Probability of survival
Exploratory analysis
Targeting HER-2
ToGA Trial: OS in pts with IHC 2+/FISH+ or IHC
3+ disease(exploratory analysis)
Bang, Lancet 2010

26. Second-line CT is effective in aGC
COUGAR-02

27. Kim HS, Ann Oncol 2013
HR for death comparing 2nd line docetaxel with BSC
HR for death comparing 2nd line CT with BSC
HR for death comparing 2nd line irinotecan with BSC
Second-line CT is effective in aGC

28. Second-line CT is effective in aGC
HR (95% CI) = 0.807 (0.678, 0.962)
Stratified log rank p-value = 0.0169
RAM + PAC PBO + PAC
Patients / Events 330 / 256 335 / 260
Median(mos)
(95% CI)
9.63
(8.48, 10.81)
7.36
(6.31, 8.38)
6-month OS 72% 57%
12-month OS 40% 30%
RAM + PAC 330 308 267 228 185 148 116 78 60 41 24 13 6 1 0
PBO + PAC 335 294 241 180 143 109 81 64 47 30 22 13 5 2 0
No. at risk
Censored
 mOS = 2.3 months
REGARD Trial
RAIMBOW Trial
Wilke H, ASCO GI 2014
Fuchs CS, ASCO GI 2013

29. Which pts should receive CT?
PS 2 pts present a very poor outcome
Shitara K,Gastr Cancer Res 2009
OS
TTP

30. Chau I, JCO 2004
PS2
Liver mets
Peritoneal mets
Alkaline Phosphatase
Overall survival by prognostic index
Which pts should receive CT?
Different risk groups

31. Does CT improve/impair QoL?
QoL and efficacy outcomes
in phase III trials
Al Batran SE Cancer,2010

32. How we will make any progress in the
treatment of advanced GC ?
5-FU monotherapy
EOX
Median overall survival in advanced gastric cancer
5-FU + LV +
Oxaliplatin (FLO)
Capecitabine +
Cisplatin (XP)
SP
Docetaxel +
Cisplatin + 5FU
11.2 mo
10.7 mo
10.5 mo
9.2 mo
7.0 mo
8.6 mo
13 moX/FP+ T HER2 +
16 moHER2 IHC 3+ or IHC 2+/FISH +X/FP+ T
Best supportive
care
4.0 mo

33. Shah MA, Clin Canc Res 2011
69
26
345
115
36
18
365
166
115
64
488
221
7247
8110
up
down
75
20
Type 2 - normalType 1 - normal
Type 3 - normal
GC: a single tumor or an heterogeneous disease?
•GC treated uniformly, despite epidemiologic, anatomic, and
histopathologic distinctions between subtypes
•Proximal non-diffuse, diffuse, and distal non-diffuse gastric cancers
can be distinguished by gene signatures

34. Targets in advanced GC
MET
FGFR2
EGFR
HER2
PI3K/mTOR
VEGF

35. 1stL
Study Target N 1st EP CT scheme mOS (m) ORR
TOGA HER2 594 OS
CX
CX + Trastu
11.1
13.8 (16.0)
34.5%
47.3%
LOGIC HER2 497 OS
CAPEOX
CAPEOX + Lapatinib
10.5
12.2
40%
53%
AVAGAST VEGF 774 OS
CX
CX + Beva
10.1
12.1
37%
46%
REAL-3 EGFR
553
(76%)
OS
EOC
mEOC-Pani
11.3
8.8
42%
46%
EXPAND EGFR 904 PFS
CX
CX-Cetuximab
10.7
9.4
29%
30%
AMG102 MET 118
PFS (phase
II)
ECX
ECX-Rilotu
8.9
11.1
2ndL
GRANITE mTOR 656 PFS
Placebo
Everolimuns
4.34
5.39
2.1%
4.5%
REGARD VEGFR-2 355 OS
Placebo
Ramucirumab
3.8
5.2
2.6%
3.4%
RAINBOW VEGFR-2 665 OS
Paclitaxel +/-
Ramucirumab
7.36
9.63
16%
28%
RAINBOW
TOGA
AMG102
REGARD
Target therapy in GC: results

36. No patient selection based on PI3K/mTOR status
Targeting PI3K/mTOR
GRANITE-1 Trial: OS
Ohtsu A, JCO 2013

37. Target therapies
• Targeting right patients with targeted agents based
on good biomarker in gastric cancer is important
• To better patient selection molecular selection is
needed
• More knowledge
• Better technique
• Better design of trials

38. Take-home messages
- CT adiuvante: si, beneficio assoluto del 7%
- CT-RT adiuvante: in casi selezionati (linfadenectomia)
- CT perioperatoria: si, meglio tollerata
- CT per malattia avanzata: si, prima possibile (PS 2: ?)
- CT a due farmaci: si, platinum-based
- CT a tre farmaci: in casi selezionati (bulky, sintomatici)
- CT target: si, trastuzumab in HER2 +
- CT di seconda linea: si, in pazienti a buon PS

39. 1st-line treatment algorithm in aGC
Immunohistochemistry (IHC) for Her2
FISH-Test for Her2
IHC Score 3+IHC Score 0/1+ IHC Score 2+
FISH +FISH -
Trastuzumab +
Cisplatin-Fluoropyrimidine
Platin-Fluoropyrimidin
(Docetaxel/Epirubicin)

40. Post-progression chemotherapy
ECOG PS 0-1(2) ECOG PS 3-4
Best
Supportive care
Irinotecan or Taxane
+
best supportive care
Second-line treatment algorithm in aGC