1) Peri-operative chemotherapy with ECX before and after surgery improves overall survival compared to surgery alone in resectable gastric cancer based on the MAGIC trial. 2) The ACTS-GT trial showed adjuvant S-1 chemotherapy improves 3-year survival compared to observation alone after D2 gastrectomy for stage II-III gastric cancer. 3) Combination chemotherapy improves survival over best supportive care alone in advanced gastric cancer, with regimens including anthracyclines and cisplatin or oxaliplatin showing better efficacy.

1. Gastric Cancer: Discussion
Prof David Cunningham
Royal Marsden Hospital
United Kingdom

2. Issues highlighted by these cases
Optimal management of early stage gastric
cancer with regards to……
staging
peri-operative treatment
surgery
Role of chemotherapy in advanced gastric
cancer

3. Operable Disease: Staging
Local assessment Assessment for distal disease
Endoscopy (diagnostic) CT Thorax/abdomen/pelvis
EUS Laparoscopy
– Local staging and – identifies CT occult
assessing proximal & metastatic disease
distal extent of (OGJ)
tumour
Improve selection of
– Staging accuracy ~75%
patients for radical Rx
in gastric cancer1
PET can provide additional information regarding local and distal disease
less sensitive but more specific than CT2 for local LN metastases
●
limitation ~30% of gastric cancer are non-FDG avid3
●
potential role for early response assessment to neo-adjuvant Rx
●
1. Abdalla & Pisters, Seminars in Oncology 2004 2. Kim et al, Eur J Nucl Med Mol Imaging 2006 3. Ott et al., Clin Cancer Res 2008

4. Peri-operative Chemotherapy:
The MRC MAGIC Trial
Post-
Pre-operative Surgical operative
Resectable ECX x3 resection ECX x3
adenocarcinoma of within 3-6/52
Randomised within 6-
the stomach, OGJ
12/52
or lower
Surgical
oesophagus n=503
resection
within 6/52
Median OS: 24 v 20 months
5 yr OS: 36% v 23%
13% OS benefit for ECF
HR for death 0.75, p=0.009
Pre-op chemo well tolerated (5% did
not complete pre-op Rx due to
toxicity)
No increase in post-op complications
Cunningham et al., NEJM 2006

5. Peri-operative Rx:
Advantages Disadvantages
Increase rate of curative (R0) Risk of disease progression during
resection1 by tumour pre-operative treatment
downstaging/downsizing Definitive surgery may be delayed if
Eradication of micro-metastatic significant toxicity occurs
disease Risk of increased peri-operative
Demonstrates in vivo chemo- morbidity - NOT seen in the
sensitivity MAGIC2 trial
Better tolerated than post-
operative therapy – MAGIC2 Peri-operative chemotherapy is
-91% pts able to complete pre- now standard of care in Europe
op Rx
-66% of pts able to commence
post-op Rx
1. Boige et al., ASCO 2007 2. Cunningham et al., NEJM 2006

6. Post-operative Chemoradiation:
SWOG 9008/Intergroup 0116 Trial
Resected stage Ib-IV (M0) Observation n=275
gastric or OGJ
adenocarcinoma n=556 Randomised
(<D1 resection 54% 5-FU/LV Chemoradiation
D1 = 36%, D2 = 10%)
(4500Gy) n=281
Median OS: 27 v 36m
HR for death 1.35; p=0.006
Highly selected population (All
had R0 resection + recovered
from surgery) yet only 64%
completed Rx
Significant Rx related toxicity:
1% toxic death
73% grade 3/4 AEs
Macdonald et al., NEJM 2001

7. Adjuvant Chemotherapy: ACTS-GT1
Observation n=530
Stage II-III gastric cancer
treated with curative Randomised
gastrectomy; all with at least D2 Adjuvant S-1 80mg/m2/day
dissection n=1059 x28 days q 6 weeks x 12
months n=529
Screening programme in Japan
allows detection of disease at
an earlier stage
S1 efficacy not proven in non-
Asian population
3 yr OS: 81.1% v 70.1%
Meta-analysis adjuvant Rx2:
HR for death 0.68, p=0.003 Despite selected nature of the
pt population, benefit of
adjuvant chemo is modest
(Relative risk of death 0.85,
95% CI 0.80-0.90)
1. Sakuramoto et al., NEJM 2007, 2. Liu et al., Eur J Surg Oncol 2008

8. Surgery: Extended D2 Lymph node
dissection
D2 v D1 resection
no survival advantage namely
due to excess morbidity and
mortality related to distal
pancreatectomy &
splenectomy1,2,3
D2 dissection without distal
pancreatectomy & splenectomy
by an experienced surgeon at
a high volume centre is
recommended current clinical
practice
1.Cuschieri et al., BJC 1999, 2. Bonenkamp et al., NEJM 1999 Hartgrink et al., JCO 2004

9. Metastatic Gastric Cancer:
The Role of Chemotherapy
Survival with best supportive care (BSC) alone ~3 months1,2
Combination chemotherapy improves OS compared to BSC
(HR 0.39, 95% CI 0.28-0.52, p<0.00001)3
Benefit in weighted mean average survival ~ 6 months3
1. Murad et al., Cancer 1993, Pyrhonen et al., BJC 995 3. Wagner et al., JCO 2006

10. Selection of patients for chemotherapy
Patients of good performance status (ECOG 0-1)
more likely to respond to chemotherapy1 and have
improved median survival1,2
Linitus plastica is a feature of poor prognosis1
Response rate is lower in patients with peritoneal
carcinomatosis3
Co-morbidities must be considered
Rougier et al., EJC 1994 2. Lavin et al, Cancer 1982 3. Preusser et al., JCO 1989

11. Selection of chemotherapy for patients1
Combination
chemotherapy
superior to
monotherapy
for OS
HR 0.83 (0.74-0.93)
OS is superior
with the addition
of anthracyclines
to platinum/
HR 0.77 (0.62-0.95)
fluorouracil
1. Wagner et al., JCO 2006

12. REAL 2
Epirubicin Cisplatin + infused 5-FU (ECF)
Randomised
Untreated
advanced Epirubicin + cisplatin + capecitabine (ECX)
oesophageal,
OGJ or gastric
cancer n=1002 Epirubicin + oxaliplatin + 5-FU (EOF)
Epirubicin + oxaliplatin + capecitabine (EOX)
Primary Endpoints:
Non-inferiority for survival
Capecitabine compared to Fluorouracil
Oxaliplatin compared to Cisplatin
Overall survival amongst the four regimens
Cunningham et al., NEJM 2008

13. REAL-2 - Results
HR 0.86 (0.8 – 0.99)
Capecitabine is non-inferior to
infused 5FU
Toxicity:
More G3/4 neutropenia (uncomplicated)
hand foot syndrome
Oxaliplatin is non-inferior to cisplatin
HR 0.92 (0.8 – 1.10)
Toxicity:
Less G3/4 neutropenia (uncomplicated)
thromboembolism, alopecia
More G3/4 diarrhoea
G3/4 peripheral neuropathy
Cunningham et al., NEJM 2008

14. Survival: ECF v EOX
Arm OS (m) 1 year survival p-value HR (95% CI)
(95% CI)
ECF 9.9 37.7 (31.8-43.6)
EOX 11.2 46.8 (40.4-52.9) 0.020 0.80
(0.66-0.97)
Improved efficacy of EOX compared to ECF for survival
EOX now an accepted first-line therapy option
Cunningham et al., NEJM 2008

15. V-325 phase III trial: DCF
Docetaxel
+cisplatin +
Untreated advanced infused 5-FU
gastric cancer Randomised
(n=445) Cisplatin +
infused 5-FU
Primary objective: Superior TTP with DCF relative to FP
Results: TTP 5.6m v 3.7m HR 1.47; p<0.001
OS 9.2m v 8.6m HR 1.29; p=0.02
BUT
Grade 3/4 AEs* All 69 v 59%
*Neutropenia 82 v 57%, complicated neutropenia 29 v 12%
Van Cutsem et al., JCO 2006

16. DCF….…reducing toxicity
ATTAX - randomised phase II trial
Weekly docetaxel
Untreated advanced 30mg/m2 D1, D8 +
gastric cancer Randomised cisplatin 60mg/m2 D1
+ infused 5-FU
200mg/m2/day
DCF DX
(n=50) (n=56) Weekly docetaxel
30mg/m2 D1, D8 +
Confirmed RR 47% 26% capecitabine 1600mg/m2
D1-14 q21d
Median PFS 5.8 4.6
Median OS 11.4 10.5
Toxicity: 4% febrile neutropenia with DCF, 2% with DCX
DCF with weekly docetaxel may be an alternative, less toxic regimen
Tebbutt et al., ASCO 2007

17. Second Line Chemotherapy
No current phase III data to support 2nd line chemotherapy
Patients sustaining prolonged benefit from first-line
chemotherapy may be re-challenged with the same regimen on
progression
Phase II data: Response rates are low, but selected patients
may benefit from second-line chemotherapy
Treatment n RR Median TTP or Median OS/
PFS /months months
Docetaxel1 49 16% 2.5 8.3
(75mg/m2 q3 weeks)
FOLFIRI2 38 29% 3.7 6.4
Irinotecan3 37 20% 2.6 5.2
(125m/m2 d1, 8,15 q4 weeks)
Irinotecan (160mg/m2) + 49 20% 2.7 8.9
docetaxel (65mg/m2)4
1. Lee et al., Cancer Chemother Pharmacol 2008, 2. Assersogn et al., Ann Oncol 2004, 3. Chun et al.,
Jpn J Clin Oncol 2004, 4. Sym et al., Cancer Chemother Pharmacol 2008

18. Current randomised phase III trials
ECX x3 Surgery ECX x3
ST03 (MAGIC-B)
Resectable
adenocarcinoma of the ECX + ECX +
Surgery
stomach or Type III OGJ bevacizumab x3 bevacizumab x3
CRITICS: ECX x3 Surgery ECX x3
Resectable
adenocarcinoma of the
stomach or Type III OGJ ECX x3 Surgery CX +RT 45Gy
EOX
REAL3
Untreated advanced adenocarcinoma or
undifferentiated carcinoma of the EOX
oesophagus, OGJ or stomach panitumumab