This document discusses treatment options for operable gastric cancer. It notes that surgical resection is currently the only potentially curative treatment, and recommends resection for all non-metastatic cancers. While the optimal extent of lymphadenectomy is still debated, removing a minimum of 15 lymph nodes is recommended. Adjuvant chemotherapy, chemoradiation, and perioperative chemotherapy are strategies that can increase cure rates. Preoperative chemotherapy followed by postoperative chemoradiation may also improve outcomes compared to postoperative treatment alone.

1. Treatment
of
operable
gastric
cancer
Razvan
Popescu
MD,
MRCP(UK)
ESO
Balkan
Masterclass
in
Clinical
Oncology
11.5.2011-­‐
15.5.2011
Dubrovnik,
CroaKa

2. Gastric
Cancer
Incidence
in
Males
GLOBOCAN
2008,
Interna3onal
Agency
for
Research
on
Cancer
0
3.2
6.9
11.6
21.9
63
Age-­‐standardised
incidence
rates
per
100,000

3. Cancer
Incidence
in
Central
and
Eastern
Europe
GLOBOCAN
2008,
Interna3onal
Agency
for
Research
on
Cancer

4. Work-­‐up
of
Gastric
Cancer
• Physical
examinaKon,
blood
count
and
differenKal,
liver
and
renal
funcKon
tests
• Endoscopy
/
EUS
• CT
scan
of
the
thorax,
abdomen
and
pelvis
• Laparoscopy
(+
peritoneal
washings)
– +ve
washings
not
independent
prognosKc
factor,
conversion
to
–ve
washings
up
to
1/3
with
preop
chemotherapy
(S.
Lorenzen
ASCO
GI
2010)
• PET
scans
– can
be
negaKve,
especially
in
paKents
with
mucinous
tumours
(up
to
30%)
– If
posiKve
can
be
used
for
early
response
assessment

5. Gastric Cancer Survival
100% 91.6
82.0
79.2
Stage 0
66.9
Stage I
47.6
50
36.4
Stage II
21.9
14.7
Stage III
0
5 10 years
CADO,1985
Years after surgery

6. EGJ
Cancers
and
Gastric
cancers
are
different
enKKes
!!
Distal esophagus
GE junction
Proximal stomach
Distal stomach

7. OGJ
Cancers
and
Gastric
cancers
are
different
!!

9. Treatment
of
M0
Gastric
Cancer
• Surgical
resecKon
is
the
only
modality
that
is
potenKally
curaKve,
and
is
recommended
for
all
non-­‐
metastaKc
cancers
• The
extent
of
opKmal
regional
lymphadenectomy
is
sKll
debated.
• A
minimum
of
15
lymph-­‐nodes
should
be
recovered
(even
if
a
formal
D2
lymphadenectomy
is
not
performed)

10. Dutch
D1D2
surgical
trial
• 996
eligible
paKents
randomized
beteween
1989
and
1993
to
D1
or
D2
lymphadenectomy
• 771
paKents
underwent
assigned
treatment,
data
reanalysed
aaer
15
years
Outcome
D1
D2
P
15-­‐y
survival
21%
29%
0.34
Gastric
cancer
death
48%
37%
0.01
Local
recurrence
22%
12%
-­‐
OperaKve
mortality
4%
10%
0.004
ComplicaKons
25%
43%
0.001

11. Strategies
that
increase
cure
rate
in
potenKally
operable
gastric
cancer
• Adjuvant
chemotherapy
• Adjuvant
Chemo-­‐Radiotherapy
• Peri-­‐operaKve
Chemotherapy
• Pre-­‐operaKve
Chemotherapy,
postoperaKve
chemoradiotherapy

12. Benefit of adjuvant chemotherapy for
resectable gastric cancer: a meta-analysis
17 RCT
3838 pts
5 year survival:
Overall effort 55.3% vs. 49.6%
HR: 0.82 (95% CI 0.76-0.91)
P<0.0001
0.40 0.50 0.60 0.70 0.80 0.90 1.00 1.10 1.20 1.30 1.40
Any Hazard ratio Surgery
chemotherapy better alone better
JAMA. 2010 May 5;303(17):1729-3

13. Challenges
of
adjuvant
chemotherapy
• Efficacy
of
treatment
is
unknown
for
the
individual
paKent
• Results
of
individual
trials
discouraging
–
Some
clearly
underpowered
to
detect
a
significant
survival
difference.
Other
trials
uKlized
inferior
surgical
techniques.
• Commencement
of
post-­‐operaKve
treatment
may
be
delayed
by
slow
recovery
from
surgery
or
peri-­‐operaKve
morbidity,
problems
with
nutriKonal
status
• Treatment
appears
to
be
less
well
tolerated
aaer
major
surgery

14. Adjuvant chemotherapy: Percentage of
Patients achieving adequate dose intensity
PRE
PRE-OP PRE
PRE-OP
POST
POST-OP
POST
POST-OP

15. SAKK
TCF
preop
vs.
postop
Trial
• 4
cycles
TCF
planned
either
pre-­‐
or
postoperaKvely
• Trial
closed
due
to
slow
accrual
(70
pats
in
6
Y)
• PreoperaKve
TCF
given
as
planned
in
74%
of
paKents,
but
only
34%
postoperaKvely
• SAE
were
more
common
in
postoperaKve
arm
(23%
vs.
11%)

16. Strategies
that
increase
cure
rate
in
potenKally
operable
gastric
cancer
• Adjuvant
chemotherapy
• Adjuvant
Chemo-­‐Radiotherapy
• Peri-­‐operaKve
Chemotherapy
• Pre-­‐operaKve
Chemotherapy,
postoperaKve
chemoradiotherapy

17. Postoperative Chemoradiotherapy For
Localised Gastric Cancer : INT-­‐0116
SURGERY
NO
TREATMENT
RANDOMIZED
N=
556
5-­‐FU/FA
x
1
(Mayo)
STRATIFIED
infusional
5-­‐FU
/
45
Gy
T
1-­‐4
5-­‐FU/FA
x
1
(Mayo)
NODES
0,
1-­‐3,
>3
McDonald
JS
et
al.
N
Engl
J
Med
2001
Sep
6;345(10):725-­‐30

18. Postoperative Chemoradiotherapy For
Localised Gastric Cancer : INT-­‐0116
• Clear
benefit
in
disease
free
and
overall
survival
with
median
follow-­‐up
of
6
years.
Risk
reducKon
of
death
by
24%.
• Surgery:
D2
resecKon
less
than
10%,
54
%
of
paKents
fewer
than
15
nodes
(less
than
D1)
• Planning
of
RadiaKon
to
be
modified
aaer
central
review
in
35%
of
cases
due
to
protocol
deviaKons
McDonald
JS
et
al.
N
Engl
J
Med
2001
Sep
6;345(10):725-­‐30

19. Postoperative Chemoradiotherapy For
Localised Gastric Cancer : INT-­‐0116
• Complex
RT
schedule
with
significant
toxicity
• SubopKmal
chemotherapy
schedule,
role
of
the
2
flanking
Mayo
5-­‐FU/FA
cycles
unclear
Not
an
approach
that
has
taken
root
in
Europe
In
the
context
of
subopKmal
surgery
or
if
preoperaKve
MDT
is
lacking
an
acceptable
approach
if
good
RT
available
McDonald
JS
et
al.
N
Engl
J
Med
2001
Sep
6;345(10):725-­‐30

20. Impact
of
Extent
of
Surgery
and
PostoperaKve
CRT
on
Recurrence
Pamern
• Leyden
retrospecKve
analysis
of
2
Dutch
trials
:
91
paKents
receiving
postop
CRT
vs.
Cohort
from
Dutch
Gastric
Cancer
Trial
(694)
split
by
D1
vs.
D2
resecKon
• PaKents
with
D2
resecKon
had
as
good
an
outcome
as
paKents
receiving
postop.
CRT
• Clear
benefit
for
D1
resected
paKents,
R1
resecKons
and
high
Maruyama
Index
of
unresected
disease
(computed
from
data
base
of
cases
giving
likelihood
of
involvement
of
unresected
LN
staKons)
JL
Dikken,
JCO
May
10,
2010

21. Strategies
that
increase
cure
rate
in
potenKally
operable
gastric
cancer
• Adjuvant
chemotherapy
• Adjuvant
Chemo-­‐Radiotherapy
• Peri-­‐operaKve
Chemotherapy
• Pre-­‐operaKve
Chemotherapy,
postoperaKve
chemoradiotherapy

22. MAGIC Trial
Eligible patients:
• Adenocarcinoma of the stomach Study entry and randomization
or lower third of the oesophagus
(from 1999), suitable for curative
resection
• Non-metastatic disease
S arm CSC arm
• Stage II or greater N=253 N=250
Primary
Surgery Pre-operative chemotherapy:
Overall survival
ECFx3
Secondary
Progression-free survival 3-6 weeks
Surgical resectability
Quality of Life
Surgery
Chemotherapy (ECF): 6-12 weeks
Epirubicin 50mg/m2, IV day 1
Cisplatin 60mg/m2, IV day 1
5-FU 200mg/m2/day, continuous Post-operative chemotherapy:
infusion, days 1-21 ECFx3
(cycles repeated every 3 weeks)
Recruitment: July 1994-April 2002
Cunningham et al NEJM 2006

23. MAGIC Trial
CSC S
N=250 N=253
Commenced pre-operative
chemotherapy
N=237 (95%)
Completed pre-operative
chemotherapy
N=215 (86%)
Proceeded to surgery Proceeded to surgery
N=219 (88%) N=240(95%)
Cunningham et al NEJM 2006

24. MAGIC Trial
Postoperative Morbidity/ Mortality
CSC S
Postoperative deaths 6% 6%
(14/219) (15/240)
Postoperative complications 46% 46%
Median duration of 13 days 13 days
post-operative hospital stay
Cunningham et al NEJM 2006

25. MAGIC Trial Pathology
Findings
• Median
maximum
diameter
of
the
resected
tumor
was
smaller
in
the
perioperaKve-­‐
chemotherapy
group
than
in
the
surgery
group
(3
cm
vs.
5
cm,
P<0.001)
• a
greater
proporKon
of
stage
T1
and
T2
tumors
in
the
perioperaKve-­‐chemotherapy
group
than
in
the
surgery
group
(51.7
%
vs.
36.8
%,
P=0.002).
• less
advanced
nodal
disease
(i.e.,
N0
or
N1)
in
the
perioperaKve-­‐chemotherapy
group
than
in
the
surgery
group
(84.4
%
vs.
70.5
%,
P=0.01)

26. MAGIC Trial Survival
PFS* Overall
1.0
1.0
0.9
Logrank p-value = 0.0001 0.9 Logrank p-value = 0.009
Progression-free Survival rate
0.8
Hazard Ratio = 0.66 0.8 Hazard Ratio = 0.75
0.7
(95% CI 0.53 - 0.81) 0.7 (95% CI 0.60 - 0.93)
Survival rate
0.6
0.6
0.5
0.5
0.4
0.4
0.3
0.3
Events
Total
Events
Total
0.2
0.2
163
250
CSC
149
250
CSC
0.1
S
0.1 170
253
S
190
253
0.0
0.0
0
12
24
36
48
60
72
0 12 24 36 48 60 72
Months from randomisation
Months from randomisation
2 year 5 year Median  On multivariate analysis,
survival survival survival treatment effect unchanged after
CSC 50% 36% 24 mo adjustment for age, performance
status, site of primary and gender
S 41% 23% 20 mo  Hazard ratio for death
Benefit to CSC 9% 13% 4 mo  Adjusted: 0.74 (95%CI:
arm 0.59-0.93)
 Unadjusted: 0.75
Cunningham et al NEJM 2006
*Included relapse, PD and death from any cause.

27. Tests for Heterogeneity of Treatment Effect According to the Baseline Characteristics of the Patients
Cunningham D et al. N Engl J Med 2006;355:11-20

28. FNLCC 94012-FFCD 9703 Trial
Randomization N=224
CT + S S
FP (*) x 2/3 every 28 days
Within 4 weeks
4 - 6 weeks
Resection
Resection
4 – 6 weeks
FP x 3/4 or no treatment
Follow-up
Trial accrual 1995-2003
*5-Fluorouracil 800 mg/m2 d1-5* Median FU 5.7 yrs
+ Cisplatin 100 mg/m2 day 1 BOIGE et al ASCO 2007

29. FNLCC 94012-FFCD 9703 Trial
PFS* Overall
Logrank p value = 0.021
Hazard Ratio = 0.69
___ S (95% CI 0.50-0.95)
RFS
OS
___ CT + S
2 year 5 year Median
survival survival survival  On multivariate analysis, treatment
effect unchanged after adjustment
Periop CT 58% 38% 29 mo for age, performance status, site of
primary and gender
Surgery 47% 24% 20 mo  Prognostic variables in Cox
multivariate analysis:
Benefit to CSC 10% 14% 9 mo  Preoperative CT
arm
 Gastric location
Median follow up: 5.7 years

30. Pre-­‐operaKve
CT:
the
EORTC
40954
trial
Surgery
144
paSents
N=
72
resectable
adenoca.
of
the
stomach
R
Surgery
N=
72
PLF
x
1
Restaging
cycle
If
NO
PD/tox/WHO
2
PLF
x
1
cycle
Surgery
144
paSents
randomized
/360
in
4
years
Study
prematurely
closed
because
of
poor
accrual

31. Pre-­‐operaKve
CT:
the
EORTC
40954
trial
Neoadjuvant
Surgery
p
Arm
arm
R0
resecSon
59
(81.9%)
48
(66.7%)
0.036
N0
node
27
(38.6%)
13
(19.1%)
0.018

32. Pre-­‐operaKve
CT:
the
EORTC
40954
trial
DFS
OS

33. ResecKon
Rates
MAGIC
FFCD
EORTC
(n=503)
(n=224)
(n
=
114)
S
Chemo+S
S
Chemo+S
S
Chemo+S
96%
92%
99%
96%
94%
96%

34. Survival
Hazard
RaKos
MAGIC
FFCD
EORTC
(n=503)
(n=224)
(n
=
114)
S
Chemo+S
S
Chemo+S
S
Chemo+S
0.75
0.69
0.84

35. Summary
pre-­‐
/perioperaKve
Chemotherapy
• All
trials
suggest
a
down
sizing
and
down
staging
of
gastric
cancers,
no
relevant
risk
of
progression
whilst
on
chemotherapy,
no
increased
complicaKons
perioperaKvely
and
improved
PFS
and
OS
• No
standard
chemotherapy
regimen
–
choose
best
advanced
chemotherapy
available

36. Strategies
that
increase
cure
rate
in
potenKally
operable
gastric
cancer
• Adjuvant
chemotherapy
• Adjuvant
Chemo-­‐Radiotherapy
• Peri-­‐operaKve
Chemotherapy
• Pre-­‐operaKve
Chemotherapy,
postoperaKve
chemoradiotherapy

37. Pre-­‐
/
peri-­‐operaKve
Chemotherapy,
postoperaKve
chemoradiotherapy
• RaKonale:
sKll
high
rates
of
local
failure,
may
be
improved
by
postoperaKve
RT,
now
combined
to
modern
preoperaKve
chemotherapy
(mostly
ECF
or
modificaKons
thereof)
• Trials
ongoing
• Not
standard,
may
be
appropriate
in
paKents
with
expected
poor
surgical
results
(e.g.
insufficient
LN
dissecKon,
high
number
/raKo
of
involved
/
resected
LN)

38. How
to
improve
benefit
of
systemic
treatment
• Improve
regimens
• Tailor
treatment

39. Role
of
PET
in
idenKfying
paKents
who
may
benefit
from
neo-­‐adjuvant
chemotherapy
PET
-­‐Responders
PET
-­‐Responders
PET
–NON
Responders
PET
–NON
Responders

41. How
to
improve
benefit
of
systemic
treatment
• Improve
regimens
• Tailor
treatment
• Establish
working
mulKdisciplinary
teams
that
meet
regularly
and
mandate
that
oncological
treatment
should
be
first
discussed
in
an
MDT

42. Summary
• Systemic
treatment
improves
outcome
of
operable
gastric
cancer
in
all
seqngs
• PreoperaKve
approaches
are
preferred
– Bemer
delivery
of
treatment
– Monitoring
of
response
– Downstaging
and
downsizing
of
tumor
• Ongoing
research
regarding
opKmal
regimen
and
tailoring
of
treatment
• MDT
essenKal
in
improving
management