MANAGEMENT OF LOCALLY

ADVANCED GASTRIC CANCER

• Fourth leading site of cancer in the world
• Second most common cause of death due to
malignancy accounting for 736,000 deaths, 9.7% of the
total.
• Gastric cancer, today, is more common in Asia than in
US or Europe.
• 42% of cases occur in China alone.
• In India, the incidence rate of gastric cancer is very low
compared to western countries.
• The number of new gastric cancers is about 34,000.
ADVANCED GASTRIC CANCER

LOCALLY ADVANCED METASTATIC

Survival: 11 months Survival: 3 months

Resectability Palliation
Survival similar to patients Quality of life; survival
operable at diagnosis
• Two-thirds of patients present with locally
advanced or metastatic disease in the United
States.
• Of those who undergo curative resection 60%
relapse both locally and with distant
metastasis.
LOCALLY ADVANCED GASTRIC CANCER

• T3/T4 LESION
• NODE POSITIVE
 TREATMENT OPTIONS
• SURGERY

• CHEMOTHERAPY

• RADIATION
 RATIONALE FOR PREOPERATIVE
CHEMOTHERAPY
• Poor long-term results of conventional treatment.
• Better effectiveness due to intact tumour
vascularisation.
• Improved tolerance
• Downstaging of the primary tumor / better
resectability.
• Eradication of micrometastatic disease
• Prognostic information
“INDUCTION” PREOPERATIVE CHEMOTHERAPY

R0 Median
Author Year Regimen Patients Stage resection survival
(%) (months)
Wilke 1989 EAP 34 NR 29 18

Rougier 1994 5-FU, P 30 NR 60 16

FAMTX, IP
Kelsen 1996 56 NR 61 15
FU-P
58 (R pts)
Melcher 1996 ECF 27 R-NR 10
10 (NR pts)
Gallardo 2000 P-ELF 60 NR 8.7 10

Barone 2004 EEP 26 NR 26/20 pts 40

Resected patients benefited from an R0 resection in 8.7%

to 61.0% of cases
 NEOADJUVANT CHEMOTHERAPY
MAGIC Trial
Cunningham NEJM 2006

• Evaluated the efficacy of preoperative and

postoperative ECF vs. surgery alone
• 503 patients, stage II or greater
• Adenocarcinoma stomach/ge junction/distal
esophagus
• ECF was chosen secondary to high RR in two prior
randomized trials for locally advanced and metastatic
gastric cancer (Webb JCO 1997; Ross JCO 2002)
MAGIC TRIAL -PROTOCOL
 SURVIVAL RESULTS
ECF Surgery Benefit to
ECF
2 yr survival 50% 41% 9%

5 yr survival 36% 23% 13%

Median 24 mo. 20 mo. 4 months

Survival
Results unchanged on multivariate analysis adjusted for age, PS, site of
Disease and gender.
 FNLCC ACCORD 07-FFCD 9703
Trial Post-
operative2
FP x3/4
Surgical within 6-
Pre-operative resection in 12/52
Resectable FP1 x2/3 4-6/52
adenocarcinoma of the
stomach, OGJ, lower Randomised
No post-
oesophagus n=224 operative
Surgical treatment
resection
within 4/52 2. Post op CT criteria:
•Curative surgery
•pT3 +/or pN+ tumour
1. FP (q28d)
•Tumour response/stable
5FU 800 mg/m² CI x 5 days
•No G3-4 toxicity
CDDP 100 mg/m² d1

Boige et al ASCO 2007

CONCLUSIONS:
Neoadjuvant chemotherapy can effectively
• downstage the tumour
•Increase chances of R0 resection
 SURGERY
• Surgery should be performed 4-6 weeks after completion
of neoadjuvant chemotherapy

• Achieve complete removal of the tumour with histologically

confirmed tumour free (R0) surgical margins.

• Preferably 5cm of grossly normal stomach on either side

should be resected.

• May not be possible in the case of the distal and proximal

margins, where a negative margin of at least 1 cm
confirmed on intraoperative frozen section is deemed
acceptable
• Gastrectomy with D2 lymphadenectomy is the
current standard of care for non-metastatic,
resectable T3/T4 gastric cancer.
• Minimum no of nodes to be removed: 15
• No role of extended (D3/D4)
lymphadenectomy.
• Addition of distal pancreactectomy with
splenectomy adds to morbidity of resection .
• Those not suited for R-0 resection undergo
2nd- line chemotherapy or CRT
• Select few undergo palliative surgery
• Patients with major bleeding and deep ulcers
may be considered for up front surgery
 RADIATION THERAPY

• May improve locoregional recurrence rates in

patients with serosal penetration (T3/T4),
nodal involvement, or positive surgical
margins.
• Emerging role in pre-operative setting as a
part of preoperative CRT.
• In radical setting as a definitive treatment
with chemotherapy for unresectable, non-
metastatic cancer.

• Resectable disease in a patient not suitable for

surgery because of medical conditions .
 ADJUVANT CHEMOTHERAPY
• More than 30 trials comparing adjuvant chemotherapy
to surgery alone.

• Varied results.

• Meta-analysis suggesting possible benefit, but no

single trial showing conclusive evidence of a benefit
Earle, Eur J Cancer 1999; 35: 1059
Mari, Ann Oncol 2000; 11: 837
Hermans, JCO 1994; 12: 879

• CAPOX for 8 cycles post R0 resection may also be

recommended based on the CLASSIC trial. (Level 2A)
ADJUVANT CHEMORADIATION
MacDonald, NEJM 2001

556 resected adenocarcinoma

Stomach/GE junction

Surgery alone Adjuvant radiation and 5FU/LV

N=275 N=281
 INTERGROUP INT-0116
Study design
R
5FU/LV 5FU/LV
A
Eligibility: N
Resected 5FU/LV RADIATION 5FU/LV x 2
D
Stage IB- IV M0 4,500 cGy
O
Gastric or M
gastroesophageal
adenocarcinoma I

S
OBSERVATION
E

Macdonald JS et al, ASCO GI Cancers Symposium 2004,

 RESULTS -Median F/U 5 Years
MacDonald NEJM 2001; 345: 725

• Median OS:
Surgery alone - 27 months
Chemoradiation - 36 months (p<0.005)

• DFS:
Surgery alone – 19 months
Chemoradiation – 30 months (p<0.001)

• Pivotal trial establishing chemoradiation as standard

of care in United States
 CALGB 80101
Built on INT-0116 trial
R
Patients with curative gastric resection,
A ECF x 3 or 5FU/LV x 3 preoperatively
N
5FU/LV 5FU/LV X 2
D 5FU LVCI + RT
(Mayo) Mayo
O

I ECF 5FU LVCI + RT ECF X 2

S

E
 CALGB 80101 -Conclusion
• Following curative resection of gastric or GEJ
adenocarcinoma, post-operative
chemoradiotherapy using ECF & 5-FU/RT does
not improve survival when compared to 5-
FU/LV & 5-FU/RT
 SECOND LINE CHEMOTHERAPEUTIC
AGENTS
• 5-Fu – anthracycline based combinations
• Etoposide based combinations
• Platinum based combinations
• Taxane based combinations
• Irinotecan based combinations
• TAX 325: TCF vs CF
• IFL vs CF
• REAL-2
 REAL2 Trial in Advanced Gastric
Cancer

Primary endpoint = OS
ECF EOF
E: Epirubicin 50 mg/m2 + O: Oxaliplatin
C: Cisplatin 60 mg/m2 + 130 mg/ m2/3 wks
F: 5-FUc 200 mg/m2/day 5-FU
Noninferiority
vs
X
ECX EOX
X: Capecitabine
1250 mg/m2/day
N = 1002

Cisplatin vs Oxaliplatin

Cunningham D, et al. N Engl J Med. 2008;358:36-46.

• Trend toward superior RR with EOX
• Secondary analysis with no greater toxicity
with increased dose of Capecitabine
compared to standard 5 FU
• Substitutions do not appear to impair efficacy
 TARGETED THERAPY
• 10% to 25% tumors overexpress HER2
• HER2 overexpression associated with poor
prognosis
– Poor survival
– Serosal invasion
– Lymph node metastases
– Advanced disease stage
– Distant metastases
Yano T, et al. Oncol Rep. 2006;15:65-71.. Jorgensen JT, et al. J Cancer. 2012;3:137-144.
 Phase III ToGA Study of Trastuzumab +
Chemo in Advanced HER2+ Gastric
Cancer
5-FU

5-FU or Capecitabine* +
Patients with Cisplatin 80 mg/m2 q3w x 6 +
Patients with Trastuzumab 6 mg/kg q3w until PD
HER2+
advanced (8-mg/kg loading dose)
advanced
gastric cancer R (n = 294)
gastric cancer
screened for
(n = 810; 22%
HER2 status
of successful (n = 584) 5-FU or Capecitabine* +
(N = 3803)
screenings) Cisplatin 80 mg/m2 q3w x 6
(n = 290)

*Selected at investigator’s discretion: 5-FU 800 mg/m2/day infusion on Days 1-5 q3w x 6;
casignificantly improved overall survival (13.8 vs 11.1 months)
itabine
Bang YJ, et al.1000 mg/m
Lancet.
2 BID on Days 1-14 q3w x 6.
2010;376:687-697.
 OTHER TARGETS

• EGFR : Gefitinib
Erlotinib
Cetuximab

• VEGFR: Bevacizumab ( AVAGAST, MAGIC B)

• 26S-proteosome: Bortezomib
 SUMMARY
• Perioperative chemotherapy followed by
Surgery is the current standard of care for
LAGC.
• Patients treated with upfront gastrectomy
should receive post op CRT
• Traztuzumab can be considered as an option
for HER2 + patients with LAGC in combination
with systemic chemotherapy.
THANK YOU