1) Preoperative chemotherapy or chemoradiotherapy can downstage tumors and increase resection rates for stomach cancer compared to surgery alone. 2) The MAGIC trial showed perioperative chemotherapy improved survival rates over surgery alone by reducing tumor size and stage. 3) The TOPGEAR trial is currently testing adding preoperative chemoradiotherapy to perioperative chemotherapy to further improve outcomes. Interim results found it to be safe and feasible.

1. Preoperative chemo and chemo-
radiotherapy in stomach ca
Susheel Yeshala

2. Introduction
• Many patients have locally advanced tumors at diagnosis.
• After gastric resection, many patients have a prolonged recovery, delaying initiation of
adjuvant therapy.
• Perioperative (pre- and postoperative) or neo-adjuvant chemotherapy is an attractive
option in gastric cancer.
• Goals of perioperative treatment:
1.To down stage tumour size
2.To increase R0 resection,
3. Higher pCR rates
4. Reduce local relapses
5. Better tolerated
• Phase 2 trials involving either purely preoperative or perioperative treatment
demonstrated that there was no increase in anticipated surgical morbidity or mortality
when compared to controls.
1.Kelsen D, Karpeh M, Schwartz G, et al. Neoadjuvant therapy of high-risk gastric cancer: a phase II trial of preoperative FAMT X and postoperative
intraperitoneal fluorouracil-cisplatin plus intravenous fluorouracil. J Clin Oncol 1996;14:1818–1828.
2.Brenner B, Shah MA, Karpeh MS, et al. A phase II trial of neoadjuvant cisplatin-fluorouracil followed by postoperative intraperitoneal floxuridine-
leucovorin in patients with locally advanced gastric cancer. Ann Oncol 2006;17:1404–1411.

3. 2cycles of CT given on days 1–5 and 29–34 Radical gastrectomy (D2)
Cisplatin @20 mg/m2 /day IV
CI 5-FU@1000 mg/m2
Patients having R0 resections were to receive three cycles of i.p. FUdR (1000 mg/m2 ) and LV (240
mg/m2 ), given on days 1–3, 15–17 and 29–31.
Intraperitoneal chemotherapy was begun 5–10 days from surgery.
Conclusions:
1.Neoadjuvant cisplatin/5-FU followed by postoperative i.p. FUdR/LV can be safely
delivered to patients undergoing radical gastrectomy and D2 lymphadenectomy.
2.The R0 resection and the survival rates are encouraging.
3.An association between pathologic response and patient outcome was suggested.
Results: N=38
T stage downstaging in 23%
R0 resection rate 84%
Median survival 30.3 months 39.5%
Good pathologic response 15%
Associated with better survival P = 0.053

4. • After phase 2 studies demonstrated safety and suggested efficacy, several
perioperative chemotherapy phase 3 trials were conducted
• Dutch trial
• English investigators led by Cunningham et al - MAGIC trial
• French Trial
• The regimen of ECF developed late 1980s achieves response rates
between 49 – 56% in randomized trials of the treatment of locally
advanced gastric cancer.
• As compared with a regimen of fluorouracil, doxorubicin, and
methotrexate (FAMTX), the ECF regimen improves survival and response
rates among patients with advanced GEJ cancer and the side-effect profile
is acceptable.

5. Operable
gastric cancer
N= 59
NACT (n=29)
4x FAMTX
Sx (D1)
Sx alone (n=30)
(D1)
Aim:
To investigate whether pre-operative
chemotherapy leads to a 15% higher
curative resectability rate compared with
surgery only.
Chemo:
5-FU 1500mg/m2 IV D1
Adriamycin 30 mg/m2 IV D15.
MTX 1500/m2 IV D1
Leucovorin 30mg q6 h (i.v. or oral) D2-3
September 1993 to February 1996

6. Result:
1.Curative resection rate in favour of Sx
arm (62% vs 56%).
2.Downstaging for stages I + II did not
occur
3. PD was more often the reason for not
completing the planned four courses
than toxicity.
Conclusion:
More active regimens than
FAMTX are required for future
randomised trials.
Consequence:
DGCG has decided to participate
in the MRC trial using ECF.

7. Eligibility
Adenocarcinoma of stomach or
lower one third esophagus(from
1999), suitable for curative
resection
CT schedule:
Epirubicin (50 mg/m2) IV D1
Cisplatin (60 mg/m2) IV D1
Fluorouracil (200 mg/m2) CI D1-21
Q3W

8. P=0.002
P=0.01

9. SIMILAR
• Adverse effects
• Rates of postoperative complications (46 vs
45%)
• Numbers of deaths within 30 days post Sx
• surgery.
 The resected tumors were significantly
smaller and less advanced in the Peri-op
group.
 Perioperative-chemotherapy group had a
higher likelihood of overall survival
 Five-year survival rate, 36% (Peri-op)vs. 23
(Sx)
 Progression-free survival
Conclusions
In patients with operable gastric or lower
esophageal adenocarcinomas, a perioperative
regimen of ECF decreased tumor size and stage and
significantly improved progression-free and overall
survival.
N Engl J Med 2006;355:11-20.

10. N=224
Adenocarcinoma of the lower
esophagus, gastroesophageal
junction (GEJ), or stomach
End point
overall survival (OS)
Chemotherapy:
-2-3 pre-op cycles of
-Cisplatin (100 mg/m2 ) IV D1
-Fluorouracil (800 mg/m2 /d)
CI days 1 to 5
every 28 days
-3-4 postoperative cycles of
the same regimen.
Ychou M, Boige V, Pignon JP, Conroy T, Bouche O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Geneve J, Lasser P, Rougier P. Perioperative
chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin
Oncol. 2011;29:1715–1721.

12. Conclusion
In patients with resectable adenocarcinoma of the lower esophagus, GEJ, or stomach,
perioperative chemotherapy using fluorouracil plus cisplatin significantly increased the
curative resection rate, disease-free survival, and OS.
Results Sx only CT+Sx
OS (5yr) 24% 38%
DFS(5yr) 21% 34%
R0 73% 84%

13. • The first prospective randomized trial conducted by the Dutch Gastric
Cancer Group failed to demonstrate a survival benefit from the NAC.
• The results of the MAGIC and ACCORD 07 trials have shown that systemic
chemotherapy regimens that are only modestly effective in patients with
advanced disease.
• Given that the role of neo-adjuvant chemotherapy in gastric cancer
remains controversial, a systematic review and meta- analysis of six RCTs
(aggregate n = 781) was conducted to gain insights about the potential
benefit of neo-adjuvant chemotherapy followed by surgery as compared
to surgery alone

14. Searched electronic databases of PUBMED, EMBASE, CBM-disc and
CNKI for studies published from 1975.
AIM- To determine if there is a benefit of preoperative chemotherapy
compared with surgery alone from available RCTs for patients with
gastric cancer.
Outcome:
OS, PFS, R0resection
Downstaging effect
Postoperative complications
Perioperative mortality

15. OS P = 0.36No difference
No difference
R0 P= 0.36

16. Medical Research Council Oesophageal Cancer Working Party: Surgical resection with or without preoperative chemotherapy in oesophageal
cancer: A ranomised controlle trial. Lancet 359: 1727-1733, 2002
• This study evaluated the effect of a combination of pre- and postoperative
chemotherapy compared with surgery alone in patients with adenocarcinoma of the
stomach or lower esophagus.
• Downsizing effect of preoperative chemotherapy was observed supporting the value
of NACT treatment.
• But the study did not show the relative contribution of the pre- versus
postoperative component to survival benefit.
• Preoperative therapy adds most to the impressive survival advantage of almost 15%.
• Role of postoperative therapy remains unclear as it is true for adjuvant
chemotherapy alone which did not prove to benefit patients in Western trials. [1]
• The high rates of local or regional recurrence in Gastric, GEJ, Esophagus cancer have
prompted groups to investigate additional radiation therapy in adenocarcinomas of
the upper GI tract.

17. Esophageal cancer
including Cardia
(n=113)
Surgery alone
(55)
Neo-adjuvant
chemoradiotherapy
(58)
Surgery
2 CT on Week 1 and 6 and RT Concurrently With 1st cycle
CT Schedule - Flurouracil (15mg/Kg D1-5)
Cisplatin (75mg/m2 on D7)
RT – 40Gy/15# concurrently with 1st cycle of CT

18. Conclusions
Multimodal treatment is superior to surgery alone for
patients with resectable adenocarcinoma of the
esophagus and cardia. (N Engl J Med 1996;335: 462-7.)

19. AIM:
To evaluate the effect of
preoperative radiotherapy
for cancer of the gastric
cardia.
N= 370 patients
Gastric cardia
Prospective
Randomized trial
Cancer Hospital, CAMS.
Gastric cardia
(n=370)
Surgery alone
(199)
NART
(171)
Surgery
2-4 Wk

20. Method:
RT- 40Gy/20#/4 wk
8MV LA/ Telecobalt
The A-P opposing parallel portals
Upper border-4-5 cm above the
upper margin of the tumor
10 LN groups

21. Downstaging

22. ARM 5 yr OS 10yr OS P value
Sx only 24.76% 16.60% p = 0.15
NART+Sx 33.30% 22.47%
ARM 5 yr OS 10yr OS P value
Sx only 19.75% 13.30%
p = 0.0094
NART+Sx 30.10% 20.26%

23. It was confirmed that preoperative irradiation of 40 Gy was
beneficial to patients with AGC
Conclusions:
1. The remote 5-, 7-, and 10-year survival rates were improved.
2. The resectability and radical resection rate were raised so that it led to a
much better remote survival
3. The downstaging of tumor had taken place after radiation. So, it brings
about favorable conditions for radical resections.
4. The incidence of local-regional lymph nodes was cut down, but distant
metastasis and positive stump remained similar.
5. The postoperative complications and mortality were not increased.

24. • Nearly 33% of postoperative radiation fields had to be redesigned in the
intergroup trial
• Surgeons are often not defining the potential radiation fields.
• These difficulties with postoperative approach make preoperative
chemoradiotherapy approach relatively easy.
• It forces a multimodality interaction before treatment, and the precise
location and extent of carcinoma are much better understood in the
preoperative setting than in the postoperative setting.
• Preoperative chemoradiotherapy could potentially address the two important
issues of poor R0 rates and the high rates of locoregional relapse.
• It is also conceivable that the rate of pathologic complete response (pathCR)

25. Purpose:
To define the pathCR rate
(20%) and toxicity of NACRT in a
limited multi-institutional setting
2 induction CT Q4w
CI 5Fu@200mg/m2/d D1-21 IV
Cisplatin@20mg/m2/d D1-5 IV
Leucovorin@20mg/m2 D1,8,15
Bolus
Radiotherapy:
45Gy/25#/5w@ 1.8Gy/# with CCT
CI 5Fu@300mg/m2/d D1-5 for 5wk
Subtotal/ Total gastrectomy
D2 nodal dissection
4 weeks

26. No correlation

28. Conclusion:
• 1st multi-institutional trial showing pathCR plus pathPR rate is possible in
NACRT setting.
• PathCR and pathPR do translate into significant survival advantage.

29. AIM:
To investigate whether Preop CRT adds to
prognosis compared to CT alone in Patients with
locally advanced adenocarcinomas of the EGJ.
GEJ tumours
(119)
NACT
(59)
Sx
NACT
(60)
CRT
Sx
3-4 wk
3-4 wk
CT: 6 weekly
CI 5Fu@2g/m2, 24hr infusion, weekly
Leucovorin@500mg/m2, weekly
Cisplatin@50mg/m2, Biweekly 2 wk
CRT:
30Gy/15#@2Gy/# with CCT
Cisplatin@50mg/m2 D1, D8 IV
Etoposide@80mg/m2 D3-5 IV

30. low total radiation dose applied, it is likely that other factors than radiation
therapy contributed to postoperative mortality which appears increased
compared with what should be observed after primary surgery.
Down staging

32. Conclusion:
• Did not meet its accrual goals
• Could not provide statistical significance,
• Improvement in both local tumor free and overall survival
• Preoperative chemoradiotherapy appears most valuable to cure patients
with localized esophagogastric adenocarcinoma.
• Evident- major response to preoperative treatment is an important
prognostic factor
• Aim to optimize preoperative treatment by combining all treatment
modalities including chemotherapy, targeted therapy, and also radiation
therapy.

33. AIM:
Adding preoperative
chemoradiation to perioperative
ECF will improve OS
TOPGEAR - Trial Of Preoperative therapy for
Gastric and Esophagogastric junction
AdenocaRcinoma
Currently Active
Target accrual – 752
Currently Accrued – 120
Interim analysis – March 2017

34. Interim analysis was done to assess safety/toxicity, feasibility, and preliminary
efficacy of preoperative chemoradiation

35. 93% 98%
65% 53%
92%
90% 85%
Feasibility

36. Toxicity
NO Difference

37. Sx complications
NO Difference

38. Trial CRT Completed CRT not completed
INT0116 (Adj CRT) 83% 17%
TOPGEAR (NACRT) 98% 2%
CRT compliance with respect to planned dose of RT
Compliance with Peri-op ECF
TOPGEAR = MAGIC
These figures highlight the benefits of delivering treatment preoperatively
when patients are better able to tolerate the toxicities of therapy.
Conclusion:
Interim results show that preoperative chemoradiation is safe and feasible and does
not adversely affect surgical morbidity.

39. COCLUSION:
• By analysing failure patterns in the INT0116 and MAGIC trials, each approach
appears to improve survival through different mechanisms.
• The perioperative ECF approach reduces systemic failure, while postoperative
chemoradiation improves locoregional control. Since both strategies provide
moderate gains in survival,
• Hence by adding chemoradiation to standard perioperative ECF chemotherapy
may achieve even greater survival.
• There are advantages to testing the addition of chemoradiation by
administering it in the preoperative rather than postoperative setting like
1.Tumor downstaging
2.Increase in the complete R0 resection rate
3.Better patient tolerability.
• The strategy of preoperative chemoradiation for gastric cancer thus can be
considered standard of care for resectable gastric cancers.

40. Thank you