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Harada et al. J Cancer Metastasis Treat 2018;4:18 I http://dx.doi.org/10.20517/2394-4722.2017.74 Page 3 of 10

group and 74.2% in XP alone group (P = 0.862), suggesting the addition of radiation to adjuvant XP did not
significantly reduce recurrence after D2 dissection . Additionally, the randomized phase III CRITICS-study
[8]
assessed perioperative chemo vs. postoperative chemoradiation after preoperative chemotherapy. Patients had
D1+ dissection with gastrectomy in this trial. In total 788 patients were randomized into chemotherapy group
(n = 393) and chemoradiation group (n = 395), and the 5-year survival is 41.3% for chemotherapy group and
40.9% for chemoradiation group (P = 0.99) . These results suggest that postoperative chemoradiation is not
[9]
useful if optimal or near-optimal surgery is performed.

Several chemotherapy regimens before and after chemoradiation were evaluated [10-12] . For instance, Korean
study evaluated 5-FU plus cisplatin (FP) before and after concurrent radiotherapy with capecitabine, and this
regimen was well tolerated . Epirubicin, cisplatin, and 5-FU (ECF) before and after concurrent radiotherapy
[10]
was assessed, and this regimen was feasible, but did not improve survival [11,12] .

Perioperative chemotherapy
Trials evaluating perioperative chemotherapy were held in Europe and its results have impacted NCCN
Guideline as category 1 evidence. MAGIC trial showed an advantage in OS but control and experimental
arms performed poorly . The NCCN guidelines have not downgraded ECF based on toxicity issues and
[13]
poor efficacy . FNCLCC/FFCD trial randomly assigned 224 patients into the 2 groups: 113 to surgery plus
[13]
perioperative chemotherapy (2 or 3 preoperative and 3 or 4 postoperative cycles of FP) and 111 to surgery
alone . Compared with the surgery alone group, the perioperative chemotherapy group had a favorable
[14]
overall survival (5-year rate, 38% vs. 24%; HR 0.69; 95% CI 0.50-0.95; P = 0.02) and significantly increased the
R0 resection rate (84% vs. 73%; P = 0.04), but 75% of patients in this trial had esophageal adenocarcinoma .
[14]
Recently, MRC-OEO5 trial compared two perioperative chemotherapy regimen, 2 cycles FP and 4 cycles
ECF/ECX (epirubicin, cisplatin and capecitabine) . This study showed no OS benefit for ECF/ECX compared
[15]
with FP (3-year rate, 42% vs. 39%; HR 0.92; 95% CI 0.79-1.08; P = 0.30), suggesting that addition of epirubicin
and longer duration does not provide any advantage. However, this trial predominantly included patients
with lower esophageal and junctional (types I and II) adenocarcinoma, not GAC.

The FLOT4 trial, which is multicenter, randomized, and phase 3 trial, compared perioperative chemotherapy
with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) and ECF/ECX [16,17] . Of 716 patients, 360
patients is assigned into ECF/ECX group and 356 patients assigned into FLOT group, and FLOT improved
median progression-free survival (PFS) (30 months vs. 18 months; HR 0.75; P = 0.001) and median OS (50
months vs. 35 months; HR 0.77; P = 0.012) compared with ECF/ECX. Fifty percent of patients in FLOT group
completed the planned postoperative treatments, while 37% of patients in ECF/ECX completed. Perioperative
complications were similar across the 2 groups [16,17] . However, the FLOT regimen resulted in considerable
toxicity and mortality. Some of the follow up is too early. FLOT could be recommended to only occasional
fit patient for perioperative chemotherapy and we don't recommend it for regular use.

Preoperative chemoradiation
Preoperative chemoradiation for GAC is not the standard of care in the USA but it is a developing strategy.
The strategy has several advantages. Firstly, radiation field is planned more accurately because primary is in
place. Postoperative radiation fields were redesigned in about 35% patients in the INT-0116 trial . Secondly,
[6,7]
preoperative chemoradiation increases R0 resection, resulting in low local relapses rate . Finally, preoperative
[5]
chemoradiation might reduce peritoneal dissemination during surgery, however this is debatable.

A multi-institutional trial, where patients received 2 cycles of FP followed by 45 Gy of radiation concurrent
with 5-FU, demonstrated that R0 resection rate was 70% and pathologic complete response (pCR) rate was
30% . Patients who achieved a good pathological response (< 10% residual carcinoma in the primary) had
[18]
a significantly longer OS than those who did not (63.9 months vs. 12.6 months; P = 0.03) . In another trial,
[18]