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preoperative strategies, considering patients’ tolerability for treatment. The subsequent ARTIST-II trial which
[49]
focused on adjuvant CRT for node-positive patients and CRIRTICS-II trial to evaluate the significance of
preoperative CRT strategies for curative gastric cancer are now in progress.

Perioperative chemotherapy
In general, prior to surgery, patients usually tolerate adjunct treatment rather well, perhaps due to an intact
performance status. Neoadjuvant chemotherapy has not been shown to increase postoperative morbidity
or mortality, while neoadjuvant chemoradiotherapy may be associated to increased morbidity, at least for
[50]
junctional tumors . On this basis, all guidelines recommend this type of down-staging treatment for pa-
tients with locally advanced gastric cancer and perioperative therapy has therefore been widely adopted as
the standard of care throughout Europe. The MAGIC trial was the first to provide the perioperative thera-
peutic option for resectable gastric cancer with favorable results of perioperative CT compared with surgery
[42]
alone . However, the epirubicin, cisplatin and fluorouracil (ECF) protocol used in the MAGIC trial has re-
quirements that limit its use in non-trial situations (e.g., the need for a central line and constant specialized
handling) and poor postoperative completion rates (42%). The REAL-2 trial showed that the ECF and epiru-
bicin, oxaliplatin, and capecitabine (EOX) regimens were equally effective for advanced tumors, whereas a
meta-analysis of the data from the REAL-2 and ML17032 trials suggested better response rates and OS with
capecitabine combinations [51-53] . EOX regimen is now widely accepted as adjunct treatment in the West.

The recent FLOT4-AIO trial offered a new option with favorable results for locally advanced gastric can-
[43]
cer . In this trial, 716 patients who had clinical stage T2 or higher and/or nodal positive disease were
randomly assigned to either three pre- and postoperative cycles of epirubicin, cisplatin and either infusion
of fluorouracil (5-FU) or capecitabine (ECF/ECX group) or four pre-and postoperative cycles of 5-FU/leu-
covorin, docetaxel and oxaliplatin (FLOT group). Thirty-five percent of patients in the FLOT group had at
least one serious adverse event involving a perioperative medical or surgical complication and 51% had grade
3-4 neutropenia, which was higher than 39% in ECF/ECX group. Overall 5-year survival was 45% in FLOT
group, significantly better than the 36% in ECX/ECF group with a hazard ratio (HR) of 0.77 (95% confidence
[54]
interval 0.63-0.94) . FLOT type perioperative chemotherapy can now be considered the Western gold stan-
dard regimen in the treatment of locally advanced, non-metastatic gastric cancer.

A number of new clinical trials are in progress to investigate new neoadjuvant and adjuvant regimens to
further improve outcomes. The reinforcement of preoperative treatment is one possible future direction.
The German POET trial, which aimed to clarify the impact of additional preoperative radiotherapy to neo-
adjuvant CT for patients with EGJ adenocarcinoma, demonstrated a non-statistically significant improved
[55]
median survival compared to the CT-alone group . However, it showed a substantially higher rate of path-
[56]
ological complete response , in the CRT group (15.6% vs. 2.0%). These results emphasized the importance
of strengthening the preoperative therapy, and thus neoadjuvant CRT has been suggested to be effective and
beneficial. The TOPGEAR trial is currently evaluating the impact of additional preoperative radiotherapy to
[57]
perioperative CT .
Another option for improving surgical outcomes is molecular targeted therapy, which has been demonstrated
in the palliative setting. Some molecular targeted agents, such as trastuzumab and lapatinib, are being in-
troduced into perioperative use. The INNOVATION trial, a 3-arm randomized phase II trial evaluating if
neoadjuvant dual HER-2 blockade with CT, may lead to higher pathologic complete response rates than
[58]
trastuzumab and CT, or CT alone, in resectable gastric cancer . The MAGIC-B trial is also investigating the
additional tyrosine kinase inhibitor lapatinib to perioperative ECX in the subset of the patients with HER2
[59]
overexpressing tumors . These new studies are expected to provide new, molecularly tailored treatment
options.