Perioperative chemotherapy with either S-1 or 5-fluorouracil plus oxaliplatin and docetaxel for locally advanced gastric or gastroesophageal junction adenocarcinoma: A prospective trial and matched comparison.
Authors: Yen Chih Chieh , Chen I Shu , Chao Ying Jui , Bai Li-Yuan , Hsu Chia Yuan , Su Ping Jui , Liao Ting Kai , Huang Chien-Jui , Liu I Ting , Shan Yan Shen , Yen Chia Jui 
Published: January 2025

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Background:
Perioperative triplet chemotherapy improves the survival and surgical outcome of patients with locally advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma in addition to curative surgery. 5-fluorouracil (5-FU), docetaxel, oxaliplatin and leukovorin (FLOT) has been suggested as the treatment of choice. S-1, an oral fluoropyrimidine chemotherapeutic, also shows compelling efficacy as one of the triplet backbone and is exempt from a prolonged infusion time. However, a comparison over efficacy and tolerability between S-1 or 5-FU-containing triplet has not been investigated.
Methods:
The study contains two parts. The first part was a prospective single-arm multi-centered phase II trial with eight cycles of perioperative leucovorin, oxaliplatin, docetaxel and S-1 (LOTS) in patients with ≥T3 any N or ≥T2N(+) non-metastatic gastric/GEJ adenocarcinoma. The primary endpoint was the treatment response assessed by pathological tumor regression (TRG). After confirming the result passing the statistical threshold, we compared them with an identical and independent patient population who received perioperative FLOT under a prospective observation. A propensity score matching (PPSM) was used to balance the heterogeneity between the two groups. The efficacy, survival and tolerability were compared in a post-hoc manner.
Results:
From Feb 2017 to Jan 2024 with a comparable median follow-up time (LOTS, 18.7 ms; FLOT, 18.9 ms), a total of 45 and 154 patients were enrolled and received either LOTS or FLOT treatment. After a one-to-two PPSM procedure, the baseline characteristics of patients were comparable (LOTS, n=45; FLOT, n=90). Patients had similar curative resection rates (LOTS, 91%; FLOT, 86%; p=.359) and above nearly complete pathological regression rates (TRG 0-1: LOTS, 23%; FLOT, 27%; p=.669). The 24-ms recurrence-free (RFS) and overall survival (OS) rates were also comparable (LOTS vs. FLOT: 66 vs. 59% in RFS, p=.463; 73 vs. 68% in OS, p=.491). The toxicities were tolerable, except that more diarrhea and nausea events were reported in the LOTS group, whereas neutropenia, thrombocytopenia and mucositis were significantly prominent in the FLOT group.
Conclusions:
Perioperative LOTS shows reasonable therapeutic efficacy and survival as compared with FLOT in patients with locally advanced gastric/GEJ cancer. While the toxicity profile is distinctive from FLOT, it could be a potential alternative regimen with the convenience to save the prolonged infusion time.
Clinical trial information: NCT04999332
.

Pathological outcome.

Prior to LOTS treatment
(n=45)

After LOTS treatment
(n=43)

Prior to FLOT treatment
(n=90)

After FLOT treatment
(n=86)

p in LOTS vs. FLOT

CAP TRG, n (%)

0.669

0

-

-

1
(2.3)
-
-
3
(3.5)

1

-

-

9
(20.9)
-
-
20
(23.3)

2

-

-

14
(32.6)
-
-
23
(26.7)

3

-

-

19
(44.2)
-
-
40
(46.5)