Neoadjuvant FLOT versus SOX chemotherapy in locally advanced gastric cancer: secondary outcomes of a single-centre, open-label, randomised, exploratory phase 2 trial

Abstract

Background Both FLOT (5-Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel) and SOX (S-1 plus Oxaliplatin) neoadjuvant regimens are widely used for locally advanced gastric cancer; however, direct head-to-head survival data to guide optimal treatment selection are lacking. This study aimed to compare long-term survival outcomes between neoadjuvant FLOT and SOX regimens in patients with locally advanced gastric cancer. Methods This study reports the prespecified secondary outcomes of the DRAGON III trial, an open-label, randomised, exploratory phase 2 trial conducted at a single hospital (Ruijin Hospital) in China. Eligible participants were adults aged 18–80 years with histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction, clinical stage cT3-4b, cN1-3, cM0 disease, adequate organ function, and ECOG performance status ≤2. Participants were randomly assigned 1:1 using computer-generated simple randomisation without stratification to receive either neoadjuvant FLOT or SOX before D2 gastrectomy. The FLOT regimen consisted of four cycles of 5-Fluorouracil 2600 mg/m 2 , Leucovorin 200 mg/m 2 , Oxaliplatin 85 mg/m 2 , and Docetaxel 50 mg/m 2 , intravenous every 2 weeks. The SOX regimen consisted of three cycles of oxaliplatin 130 mg/m 2 intravenous on day 1 and oral Tegafur/Gimeracil/Oteracil (S-1) 80 mg/m 2 twice daily on days 1–14, repeated every 3 weeks. Neither patients nor investigators were blinded due to different administration protocols. The secondary endpoints were overall survival (defined as time from randomisation to death from any cause) and disease-free survival (defined as time from randomisation to first occurrence of local recurrence, regional recurrence, distant metastases, or death from any cause) with 5-year follow-up. Survival differences were assessed using log-rank test and Cox proportional hazards regression. All analyses followed intention-to-treat principles including all 74 randomised patients regardless of treatment completion. The trial is registered with ClinicalTrials.gov, NCT03636893. Findings Between Aug 22, 2018, and Nov 14, 2019, 74 patients were randomised (40 FLOT, 34 SOX). In the FLOT group, 31/40 (77.5%) completed chemotherapy and surgery, with 9 patients not proceeding to surgery (1 withdrew consent, 4 refused surgery, 3 required early surgery due to bleeding, 1 serious adverse event). In the SOX group, 24/34 (70.6%) completed treatment, with 10 patients not proceeding to surgery (2 withdrew consent, 3 refused surgery, 1 died from treatment-related toxicity, 3 protocol violations, 1 adverse event). All survival analyses included the full intention-to-treat population of 74 patients. With median follow-up of 65.7 months, both regimens demonstrated comparable long-term survival outcomes. Median overall survival was 61.5 months (95% CI: not reached) for FLOT versus 67.8 months (95% CI: 25.7–109.9) for SOX, with no significant difference (HR 1.101, 95% CI: 0.595–2.036, p=0.76). Disease-free survival was similarly comparable (median 23.0 versus 25.5 months, HR 1.060, 95% CI: 0.597–1.884, p=0.84). Grade 3–4 haematological toxicity occurred in 9/40 (22.5%) FLOT patients versus 5/34 (14.7%) SOX patients. One treatment-related death occurred in the SOX group (2.9%) due to grade IV haematological toxicity followed by multiple organ failure. Interpretation The findings of our exploratory phase 2 study suggest equivalent long-term survival between FLOT and SOX regimens, with both achieving favourable 5-year survival outcomes. However, these results should be interpreted cautiously given several important limitations. As an exploratory study without formal power calculations for survival endpoints, conducted at a single centre with a relatively small sample size, these findings require validation in adequately powered phase 3 trials before definitive conclusions can be drawn. The single-centre design and exclusively Asian population may limit generalizability to other settings and ethnic groups. Additionally, the study was not designed to formally test equivalence between regimens. Within these limitations, the results suggest that treatment selection may reasonably prioritise patient factors, institutional experience, and practical considerations. Funding None.

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