Perioperative chemotherapy with FLOT in the setting of curative treatment of gastric adenocarcinoma: impact in the survival and pathologic downstaging - systematic review

Gastric cancer remains a global health burden with poor prognosis despite advances. Adding systemic therapy to surgery has improved outcomes, and perioperative FLOT chemotherapy is the European standard of care following the FLOT4 trial, showing superiority over ECF/ECX. However, practices remain heterogeneous worldwide, and recent studies have assessed whether adding targeted therapies to FLOT further improves outcomes. This systematic review aimed to evaluate the efficacy of perioperative FLOT, alone or combined with immunotherapy or targeted agents, in resectable gastric adenocarcinoma. We systematically searched PubMed (MEDLINE), Scopus, and Web of Science. Randomised controlled trials, non-randomised trials, and cohort or observational studies published between 2019 and 2025 evaluating perioperative FLOT, alone or combined with immunotherapy or targeted agents, in resectable gastric adenocarcinoma were included. Data on tumour stage, margin-negative resection rate, pathological and radiological response, overall survival, and other time-to-event outcomes were extracted and synthesised narratively, as substantial heterogeneity precluded meta-analysis. Eighteen studies were included. Across studies comparing perioperative regimens, FLOT was associated with more favourable pathological and survival outcomes in most, though not all, comparisons; however, the evidence rests largely on non-randomised studies, and the magnitude of benefit varied with the comparator. In the adjuvant setting, FLOT improved survival compared with omitting adjuvant chemotherapy, though this appeared restricted to selected subgroups. Regarding the addition of immunotherapy or targeted agents, most studies reported improved pathological outcomes in the experimental arm; however, these have not yet translated into consistent survival benefits. This review reinforces perioperative FLOT as the current standard of care for resectable gastric adenocarcinoma and highlights the potential of adding immunotherapy or targeted agents. Interpretation is limited by between-study heterogeneity, predominance of non-randomised evidence, and immature survival data in the targeted-therapy studies, underscoring the need for longer-term follow-up and prospective comparative trials.