Gastric cancer and the TNT era: have we solved the timing question, or only redistributed the treatment?

Perioperative chemotherapy has become standard of care for locally advanced resectable gastric cancer, supported by landmark trials including MAGIC, FLOT4, PRODIGY, RESOLVE, and RESONANCE. However, a methodological question remains insufficiently addressed: to what extent can the observed benefits of perioperative treatment be attributed to an independent effect of treatment timing rather than to the consequences of delivering systemic therapy before surgery? Western and East Asian research traditions have approached this question differently. Western trials primarily tested whether adding a neoadjuvant component improves outcomes, whereas East Asian trials established the value of adjuvant therapy after high-quality D2 surgery. Consequently, most landmark trials were not designed to isolate timing as an independent variable, and even same-regimen comparisons may be influenced by differences in treatment completion, cumulative exposure, and patient selection. Despite this uncertainty, the field has shifted toward total neoadjuvant therapy (TNT), redistributing more systemic treatment to the preoperative period. Depending on the protocol, TNT may represent treatment redistribution, intensification, or both. Although randomized trials have evaluated modified preoperative strategies, confirmatory phase III evidence specifically isolating treatment timing under comparable systemic treatment exposure remains lacking, leaving the independent oncological value of treatment sequence uncertain. Future trials should directly compare perioperative and postoperative delivery of the same systemic regimen under comparable planned cumulative treatment exposure while incorporating molecular stratification. Rather than assuming earlier systemic treatment is superior, studies should determine whether it provides an independent oncological advantage beyond improved treatment completion and patient selection, and whether this effect varies across biological subgroups.