{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T05:02:58Z","timestamp":1789448578584,"version":"build-2803163510"},"reference-count":19,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3389\/fonc.2026.1949844","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T04:27:10Z","timestamp":1789446430000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Gastric cancer and the TNT era: have we solved the timing question, or only redistributed the treatment?"],"prefix":"10.3389","volume":"16","author":[{"given":"Serdar","family":"Gumus","sequence":"first","affiliation":[{"name":"Department of Surgical Oncology, \u00c7ukurova University","place":["Adana, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim","family":"Cogal","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology, \u00c7ukurova University","place":["Adana, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ishak","family":"Ayd\u0131n","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology, \u00c7ukurova University","place":["Adana, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cem Kaan","family":"Parsak","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology, \u00c7ukurova University","place":["Adana, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1056\/NEJMoa055531","article-title":"Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer","volume":"355","author":"Cunningham","year":"2006","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)32557-1","article-title":"Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2\/3 trial","volume":"393","author":"Al-Batran","year":"2019","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.20.02914","article-title":"PRODIGY: A phase III study of neoadjuvant docetaxel, oxaliplatin, and S-1 plus surgery and adjuvant S-1 versus surgery and adjuvant S-1 for resectable advanced gastric cancer","volume":"39","author":"Kang","year":"2021","journal-title":"J Clin Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.02167","article-title":"Neoadjuvant docetaxel, oxaliplatin, and S-1 plus surgery and adjuvant S-1 for resectable advanced gastric cancer: updated overall survival outcomes from phase III PRODIGY","volume":"42","author":"Kang","year":"2024","journal-title":"J Clin Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(24)00676-4","article-title":"Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): final report of a randomised, open-label, phase 3 trial","volume":"26","author":"Zhang","year":"2025","journal-title":"Lancet Oncol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/s13045-024-01536-7","article-title":"Perioperative versus adjuvant S-1 plus oxaliplatin chemotherapy for stage II\/III resectable gastric cancer (RESONANCE): a randomized, open-label, phase 3 trial","volume":"17","author":"Wang","year":"2024","journal-title":"J Hematol Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa072252","article-title":"Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine","volume":"357","author":"Sakuramoto","year":"2007","journal-title":"N Engl J Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)61873-4","article-title":"Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial","volume":"379","author":"Bang","year":"2012","journal-title":"Lancet"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(26)00974-8","article-title":"Perioperative serplulimab with neoadjuvant chemotherapy versus perioperative chemotherapy in PD-L1-positive gastric cancer (ASTRUM-006): a randomised, double-blind, multicentre, phase 3 study","volume":"407","author":"Shen","year":"2026","journal-title":"Lancet"},{"key":"B10","doi-asserted-by":"publisher","first-page":"69","DOI":"10.5230\/jgc.2018.18.e9","article-title":"Survival benefit of perioperative chemotherapy in patients with locally advanced gastric cancer: a propensity score matched analysis","volume":"18","author":"Eom","year":"2018","journal-title":"J Gastric Cancer"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.7150\/jca.46847","article-title":"The effect of neoadjuvant therapies for patients with locally advanced gastric cancer: a propensity score matching study","volume":"12","author":"Wang","year":"2021","journal-title":"J Cancer"},{"key":"B12","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1186\/s40001-023-01400-3","article-title":"Perioperative chemotherapy versus adjuvant chemotherapy treatment for resectable locally advanced gastric cancer: a retrospective cohort study","volume":"28","author":"Su","year":"2023","journal-title":"Eur J Med Res"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1007\/s12664-025-01767-7","article-title":"Perioperative versus adjuvant chemotherapy in carcinoma stomach\u2014a retrospective propensity-matched analysis","author":"Elangovan","year":"2025","journal-title":"Indian J Gastroenterol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2026.44.2_suppl.283","article-title":"CRITICS-II: a multicenter randomized phase II trial of neo-adjuvant chemotherapy followed by surgery versus neo-adjuvant chemotherapy and subsequent chemoradiotherapy followed by surgery versus neo-adjuvant chemoradiotherapy followed by surgery in resectable gastric cancer","volume":"44","author":"Verheij","year":"2026","journal-title":"J Clin Oncol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.34133\/cancomm.0006","article-title":"Preoperative chemoradiotherapy versus chemotherapy for locally advanced gastric cancer or gastroesophageal junction adenocarcinoma: a phase III randomized controlled trial from China","volume":"46","author":"Liu","year":"2026","journal-title":"Cancer Commun (Lond)"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2024.08.042","article-title":"Phase 1 trial of total neoadjuvant therapy with short-course chemoradiotherapy followed by chemotherapy for patients with potentially resectable gastric cancer","volume":"121","author":"Badgwell","year":"2025","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.21037\/jgo-23-4","article-title":"Perioperative versus total neoadjuvant chemotherapy in gastric cancer","volume":"14","author":"Yang","year":"2023","journal-title":"J Gastrointest Oncol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/jso.27934","article-title":"The new era of total neoadjuvant FLOT therapy for locally advanced, resectable gastric cancer: a propensity-matched comparison with standard perioperative therapy","volume":"131","author":"Rencuzogullari","year":"2025","journal-title":"J Surg Oncol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2016.6762","article-title":"Mismatch repair deficiency, microsatellite instability, and survival: an exploratory analysis of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial","volume":"3","author":"Smyth","year":"2017","journal-title":"JAMA Oncol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1949844\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T04:27:11Z","timestamp":1789446431000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1949844\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,15]]},"references-count":19,"alternative-id":["10.3389\/fonc.2026.1949844"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1949844","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,15]]},"article-number":"1949844"}}