Oesophagogastric junction adenocarcinoma (OGJ AC) represents an increasingly prevalent malignancy for which treatment recommendations remain challenging, as patients are frequently included within trials addressing gastric or oesophageal cancer. We conducted a systematic review and meta-analysis of randomized clinical trials (RCTs) published between 2000 and 2025 including patients with OGJ AC to provide a comprehensive assessment of contemporary treatment strategies for this disease across all stages. A total of 100 high-quality RCTs including more than 13,000 patients with OGJ tumours were identified. In localized disease, 36 studies evaluated surgical procedures, adjuvant/neoadjuvant/perioperative treatments and definitive approaches. Surgery is still the cornerstone of curative treatment, increasingly incorporating minimally invasive techniques. Perioperative chemotherapy and chemoimmunotherapy represent standard approaches, while neoadjuvant chemoradiotherapy followed by adjuvant nivolumab represents an alternative strategy. In advanced disease, 64 studies assessed systemic therapies in first/second/third lines or palliative interventions. Platinum-fluoropyrimidine chemotherapy persists as the backbone of first-line treatment, with treatment intensification guided by biomarkers. While the benefit of trastuzumab in HER2-positive tumours appears greater in OGJ than in gastric cancer, the opposite pattern is observed with zolbetuximab in CLDN18.2-positive tumours. Several trials testing anti-PD-1 therapies confirm their activity in OGJ AC, despite the predictive value of PD-L1 appearing uncertain in this anatomical subgroup. In later lines, paclitaxel plus ramucirumab, trastuzumab deruxtecan for HER2-positive disease, and trifluridine-tipiracil remain established options. The available evidence suggests clinically meaningful differences in treatment efficacy according to tumour location, supporting the consideration of OGJ AC as a distinct disease entity. Dedicated OGJ AC trials incorporating standardized anatomical classification are needed to improve outcomes in this aggressive disease.
