2024 Top Story in Oncology: The Role of Radiotherapy in Operable Gastro-Oesophageal and Gastric Cancer — Time for Change

Recent landmark trials, including the TOPGEAR study and ESOPEC trial, have re-evaluated the role of radiotherapy in the management of operable gastro-oesophageal and gastric adenocarcinomas.^1,2 These trials provide convincing evidence that the addition of radiotherapy to standard chemotherapy offers no survival advantage and raises questions about its continued use in this setting.

The international phase III TOPGEAR trial directly compared the use of perioperative chemotherapy alone with that of perioperative chemotherapy combined with preoperative chemoradiotherapy in patients with resectable gastric and gastro-oesophageal junction adenocarcinoma. Despite patients in the chemoradiotherapy arm achieving higher rates of pathological complete response (16.7% vs 8.0%) and improved tumour downstaging, these benefits failed to translate into improved overall survival (OS) or progression-free survival. The median OS was nearly identical between the groups: 49.4 months with chemotherapy alone versus 46.4 months with chemoradiotherapy.

Similarly, the ESOPEC trial examined perioperative chemotherapy using the FLOT regimen versus neoadjuvant chemoradiotherapy using the CROSS protocol³ in patients with oesophageal and gastro-oesophageal junction adenocarcinomas. In ESOPEC, FLOT perioperative chemotherapy resulted in better disease-free survival (DFS) and OS outcomes (median DFS, 38 vs 16 months; HR, 0.66; P = .001 and median OS, 66 vs 37 months; HR, 0.7; P = .012). In terms of local disease control (pathological complete response), the results of CROSS chemoradiotherapy in ESOPEC were inferior to those demonstrated in the original CROSS trial, which could be attributed to the enrollment of patients with more advanced tumours (cT4) or less adherence to neoadjuvant chemoradiotherapy protocols.

The implications of these findings are profound. Perioperative chemotherapy has become the standard of care for resectable gastric and gastro-oesophageal adenocarcinoma, supported by robust evidence from trials such as MAGIC and FLOT4.^4,5 Chemotherapy not only provides systemic control but also enables robust preoperative tumour reduction. In contrast, the addition of radiotherapy has consistently failed to improve survival outcomes despite more pronounced tumour downstaging.

Several factors may explain these results. First, systemic disease remains the primary driver of mortality in patients with these cancers, rendering local control benefits of radiotherapy insufficient to impact long-term survival. Secondly, advances in surgical techniques and systemic therapies have diminished the incremental benefits of radiotherapy in modern multimodal treatment paradigms.

From a clinical and resource perspective, these findings challenge the justification for the routine use of radiotherapy in operable gastric and gastro-oesophageal adenocarcinoma in the preoperative setting. However, despite the success of perioperative FLOT over chemoradiation, long-term survival in this disease is still 50%, which suggests that future trials should focus on more effective novel systemic therapies and enhancing surgical outcomes.

From a chemoradiotherapy perspective, this may have a role in bulky locally advanced disease — where, in combination with effective systemic therapy, it may enable optimal downstaging prior to surgery; however, its role in this specific subgroup has not been formally investigated. As the most likely reason for the failure of a radiation-based strategy is because of the systemic nature of the disease, research should focus on refining patient selection criteria, identifying radiology or pathology biomarkers that may identify truly localised disease, and identifying biomarkers of radiosensitivity, which may predict the subgroup that derives meaningful benefit from radiotherapy, including organ preservation. For now, however, the evidence is clear: radiotherapy has a very limited role in the routine treatment of operable gastric and gastro-oesophageal cancers when modern perioperative chemotherapy regimens are used.