Neoadjuvant Chemoradiotherapy for Locally Advanced Gastric Cancer: Where Are We at?

Simple Summary More than 50% of gastric cancer are at least locally advanced at presentation. For such patients, a multimodal approach rather than mere surgical resection leads to better long-term prognosis. Neoadjuvant chemoradiotherapy is one of the common treatment strategies for local advanced gastric cancer. Based on the experience and evidence from esophago-gastric cancers, the incorporation of systemic and locoregional therapy has shown superior disease control and reduced local recurrence. However, the optimal chemotherapy regimen, patient selection, technical consideration and potential biomarkers are still under investigation. Furthermore, the comparison of neoadjuvant chemoradiotherapy with neoadjuvant/perioperative chemotherapy is also an important issue to be answered. In the review article, we addressed the current available evidence to provide a comprehensive understanding and the use of neoadjuvant chemoradiotherapy for locally advanced gastric cancer. Future studies and ongoing trials will be necessary to determine the best candidate and the role of newer systemic and radiation therapies in such patients. NCRT is a feasible treatment option for LAGC, with the ability to achieve favorable disease control and enable higher radical resection rates over those afforded by perioperative chemotherapy or surgery alone. Large clinical trials examining the comparative efficacy of NCRT and NCT are underway. The discrepancy between the satisfactory pCR rates associated with NCRT and the nonsignificant association between NCRT and survival warrants further exploration. Furthermore, newer therapies such as immunotherapy and adaptive radiotherapy may be implemented in con-junction with NCRT, and the development of useful biomarkers may ultimately lead to the de-velopment of personalized treatments for LAGC. These research directions may lead to the dis-covery of the optimal approach to administering NCRT to patients with LAGC. They may also aid in the determination of the optimal candidates for undergoing NCRT. Locally advanced gastric cancer (LAGC) has a poor prognosis with surgical resection alone, and neoadjuvant treatment has been recommended to improve surgical and oncological outcomes. Although neoadjuvant chemotherapy has been established to be effective for LAGC, the role of neoadjuvant chemoradiotherapy (NCRT) remains under investigation. Clinical experience and research evidence on esophagogastric junction adenocarcinoma (e.g., cardia gastric cancers) indicate that the likelihood of achieving sustainable local control is higher through NCRT than through resection alone. Furthermore, NCRT also has an acceptable treatment-related toxicity and adverse event profile. In particular, it increases the likelihood of achieving an R0 resection and a pathological complete response (pCR). Moreover, NCRT results in higher overall and recurrence-free survival rates than surgery alone; however, evidence on the survival benefits of NCRT versus neoadjuvant chemotherapy (NCT) remains conflicting. For noncardia gastric cancer, the efficacy of NCRT has mostly been reported in retrospective studies, and several large clinical trials are ongoing. Consequently, NCRT might play a more essential role in unresectable LAGC, for which NCT alone may not be adequate to attain disease control. The continual improvements in systemic treatments, radiotherapy techniques, and emerging biomarkers can also lead to improved personalized therapy for NCRT. To elucidate the contributions of NCRT to gastric cancer treatment in the future, the efficacy, potential toxicity, predictive biomarkers, and clinical considerations for implementing NCRT in different types of LAGC were reviewed.