Neoadjuvant treatment of locally advanced esophageal and junctional cancer: the evidence-base, current key questions and clinical trials

Recent trials, including CROSS, MAGIC, ACCORD, and OEO2, have established neoadjuvant therapy as standard of care for locally advanced (cT_2-3N_anyM₀) esophageal and junctional cancer compared with surgery alone. The CROSS trial in particular defines a new benchmark for outcomes from multimodal therapy, with a 5 year survival rate of 47% , a median survival of 47 months, a pathologic complete response rate (pCR) of 29% and an R0 resection rate of 92%. Several key questions remain, in particular whether CROSS-regimen chemoradiotherapy is superior to neoadjuvant chemotherapy alone for esophageal cancer, in particular adenocarcinoma. Second, with respect to neoadjuvant chemoradiation, whether an apparent complete clinical response can justify a “watch and wait” surveillance policy, with salvage surgery reserved for where relapse occurs. Third, whether with modern staging, predicted node negative cT2 tumors merit neoadjuvant therapy as standard. Finally, with the enormous interest in the application of targeted and immune-based therapies, and positive leads from other cancers, whether such approaches can improve outcomes in patients undergoing treatment with curative intent. We review herein a brief overview of the existing evidence-base and current active trials addressing these key questions.