FOLFOX in Esophageal Squamous Cell Carcinoma: Current Evidence and Future Role as a Cisplatin-Sparing Chemoimmunotherapy Backbone.

Fluorouracil plus cisplatin has historically served as the dominant platinum-fluoropyrimidine backbone for esophageal squamous cell carcinoma (ESCC). In the immunotherapy era, the key practical question is not whether oxaliplatin can universally replace cisplatin, but whether FOLFOX can provide a rational, patient-centered cisplatin-sparing backbone for selected patients receiving first-line chemoimmunotherapy. CheckMate 648 established nivolumab plus chemotherapy using fluorouracil plus cisplatin, whereas RATIONALE-306 demonstrated that oxaliplatin-containing backbones can be incorporated into successful global phase III immunochemotherapy. Recent Japanese retrospective data in cisplatin-unfit patients showed clinically meaningful activity of nivolumab plus FOLFOX, with reduced renal and hydration burden, outpatient feasibility, and treatment continuity representing potential practical advantages. Oxaliplatin-induced immunogenic cell death provides an additional mechanistic rationale, although this remains predominantly preclinical. Prospective evaluation is underway in Japan through the FLONTALE and OXA-REPLACE phase II trials. This review summarizes the clinical and biological rationale, current evidence, limitations, and future positioning of nivolumab plus FOLFOX. At present, it should be regarded as an emerging selective strategy rather than an established alternative to cisplatin-based chemoimmunotherapy.