An Update of Management Strategies in Locally Advanced Oral Cancer

INTRODUCTION: Locally advanced oral squamous cell carcinoma (OSCC) remains surgically anchored, but systemic treatment is evolving rapidly, particularly with perioperative immunotherapy. METHODS: We reviewed clinical evidence on neoadjuvant, adjuvant, maintenance, and altered-dose systemic strategies for resectable locally advanced OSCC and relevant head and neck squamous cell carcinoma. RESULTS: Conventional neoadjuvant chemotherapy has not improved survival in unselected resectable OSCC and should be reserved for selected indications including borderline resectability, mandibular preservation, and conversion to surgery. Neoadjuvant immunotherapy studies using PD-1 blockade, dual checkpoint inhibition, chemoimmunotherapy, targeted-immunotherapy combinations, and SBRT-immunotherapy have demonstrated feasible delivery and meaningful pathological responses. KEYNOTE-689 established improved event-free survival with perioperative pembrolizumab. Postoperatively, cisplatin-radiotherapy remains standard for positive margins and extranodal extension, while NIVOPOST-OP supports nivolumab intensification in high-risk disease. Maintenance therapy remains uncertain, with negative MACE results but a possible benefit from tegafur-uracil in selected patients. CONCLUSION: Perioperative immunotherapy is reshaping resectable OSCC treatment. Postoperative intensification, maintenance therapy, and lower-dose strategies, including low-dose nivolumab with metronomic therapy, require prospective validation. These approaches may be especially important in resource-constrained settings, where treatment cost and access remain major barriers.