Triple Oral Metronomic Chemotherapy Versus Chemotherapy of Physician Discretion After Failure of Platinum-Based Therapy in Advanced Head and Neck Cancer: A Phase III Randomized Study (METRO-CHASE Study)

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Abstract
PURPOSE: Platinum-refractory advanced head and neck squamous cell carcinoma (HNSCC) has poor outcomes and limited treatment options, especially in resource-constrained settings. Triple oral metronomic chemotherapy (OMCT), involving low-dose continuous administration of chemotherapeutic agents, has shown promise in phase II studies but lacks evidence from randomized controlled trials. This study evaluated whether triple OMCT improves overall survival (OS) compared with chemotherapy of physician discretion (CPD). PATIENTS AND METHODS: In this phase III randomized open-label study, 214 patients with advanced HNSCC who had previous platinum-based chemotherapy were randomly assigned 1:1 to receive either triple OMCT (arm A) with erlotinib, celecoxib, and methotrexate, or CPD (arm B). The primary end point was OS, with secondary end points including progression-free survival (PFS), quality of life (QOL), and safety. Kaplan-Meier and log-rank tests were used for OS and PFS, and Cox-proportional hazard models estimated hazard ratios. QOL was evaluated using European Organisation for Research and Treatment of Cancer QLQ-C30 and FACT H&N. RESULTS: Median OS was 5 months in arm A and 3.1 months in arm B (hazard ratio [HR], 0.63 [95% CI, 0.47 to 0.83]; P = .00011). Median PFS was 4.8 months in arm A and 2.7 months in arm B (HR, 0.67 [95% CI, 0.52 to 0.87]; P < .0001). Previous treatment was a significant prognostic factor for OS, while age, tumor site, and previous treatment were significant for PFS. Triple OMCT improved global health status, physical functions, fatigue, and insomnia. It was well tolerated, with fewer grade 3 or higher adverse events than CPD (28.0% v 39.3%, P = .03). CONCLUSION: Triple OMCT is an effective and safe treatment for advanced HNSCC after platinum-based chemotherapy.

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