Metronomic adjuvant chemotherapy (MACE) in locally advanced oral cavity squamous cell carcinoma post-surgery and adjuvant treatment (MACE postop): A phase III randomized controlled trial.

6002 Background: The role of maintenance systemic therapy following definitive surgery and adjuvant treatment in locally advanced oral cavity squamous cell carcinoma (OCSCC) remains undefined. This phase III trial evaluated whether oral metronomic adjuvant chemotherapy (MACE) improves survival compared with observation. Methods: This multicenter, open-label, phase III superiority trial conducted in India enrolled patients with stage II–IV OCSCC (AJCC 7th edition) who were clinico-radiologically disease-free 1–2 months after completion of definitive surgery with adjuvant treatment. Patients were randomly assigned (1:1) to observation (OBS) or oral MACE for up to 18 cycles. MACE comprised methotrexate 15 mg/m² once weekly (four doses per 28-day cycle) plus celecoxib 200 mg twice daily. Adherence to MACE was monitored at 3-monthly follow-up visits using patient-reported medication logs, supplemented by objective verification through review of returned empty drug containers. The primary endpoint was 2-year overall survival (OS). The planned sample size was 712; accrual was stopped early following emerging external evidence, with ethics committee approval. Results: Between February 2017 and April 2025, 410 patients were enrolled (OBS, n=208; MACE, n=202); approximately three-quarters had stage IV disease in both arms. The median number of MACE cycles delivered was 15; 92 patients discontinued treatment, most commonly because of noncompliance (n=55) or disease progression (n=27). At a median follow-up of 42.5 months, 129 deaths were observed (70 in OBS and 59 in MACE). Two-year OS was 70.2% (95% CI, 63.0–76.2) in the OBS arm and 79.2% (95% CI, 72.5–84.4) in the MACE arm (hazard ratio [HR], 0.76; p=0.13). Two-year progression-free survival was 68.0% (95% CI, 61.0–74.1) with OBS and 77.0% (95% CI, 70.2–82.4) with MACE (HR, 0.72; p=0.044). Distant recurrences occurred in 30 patients (14.4%) in the OBS arm and 17 patients (8.4%) in the MACE arm, while second primary malignancies were observed in 8 (3.8%) and 3 (1.5%) patients, respectively. Grade 3–4 toxicity with MACE was observed in 6.9%. Exploratory subgroup analyses suggested greater benefit in patients with extranodal extension and stage IV disease. The average cost of MACE per cycle, including toxicity management, was approximately USD 10. Conclusions: MACE following definitive local therapy did not significantly improve overall survival in locally advanced OCSCC. However, a statistically significant improvement in progression-free survival was observed, driven by a reduction in distant metastases and second primary malignancies. These findings suggest that selected high-risk subgroups—particularly patients with extranodal extension and advanced-stage disease—may derive benefit from this low-cost and well-tolerated strategy. Clinical trial information: CTRI/2017/02/007777.