A Comparative Assessment of the Efficacy and Toxicity Profiles of Dual and Triple Oral Metronomic Chemotherapy in Advanced Head and Neck Cancers in a Tertiary Care Center.

Background The standard of care for unresectable or metastatic advanced head and neck squamous cell carcinoma (HNCSCC) is either immunotherapy, cetuximab-based monotherapy, or combination therapy. However, this is often unavailable to most patients due to financial constraints. Existing studies have already demonstrated that oral metronomic therapy (OMT) outperforms other standard chemotherapy options. In this study, we aim to compare the efficacy of dual versus triple OMT in improving overall survival (OS) and progression-free survival (PFS) and assess the factors that affect these outcomes. Methodology This retrospective analysis, conducted after receiving approval from the All India Institute of Medical Sciences Institutional Ethics Committee, included patients diagnosed with HNCSCC who received either dual or triple metronomic chemotherapy between 2019 and 2024. The patients received methotrexate 40 mg/m² PO weekly, celecoxib 200 mg twice daily, with or without erlotinib 150 mg daily. Palliative radiotherapy was administered at the physician's discretion (30 Gy/10 fractions). The primary endpoints were OS and PFS. Secondary endpoints included the assessment of safety and other factors affecting survival. OS and PFS were analyzed using Kaplan-Meier and log-rank tests, with hazard ratios (HRs) estimated by Cox proportional hazard models. Results The study included 97 patients, with 45 receiving dual OMT and 52 receiving triple OMT. With a median follow-up of 10.5 months, the median OS was five months in the dual OMT group and seven months in the triple OMT group (HR = 0.56; 95% confidence interval (CI) = 0.33-0.93; p = 0.025). Median PFS was two months in the dual OMT group and 5.6 months in the triple OMT group (HR = 0.29; 95% CI = 0.18-0.47; p < 0.000001). In addition to the regimen (dual vs. triple OMT), age, sex, tumor site, receipt of prior chemotherapy, presence of metastasis, receipt of palliative radiotherapy, whether the disease was de novo or residual/recurrent, and other factors were analyzed for their effect on OS and PFS. The addition of palliative radiotherapy significantly increased both PFS (one vs. four months, HR = 0.4; 95% CI = 0.24-0.67; p = 0.00015) and OS (4.2 months vs. 7.8 months, HR = 0.42; 95% CI = 0.25-0.72; p value = 0.01). The sequence of radiotherapy did not affect OS or PFS. Grade 3 oral mucositis occurred in 5.7% of the triple OMT group and 4.4% of the dual OMT group patients. Only one patient had a Grade 3 rash with erlotinib. Conclusions The addition of erlotinib to the dual metronomic chemotherapy regimen demonstrated a significantly improved OS and PFS and a well-tolerated toxicity profile. Palliative radiotherapy quadrupled the PFS and nearly doubled the OS in HNCSCC, even in patients with prior exposure to radiotherapy. These findings suggest a potential benefit in utilizing triple therapy in combination with palliative radiotherapy for specific subgroups of patients with HNCSCC, warranting further prospective clinical trials to validate these results.