Low-Cost Methotrexate Chemoselection to Predict Radiotherapy Response in Advanced Oral Squamous Cell Carcinoma: A Prospective Feasibility Study From South India.

IntroductionOral squamous cell carcinoma (OSCC) represents a disproportionate cancer burden in South Asia, where advanced-stage presentation, limited radiotherapy infrastructure, and constrained chemotherapy resources necessitate pragmatic approaches to treatment selection. Platinum-based combinations remain the standard for induction chemotherapy; however, a substantial proportion of OSCC patients present with malnutrition, poor performance status, and limited financial resources that preclude these regimens. This is a hypothesis generating feasibility study which explores whether early response to single-agent low-dose methotrexate (MTX) can serve as a functional assay of tumour biology, predicting subsequent radiotherapy response in patients ineligible for conventional multi-agent induction chemotherapy.MethodsThis prospective, observational feasibility study was conducted at a comprehensive cancer centre in South India. Treatment-naïve patients (n=30) with histologically confirmed stage III-IV OSCC underwent three weekly intramuscular MTX cycles (20 mg/m2 BSA); tumour response was evaluated by serial imaging and clinical assessment before and after MTX, and post-radiotherapy. Baseline demographics and clinical features were collected. Exploratory analysis using Youden's J index identified tumour size reduction thresholds associated with radiotherapy response.ResultsMTX administration was well tolerated with no severe toxicities observed in any participants during chemotherapy. Statistically significant reductions in tumour size occurred following MTX (mean = 0.90 cm, p < 0.001), with further reduction after definitive radiotherapy (mean = 3.50 cm, p < 0.001). An exploratory optimal cutoff of 21% tumour size reduction identified patients unlikely to achieve complete radiotherapy response (specificity 94.12%, sensitivity 46.1%).ConclusionThis feasibility study demonstrates proof-of-concept that early tumour response to low-cost, single-agent MTX correlates with subsequent radiotherapy outcomes in advanced OSCC patients. The strategy offers potential as a triage tool in South Asian resource-constrained settings, but the exploratory 21% cutoff requires external validation in independent cohorts before clinical application.