Treatment-related lymphopenia predicts long-term survival in locally advanced head and neck cancer: Post-Hoc analysis of a randomized phase III trial.

PURPOSE: To evaluate the prognostic value of treatment related decline of peripheral absolute lymphocyte count (ALC) in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) after preoperative radiation therapy (RT) with or without chemotherapy. METHODS: This post-hoc analysis was performed using data of 222 patients from a phase III, randomized controlled trial in LA-HNSCC. ALCs were measured before, during, and after RT. The ALC decline was defined as the difference between pre-treatment ALC and the nadir ALC observed during RT. Optimal cut-off values for hematologic and nutritional indices were determined by ROC analysis. Survival outcomes were estimated using Kaplan-Meier analysis and compared with the log-rank test. Prognostic factors were identified using LASSO regression and multivariable Cox models. A nomogram was constructed based on independent prognostic variables. RESULTS: With a median follow-up of 132.0 (IQR: 104.17-151.73) months, no significant difference was observed in the 10-year overall survival (OS) and progression-free survival (PFS) between treatment groups. Lymphopenia during RT occurred in 197 patients (88.7%), including grade 3 in 112 (50.5%) and grade 4 in 10 (4.5%). An ALC decline > 0.74×109/L was independently associated with poorer OS and PFS. The nomogram integrating T stage, N stage, ALC decline, and neutrophil-to-albumin ratio (NAR) yielded a C-index of 0.66, a 5-year AUC of 0.738, good calibration, and favorable net benefit on DCA. CONCLUSION: Treatment-related ALC decline is an independent adverse prognostic factor in LA-HNSCC. A nomogram incorporating ALC decline performs favorably in individualized survival prediction.