Biophysical Skin Response in Head and Neck Cancer: Longitudinal Comparison of Modern Photon and Proton Radiotherapy

Acute radiation dermatitis (ARD) is a frequent toxicity in head and neck radiotherapy (RT), yet the interplay among skin dose, patient phenotype, treatment modality, and objective biophysical skin responses remains poorly defined. Previous studies have been limited by small sample sizes, older RT techniques, absence of dose-response modeling, or reliance on subjective grading. In this prospective cohort study, we evaluated temporal changes in skin erythema, melanin index, hydration, and sebum using standardized multiprobe devices at baseline (T1), end of RT (T2), and three months post-RT (T3) in 130 patients with head and neck cancer treated by modern photon RT (volumetric modulated arc therapy, VMAT, n = 90) or proton RT (intensity-modulated proton therapy, IMPT, n = 40). Multivariable analyses examined associations between RT technique, superficial skin dose, baseline phenotypic characteristics, and biophysical outcomes. VMAT and IMPT demonstrated similar temporal biophysical profiles across all time points. Superficial skin dose, rather than modality or ARD grade, independently predicted higher erythema and melanin indices and lower hydration and sebum at T3. Baseline levels, male sex, and higher Fitzpatrick skin type were strong determinants of biophysical skin response at T2 and T3. Hydration and sebum did not recover to baseline at T3, indicating persistent subclinical barrier and adnexal impairment despite clinical resolution of erythema. These findings suggest that biophysical skin response after head and neck RT is more strongly associated with dose and phenotype. Objective assessments reveal latent barrier dysfunction not captured by standard ARD grading, underscoring the value of integrating skin dose metrics and quantitative monitoring into individualized risk stratification and skin-sparing strategies in modern RT.