Dynamics of tissue fatty acid profiles and association with radiotherapy toxicity in locally advanced nasopharyngeal carcinoma.

Abstract

e18048 Background: Tissue levels of n-6 and n-3 fatty acids (FAs), reflected by erythrocyte membrane composition, modulate inflammatory processes and may influence tolerance to cancer therapy. Their dynamics during multimodality treatment for locally advanced nasopharyngeal carcinoma (LA-NPC) and predictive value for radiotherapy (RT) toxicity remain undefined. Methods: This prospective study enrolled 70 patients with LA-NPC (Stage III-IVA, AJCC 9th) receiving induction chemotherapy (toripalimab + cisplatin + nab-paclitaxel) for three cycles, followed by concurrent toripalimab and RT. Serial erythrocyte FA profiles, inflammatory cytokines, and nutritional indices were assessed at baseline (T0), each induction chemotherapy cycle(T1-T3), pre-RT (T4), mid-RT (T5; 40 Gy), and post-RT (T6-T7). Logistic regression and ROC analysis evaluated the n-6/n-3 ratio at T4 as a predictor of grade ≥3 radiation-induced oral mucositis (RIOM). Baseline profiles were also compared to 70 healthy volunteers, and differences between Stage III and IVA patients were examined. Results: Erythrocyte FA profiles in patients with LA-NPC demonstrated treatment-phase-specific dynamics. The n-6/n-3 ratio declined during induction chemotherapy, then increased sharply to a peak at mid-RT (T5: 10.10 ± 1.30 vs. T0: 7.38 ± 1.74; p<0.001), and declined post-RT. The peak n-6/n-3 ratio at T5 was driven by RT-induced depletion of omega-3 (EPA, DHA), while omega-6 levels remained stable, which also resulted in an increase in the AA/EPA ratio (T5:39.0±5.89 vs.T0:32.3±6.00; p<0.001). At the same time, a pro-inflammatory state (increased IL-6 and IFN-γ and decreased IL-10) was observed, accompanied by a decrease in serum albumin and body weight. The incidence and severity of RT-related adverse events peaked at T5 and were mainly ≥ grade 3 RIOM. At this time, the n-6/n-3 ratio was positively correlated with RIOM severity (r=0.60) and dermatitis risk (r=0.60), whereas EPA and DHA levels were negatively correlated (r=-0.4 to -0.9). Critically, the n-6/n-3 ratio at T4 was a strong independent predictor of subsequent severe RIOM (OR 6.15, 95% CI 2.43–15.55; p<0.001), with an AUC of 0.935 (cutoff 7.16; sensitivity 78.6%, specificity 93.0%). At baseline, compared with healthy volunteers, patients showed a pro-inflammatory metabolic profile, as indicated by significantly higher n-6/n-3 ratio, DTA, IL-6, and IFN-γ, and lower omega-3 levels (all p<0.05). There was no significant difference in FA profiles between stage III and IVA patients. Conclusions: Erythrocyte FA profiles undergo marked reprogramming during LA-NPC treatment, characterized by RT-driven omega-3 depletion. The pre-RT erythrocyte n-6/n-3 ratio is a potent predictive biomarker for severe RIOM, identifying a window for nutritional intervention.