Head and neck cancer patients under (chemo-)radiotherapy undergoing nutritional intervention: Results from the prospective randomized HEADNUT-trial.

PURPOSE/OBJECTIVE: Patients with squamous cell carcinoma of the head and neck undergoing (chemo-)radiotherapy are at high risk of malnutrition. Nevertheless, there is still a lack of prospective, randomized trials investigating the influence of nutritional status on therapy-related toxicity and patients' outcome. MATERIALS AND METHODS: Between October 2018 and October 2020, 61 patients were randomized into an intervention and control group. Questionnaires (MUST, NRS-2002, and Nutriscore), clinical examinations, laboratory analyses, and bioelectrical impedance analysis (BIA) were used to assess nutritional status for all patients at the beginning and end of therapy as well as every 2 weeks during therapy. The intervention consisted of an individualized nutritional counseling every 2 weeks during therapy. RESULTS: Median baseline BMI for all participants was 23.8 (14.5-37.2) kg/m2 and dropped to 22.9 (16.8-33) kg/m2 after therapy (p < 0.001). In all patients, median baseline fat-free mass index (FFMI) was 18.1 (14-24.7) kg/m2 and decreased to 17.8 (13.4-21.6) kg/m2 till the end of therapy (p < 0.001). Compliant patients with a BMI < 22 kg/m2 presented with less weight loss in the intervention group compared to the control (p = 0.015, CI: 0.33-2.95). At baseline, MUST was the only screening-test which showed both good sensitivity (86%) and specificity (88%) in detecting malnutrition. Median follow-up was 15 (1-26) months and is still ongoing. 2-year overall survival rate was 70% in the control and 79% in the intervention group (log-rank p = 0.79). Pretherapeutic phase angle, posttherapeutic FFMI and albumin level were prognostic indicators for overall survival (log-rank p = 0.002, p = 0.008 and p = 0.016). CONCLUSIONS: Malnutrition negatively impacts patients' outcome under (chemo-)radiotherapy. Baseline phase angle, posttherapeutic FFMI and albumin level are proposed as reliable indicators for overall survival. This study was registered within the German Clinical Trials Register (DRKS00016862).

Dual role of ER stress in response to metabolic co-targeting and radiosensitivity in head and neck cancer cells.

Arginine deprivation therapy (ADT) is a new metabolic targeting approach with high therapeutic potential for various solid cancers. Combination of ADT with low doses of the natural arginine analog canavanine effectively sensitizes malignant cells to irradiation. However, the molecular mechanisms determining the sensitivity of intrinsically non-auxotrophic cancers to arginine deficiency are still poorly understood. We here show for the first time that arginine deficiency is accompanied by global metabolic changes and protein/membrane breakdown, and results in the induction of specific, more or less pronounced (severe vs. mild) ER stress responses in head and neck squamous cell carcinoma (HNSCC) cells that differ in their intrinsic ADT sensitivity. Combination of ADT with canavanine triggered catastrophic ER stress via the eIF2α-ATF4(GADD34)-CHOP pathway, thereby inducing apoptosis; the same signaling arm was irrelevant in ADT-related radiosensitization. The particular strong supra-additive effect of ADT, canavanine and irradiation in both intrinsically more and less sensitive cancer cells supports the rational of ER stress pathways as novel target for improving multi-modal metabolic anti-cancer therapy.