Inflammation and Metabolism After Radiotherapy- Predictors of Survival in Patients with Head and Neck Cancer

The incidence of head and neck cancer (HNC) has increased in Sweden during the last decades. Radiotherapy (RT) is a cornerstone of treatment either as single or combined modality treatment. There is emerging awareness that RT affects the immune system. For HNC patients treated with RT nutritional problems and fatigue are the most common long-term adverse effects. About 60% have advanced stage of disease at time of diagnosis. Recurrence as well as early death within two years is common.

Our hypothesis: there is a complex association between immune response, metabolic factors and survival.

The aim of this multicenter patient-centered observational longitudinal study is to prospectively identify immunological and nutritional/metabolic variables that affect the outcome of HNC patients. We will systematically investigate the local and systemic immune response induced by RT as well as explore alterations in metabolite composition induced by disease and treatment through global metabolite profiling (metabolomics). This highly biologically relevant data may be used to search for specific biomarkers of malnutrition, markers which would be of prognostic and/or diagnostic value. Moreover, analytically reliable data allows for a more comprehensive mechanistic understanding, as such, a particular focus lies in ensuring a high data quality. We have established a platform for a study on immuno-metabolic changes in HNC patients in the Uppsala-Orebro and Northern regions. Findings in this large-scale observational study can have implications on the development of personalized therapy in patients with HNC.

Survey of the field. There is restricted information on the importance of local and systemic immune response to RT in HNC patients. RT has systemic effects in addition to its local effects on tumors and surrounding tissue. Pro-inflammatory cytokines are activated by RT and have been associated with increased symptom burden in cancer treatment. Interleukin-6 (IL-6) is a potent inflammatory cytokine with diverse functions. In lung cancer mice xenograft studies irradiation has shown to induce an increase in IL-6 levels and migration of macrophages to the tumor tissue. An association between C-reactive protein (CRP) and IL-6 in plasma has been demonstrated in esophageal adenocarcinoma patients. Relapse-free patients are reported to have an increased proportion of Natural killer cells (NK-cells) in peripheral blood long-term after treatment. We have earlier followed a cohort of HNC patients during RT with repeated blood samples. high-sensitivity C-reactive protein (hCRP) increased during RT, and patients with the most pronounced weight loss had the greatest hCRP increase. Metabolic factors are reported to affect HNC patients in many ways. Severe malnutrition before treatment of HNC is reported to lead to increased mortality. In a secondary study in patients with oropharyngeal cancer (n = 357) we found that a high BMI gives significantly better 5-year survival than a low BMI. However, it is difficult to evaluate the results in the majority of nutritional studies in HNC patients because most prospective studies have included relatively few patients and many of the results obtained in retrospective studies have been conflicting. Patient's metabolic profile might work as a nutritional marker and be distinctly linked to nutritional status. The blood metabolome can be examined in detail in cancer patients to better identify different metabolic pathways. The nutritional status is strongly connected to the immune status. It is e.g. reported that L-arginine is crucial for the function of T-cell. As the immune system at the site of the tumor can inhibit cancer growth the local anti-tumorigenic immune status is important. Thus the nutritional status predicts the immune status and malnutrition is connected to a weaker immune response. It is unclear how the nutritional status is connected with the systemic immune status.

Research questions