New perspectives of clinical features and salivary protein biomarkers of radiation induced oral toxicities

Author(s)

Natália Rangel Palmier

• Document type: Doctoral Thesis
• Press: Piracicaba, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Odontologia de Piracicaba
• Defense date: 2021-08-20

Examining board members

Alan Roger Santos Silva; Cesar Augusto Migliorati; Luiz Alcino Monteiro Gueiros; Márcio Ajudarte Lopes

• Advisor: Ana Carolina Prado Ribeiro; Alan Roger Santos Silva

Abstract

Recent discoveries about the synergistic effect between the several oral toxicities induced by radiotherapy (RT) in the treatment of head and neck cancer (HNC) have renewed the importance of a better understanding on the pathophysiological features of the cluster of oral symptoms and how they impact dental and medical outcomes of cancer patients. In this context, lately, there is a great search for knowledge of the molecular profile of diseases with diagnostic potential for more efficient and less toxic personalized treatments. Considering this, the present doctoral thesis aimed to categorize clinical and molecular salivary patterns of oral toxicities induced by RT in patients with squamous cell carcinoma (SCC) of the oral cavity and oropharynx. The results of this thesis are presented through two clinical cohort studies, one systematic review, one narrative review and two studies of salivary molecular analysis. Clinical studies included patients with HNC undergoing RT with curative intent, associated or not with previous surgery or concomitant with chemotherapy protocols. Clinical results demonstrate a clear impact of the introduction of concomitant chemotherapy on the early development of severe dysgeusia, as well as a statistically significant correlation between xerostomia and oral mucositis (OM) on the development of dysgeusia (r=0.29 and r=0.42, respectively - p<0.001 for both). These associations were validated by the systematic review, which revealed a specific pattern of a cluster of oral and gastrointestinal symptoms that correlate and overlap, leading both to worsening acute toxicities and favoring the development of chronic toxicities such as radiation caries (RC) and osteoradionecrosis (ORN). From the results of the proteomic analysis of saliva, it was possible to identify potential salivary biomarkers, mainly related to biological processes, such as innate immune responses, inflammatory response, cell migration, peptidase inhibitor activity and iron coordination, which can be considered predictors of acute toxicities of RT. Interestingly, eight biomarkers were associated with clinical severity of xerostomia and oral candidiasis and one biomarker associated with dysgeusia and oral candidiasis, bringing original evidence, in biological terms, for the existence of a cluster of symptoms and oral toxicities resulting from RT. Originally, the results of this thesis also suggest the potential impact of the cluster of oral symptoms on the development of RC, which, in turn, had an important impact on the morbidity of patients included in this study, who had a greater need for specialized dental appointments, higher incidence of ORN and consequently a greater need for invasive surgical procedures after RT. The results of the present thesis demonstrate new perspectives regarding the pattern of development as well as the impact that acute toxicities induced by RT can represent on the development and aggravation of each other in the form of the just described cluster of oral symptoms. The present thesis also originally presents salivary proteomic predictors of acute debilitating oral toxicities induced by RT in patients with advanced oral and oropharyngeal SCC, with potential to improve clinical protocols for personalized dental support in Oncology. In this context, findings regarding the patterns of cluster of oral symptoms support the theory that the main etiological factor of RC is related to the indirect effects of RT, and through the observed results it was possible to propose a new methodology to guide dentists in early diagnosis and proper treatment of RC (AU)

• FAPESP's process: 18/04657-8 - Salivary protein markers of radiation-related oral toxicites
• Grantee: Natália Rangel Palmier
• Support Opportunities: Scholarships in Brazil - Doctorate