Impact of Clinical and Dosimetric Factors on Severe Oral Mucositis in Head and Neck Cancer: Insights from a Phase II Clinical Trial

Alicia Lozano-Borbalas^1,2,3*Olivia Jordi-Ollero⁴Jordi Marruecos⁵Nuria Farre⁶Isabel Planas⁷Maria Dolores Toledo^10,8,9Ricard Mesia^11,12Arturo Navarro-Martin^1*

• ¹Radiation Oncology, Catalan Institute of Oncology, Barcelona, Spain
• ²Universitat de Barcelona, Barcelona, Spain
• ³Institut d'Investigacio Biomedica de Bellvitge, Barcelona, Spain
• ⁴Physics department, Catalan Institute of Oncology, Barcelona, Spain
• ⁵Radiation Oncology, Catalan Institute of Oncology, Girona, Spain
• ⁶Radiation Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
• ⁷Radiation Oncology, Catalan Institute of Oncology, Badalona, Spain
• ⁸Radiation Oncology department, Hospital Universitario Virgen de la Victoria, Málaga, Spain
• ⁹Instituto de Investigacion Biomedica de Malaga, Málaga, Spain
• ¹⁰Plataforma en Nanomedicina- IBIMA Plataforma Bionad, Málaga, Spain
• ¹¹Medical Oncology, Catalan Institute of Oncology, Badalona, Spain
• ¹²B.ARGO Badalona Applied Research Group in Oncology, Badalona, Spain

Introduction: Oral mucositis (OM) is the most common acute treatment-limiting adverse effect in patients with head and neck cancer (HNC), particularly following concomitant radiotherapy (RT) and systemic therapy. However, the effects of clinical and dosimetric parameters on the onset of severe OM remain controversial. We aimed to determine the association between clinical and dosimetric parameters and severe OM in the oral and pharyngeal mucosae inside a randomized phase II clinical trial. Patients and methods: Subgroup analysis of data from a clinical trial conducted to assess the efficacy of a 3% melatonin oral gel (MucomelR) to prevent OM in patients with HNC. A total of 54 patients treated with intensity-modulated radiotherapy (IMRT) (66-69.96 Gy/33 fractions) plus concomitant systemic therapy (cisplatin or cetuximab) +/- melatonin rinses were included. The association between clinical and dosimetric parameters and grade (G) ≥3 OM was determined. For this analysis, the oral mucosa was divided into the oral and pharyngeal mucosae. Results: The following variables were significantly associated with G3 OM in the oral mucosa: oropharyngeal localization (p=0.03); treatment with cetuximab (p=0.01); the oral mucosa volume included in low Planning Target Volume (PTV) (PTV1: 54.12 Gy) and intermediate treatment doses in (PTV2: 60 Gy); V35 > 70% (p=0.007); and median RT dose of 56,6Gy (p=0.02). The absolute healthy volume of the oral mucosa was a significant protective factor (p=0.03; McFadden pseudo R2=0.46). None of the clinical or dosimetric variables were significantly associated with G3 OM in the pharyngeal mucosa. Conclusion: Oropharyngeal cancer, Cetuximab and low and intermediate RT dose to the oral cavity mucosa were significantly associated with onset of severe oral mucositis. Given the association between these previous factors with higher risk of G3 OM, they should be considered during treatment planning and dosimetry in patients treated with cetuximab in oropharyngeal cancer.