Project Summary/Abstract Oral mucositis is among the most common, painful, and debilitating toxicities of cancer treatment. OM presents as large, irregular, deep ulcers of the movable mucosa, often covered by a pseudomembrane. Among patients receiving aggressive anti-cancer regimes a dramatic change in the oral environment occurs causing an imbalance of the bacteria, fungi, and viruses of the oral cavity. Currently, there are no effective therapies or preventive treatments for OM. Most suggested treatments or therapies provide minor improvements in infection rates, inflammation, irritation, or pain relief. OM occurs in 80% of patients receiving radiation therapy (RT) or chemoradiation therapy (chemoRT) for head and neck malignancies; severe mucositis affects more than two- thirds of this population. Pain, malnutrition, dehydration, and risk of infection all contribute to the morbidity of OM. In patients with severe OM, nutritional intake is drastically reduced, and the cost of care is increased due to the necessity of percutaneous endoscopic gastrostomy tube insertion, administration of systemic analgesics and intravenous antibiotics, and prolonged hospital stay. Clinically significant OM could lead clinicians to reduce the chemotherapeutic dosage, or delay or discontinue cancer therapy, which impacts definitive treatment of the cancer. Novel discoveries in OM have focused on understanding the host-microbial interactions, as current pathways have shown that major virulence factors from microorganisms have the potential to contribute to the development of OM and may even prolong the existence of already established ulcerations. Thus, intervention studies based on this pathobiological model are urgently needed for the development of better oral care treatments and/or antimicrobial agents targeted at the treatment of OM. Our proposed study will investigate in a randomized controlled clinical trial the effects of a novel oral care protocol on the severity of OM in patients undergoing RT and chemoRT for head and neck cancer. Additionally, it will evaluate the effect of RT/chemoRT on the oral microbiome and its impact on OM severity and local inflammation. The central hypothesis is that a weekly regimen of targeted professional oral care during cancer treatment prevents harmful ecological shifts in the oral cavity and consequently reduces the duration and severity of OM, reduces OM local inflammation, and improves oral health, thereby improving overall quality of life during cancer treatment. The rationale is that the cleansing of dead, damaged, or infected oral mucosal tissues in combination with the mechanical removal of dental plaque and calculus in the oral cavity improves the healing potential of the oral tissues and suppresses OM severity. Hence, findings from our study may identify important biochemical and microbiological alterations that can be targeted in the future as well as inspire further etiological studies of the OM microbiome, which may lead to better-targeted oral health preventive treatments, interventions and therapies aimed at improving quality of life during cancer treatment.