Preclinical Studies for Cryoprevention of Oral Mucositis

Abstract: Oral mucositis (OM) is a debilitating adverse effect, with a prevalence of up to 80% in patients with cancer who are conditioned with high-dose chemotherapy prior to hematopoietic stem cell transplantation. In its mildest form, OM is characterized by erythema. However, as it worsens, it can give rise to painful ulcerations in the oral mucosa. This may lead to an increased need for analgesics (and sometimes intravenous morphine) for pain relief, and there is an increased risk of systemic infections. Overall, OM-related complications entail increased health care costs. In fact, despite its frequency, impact on patients, and healthcare and economic burdens, current literature indicates few evidence-based interventions with confirmed efficacy for the prevention of OM. In response to this gap in the knowledge, a novel intraoral cooling device has been developed. The long-term goal of the research described in this thesis is to establish an effective and well-tolerated method for cryoprevention of OM. The specific aims of this thesis were to: (i) investigate whether cooling, using a constant low temperature, is effective for oral tissue preservation; (ii) develop an animal model to study the early events which precede OM; (iii) assess the effectiveness of a novel intraoral cooling device as a cryopreventive method; (iv) evaluate whether local cooling affects the oral hemodynamics; and (v) establish how a research protocol should be designed for a randomized controlled trial to evaluate cryoprevention of OM. Oral tissue preservation was better at lower temperatures (Study I). Proinflammatory cytokines were significantly upregulated (Study II). Several promising results were obtained with the intraoral cooling device (Study III). Local cooling may elicit other mechanisms in the oral mucosa than previously suggested that may be of importance for the prevention of OM (Study IV). A research protocol, to assess cryoprevention of OM, should be established through multidisciplinary collaborations and should include both objective- and subjective assessments (Study V). In conclusion, this thesis is the first to focus on the prevention of OM using an alternative cryotherapeutic technique. The work is mainly concerned with preclinical studies to identify the ideal temperature for the prevention of OM. Furthermore, this thesis demonstrates the tolerability and cooling efficacy of the intraoral cooling device and shows that cooling may elicit other mechanisms in the oral mucosa than previously suggested. However, despite its promising capacity, the randomized controlled trial will elucidate the definite role of the intraoral cooling device in cryoprevention.