Radiotherapy-induced OM

Oral mucositis (OM) is a painful and problematic complication during cancer treatment, especially radiation therapy that hits the lining of the mouth. It is a process believed to be initiated by excessive superoxide generated during treatment and that breaks down epithelial cells that line the mouth. Patients suffering from oral mucositis experience severe pain, inflammation, ulceration, and bleeding that can significantly impede the patient’s ability to swallow.

OM is a serious side effect of radiotherapy

OM is a debilitating side effect of radiotherapy during the treatment of head and neck cancer (HNC) and it occurs in almost all patients who undergo combined radiation and chemotherapy treatment of HNC.

Severe OM occurs in approximately 70% of patients receiving combined radiation and chemotherapy for HNC, with the radiation portion playing the biggest role.1 As classified by the World Health Organization, Grades 3-4 of OM are severe and mean that the patient not only has ulcerations but also cannot eat solid food (Grade 3) or drink liquids (Grade 4).

Severe OM consequences are serious and may include:

Interruption of treatment

  • Interruptions in radiotherapy caused by severe OM can seriously compromise the otherwise good prognosis for tumor control in many of these patients.

Poor quality of life

  • Patients with severe OM suffer from significant pain, even with aggressive pain management. They are unable to eat solid food and may not even be able to drink liquids, with weight loss and dehydration becoming significant medical concerns. With disruption of the protective mucosa, serious infections can also occur.

Increased healthcare costs

  • The costs of managing these side effects are substantial, particularly when hospitalization and/or surgical procedures such as feeding tubes are required to maintain nutrition and hydration or battle infection.

Disarming OM

Superoxide plays key role in oral mucositis (OM)

Radiation causes direct damage to the oral mucosa, at least in part via superoxide generated directly by radiation and by activation of superoxide-producing enzymes shortly thereafter. This damage then activates pathways—which may also involve excessive superoxide—all of which combine to result in mucositis.

As this damage accumulates with successive radiation doses, OM can progress until it becomes severe. If severe OM occurs early enough during the course of radiotherapy, or if it is prolonged or becomes even more severe, aggressive management is required including potentially interrupting or even ending radiotherapy.

Conversion of superoxide to hydrogen peroxide

Our dismutase mimetics are designed to convert the bursts of superoxide induced by radiotherapy to hydrogen peroxide, which is then converted to O2 and H2O. As a result, in various nonclinical experiments they significantly reduce the immediate and long-term radiation damage to normal tissue in a variety of organs.2,3

Given this and the central role of superoxide in the process of OM, we are currently studying our dismutase mimetics in clinical trials to investigate the impact of reducing this elevated superoxide on OM in HNC patients.

References:
1. Wissinger E, Griebsch I, Lungershausen J, Foster T, Pashos CL. The economic burden of head and neck cancer: a systematic literature review. Pharmacoeconomics. 2014;32(9):865-882.
2. Thompson JS, Chu Y, Glass J, Tapp AA, Brown SA. The manganese superoxide dismutase mimetic, M40403, protects adult mice from lethal total body irradiation. Free Radic Res. 2010;44(5):529-540.
3. Coleman MC, Olivier AK, Jacobus JA, et al. Superoxide mediates acute liver injury in irradiated mice lacking sirtuin 3. Antioxid Redox Signal. 2014;20(9):1423-1435.