Radiotherapy-induced OM

Oral mucositis occurs when radiotherapy induces the production of superoxide that attacks and breaks down the epithelial cells lining the mouth. The severity of OM is commonly measured using the WHO scale. The scale consists of five Grades: Grade 0 through Grade 4. SOM is commonly defined as Grade 3 or Grade 4 OM.

Grade WHO Scale Description
0 No OM
1 Erythema (redness) and soreness
2 Erythema and ulcers but patients can swallow solid food
3 Ulcers with extensive erythema and patients cannot swallow solid food
4 Oral alimentation (solid or liquid) is not possible

 

SOM can lead to devastating complications, including:

  • Pain. A majority of patients experience severe pain, often requiring opioids to manage the pain. A publication describing 191 patients being treated for HNC noted that of the 157 patients reporting the greatest amount of mouth and throat soreness, 70% were taking opioids to alleviate their pain.
  • Dehydration and malnutrition. Approximately 70% of patients with HNC receiving radiotherapy become unable to eat, drink, or both, often requiring nutrition through a gastrostomy tube or intravenous line.
  • Treatment interruption. SOM can be dose-limiting, requiring a reduction or delay in radiotherapy, leading to poorer clinical outcomes. Approximately 11% of patients experience unplanned breaks of a week or more in radiotherapy, with each week of treatment delay decreasing tumor control by over 10%.
  • Increased economic burden. Approximately 16% of patients receiving radiotherapy for HNC are hospitalized due to SOM. Based on a third-party analysis of medical insurance claims covering 40 million patient years, patients with HNC and treated with radiotherapy who developed OM incurred, on average, approximately $32,000 in additional medical expenses in the first six months from the start of radiotherapy compared to such patients who did not develop OM.

Each year in the United States, approximately 65,000 patients are diagnosed with HNC, according to the American Cancer Society. In the five largest European markets, approximately 68,000 patients are diagnosed annually with HNC, and an additional 23,000 in Japan.

All of the patients with locally advanced HNC being treated with standard-of-care radiotherapy are at risk for developing SOM and, based on observations from multiple studies, we estimate that approximately 70% will develop SOM and between 20% to 30% will develop Grade 4 OM.

Disarming OM

Superoxide plays key role in oral mucositis (OM)

Radiotherapy 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 oxygen and water. 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.