Oral Mucositis and Oral Mucosal Toxicities: Review Includes Clinical Presentation and Management Strategies

Oral mucosal lesions (mouth ulcers) are a common and debilitating side effect of many anticancer drug treatments and of head and neck radiation therapy. Patients with severe oral mucositis often suffer such extreme pain that they cannot tolerate their cancer treatment regimens and they are at greater risk of local and systemic infection. Oral mucositis is associated with increased mortality risk in patients undergoing hematopoietic stem cell transplantation (HSCT).

A recently published review of oral mucositis presents an update on the pathogenesis, epidemiology, assessment, risk prediction, and management strategies. The authors, led by Sharon Elad, DMD, MSc, Professor of Dentistry at the University of Rochester, NY, note that although research into the pathogenesis of oral mucositis has revealed targets for intervention, few strategies have emerged to alleviate the oral mucosal effects of anticancer treatments, and that as new classes of targeted and immune anticancer therapies become available, new types of oral mucosal toxicities are being identified.

Epidemiology
The incidence of oral mucositis is not often documented except as an adverse event in clinical trials. Patients undergoing HSCT report oral mucositis as their most severe toxicity (between 71-92% incidence). The severity of the oral mucositis correlates with intensity of the treatment. Similarly, patients with head and neck cancer receiving radiation or chemoradiation have a high incidence of oral mucositis (around 59-100%). Oral mucositis incidence varies widely with different chemotherapy regimens and tumor types (e.g., as high as 35% for patients with colon cancer receiving FOLFIRI, but only 6.6% overall in patients treated for non-Hodgkin lymphoma with any regimen). Certain classes of targeted anticancer therapy are strongly associated with the development of oral mucosal toxicities, including mTOR inhibitors (e.g., everolimus, tacrolimus), while these toxicities are less often associated with others, such as immune checkpoint inhibitors.

Clinical presentation
Oral mucositis presents as a reddening (erythema) of the oral tissues, eventually leading to atrophy and ulceration. Tissue inside the cheeks, the sides and undersurface of the tongue, the back of the mouth are most frequently affected. The first signs typically appear three to four days after infusion treatment, with ulcers forming soon afterward. While the ulcers progressively get worse for two weeks, they usually heal spontaneously by three weeks after infusion. With radiation therapy, oral mucositis progressively worsens with higher radiation doses, then usually improves two to four weeks after therapy has been completed. However, about 8% of head and neck cancer patients treated with radiation therapy will have chronic oral mucositis lasting over three months.

The most common symptom of oral mucositis is pain that increases in intensity over time. Patients with head and neck cancer who receive radiation therapy often experience significant weight loss that requires a feeding tube. In HSCT patients, oral mucositis is associated with days of injectable narcotic therapy, fever, parenteral nutrition, and mortality 100 days post HSCT, which can lead to delays or changes in treatment, ultimately affecting outcome and survival.

Risk factors
Patient factors reported to increase the risk for oral mucositis include female gender, low baseline performance status, genetic variations, comorbidities (especially diabetes mellitus), use of certain medications, and previous therapies. Evidence about other systemic factors is inconclusive. Tumor factors that increase risk and severity of oral mucositis include the site of the tumor and cancer stage. Treatment factors include the number of doses of radiation (though intensity modulated radiation and exposure <30 Gy is associated with lower risk), myeloablative condition prior to HSCT, and chemotherapy such as methotrexate and melphalan. In pediatric patients, risk of oral mucositis is associated with low body weight, anxiety, nausea and vomiting, and previous oral mucositis episodes. Children with leukopenia and neutropenia are also more likely to report oral mucositis.

Pathobiology
The effects of chemotherapy or radiation on the oral mucosa are now known to account for only one-third of the cell injury in oral mucositis. A more complex pathway of tissue injury is believed to be triggered immediately after chemotherapy or radiation initiation, involving direct damage to the DNA, oxidative responses mediated by reactive oxygen species (ROS), and activation of the innate immune response. These changes result in apoptosis and necrosis of tissue in the mouth. From this stage, several pathways appear to be initiated that lead to a positive feedback cycle of worsening cellular damage, especially with repeated chemotherapy and radiation treatments. Oral bacteria colonizing the ulcers increase the extent and severity of the mucosal damage by stimulating secretion of further proinflammatory cytokines.

Management
Treatment of oral mucositis focuses on reducing the risk of infection, pain management, maintaining oral function, improving quality of life, and managing other oral complications related to cancer and/or treatment. Although there are currently no therapeutic interventions for oral mucositis, the review authors refer to the latest evidence-based guideline produced by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer and the International Society of Oral Oncology (MASCC/ISOO) for recommended or suggested interventions for specific populations.

The MASCC/ISOO guideline recommendations include: (1) cryotherapy for prevention in patients receiving bolus doses of 5-fluorouracil and those undergoing autologous HSCT conditioned with high-dose melphalan; (2) photobiomodulation therapy for prevention in certain patients receiving HSCT and head and neck radiation therapy; (3) benzydamine in some head and neck cancer patients; (4) KGF-1 (keratinocyte growth factor in certain patients receiving high-dose chemotherapy and TBI before HSCT; and (5) patient-controlled analgesia in patients undergoing HSCT. Dr Elad and co-authors caution that not all these therapies are available in every country. They also stress the importance of optimal nutritional support.

The “significant” health economic burden of oral mucositis, especially for patients who require long-term treatment, is highlighted in the review. The authors found that the incremental cost of treating oral mucositis in cancer patients ranged from $5,000-30,000 for those receiving radiation therapy and $3,700 per cycle for those receiving chemotherapy to over $70,000 for patients undergoing HSCT.

Future directions
Dr Elad and her co-authors stress the need to develop new, effective, personalized mucositis interventions, which they believe should be facilitated by the increasing understanding of its pathogenesis. Aside from the unmet current clinical need, pharmaceutical industry interest has been stimulated by the expanding mucositis market, they note. Currently, most clinical trials are focused on treatment of oral mucositis related to radiation therapy regimens in head and neck cancers, but “the needs and opportunities for developing effective, personalized interventions are likely to grow and remain for the foreseeable future,” they believe, spurred on by demand from clinicians whose patients need these interventions to ensure the success of their cancer treatments.