Oral Complications
Summary of Key Points
Incidence
• Mucositis, a major dose-limiting toxic effect of chemotherapy for solid tumors, develops in 5% to 40% of patients.
• Mucositis develops in 70% to 100% of patients who receive high doses of chemotherapy with bone marrow rescue.
• Mucositis is the most troublesome acute reaction for patients undergoing radiation therapy directed at the oral cavity.
• Radiation therapy directed at the oral cavity frequently causes a host of other oral complications including xerostomia, dental caries, tissue necrosis, and taste alterations.
Etiology of Complications
• Oxidative stress caused by cytotoxic chemotherapy and radiation therapy leads to upregulation and subsequently amplification of multiple inflammatory pathways in a complex process. This subsequently leads to mucosal ulceration.
• Secondary infections occur as a result of treatment-induced immunosuppression.
Prophylactic Measures
• The importance of instituting oral hygiene protocols in patients receiving chemotherapy is well established.
• Cryotherapy is the most conventional and easy to use preventative method, at least for 5-fluorouracil–based bolus therapy, and it appears to have implications for other chemotherapeutic regimens as well, such as edatrexate and high-dose melphalan therapy.
• Keratinocyte growth factor has been approved by the Food and Drug Administration for use with high-dose chemotherapeutic regimens associated with high rates of mucositis and has shown promise in other settings as well.
• Low-level laser therapy has shown promise, but its use is limited for now to centers that are able to support its use.
• Pretreatment dental care, good oral hygiene, and sophisticated treatment planning is recommended for patients receiving radiation therapy.
Treatment
• Overall, evidence is lacking regarding the efficacy of various agents in promoting healing of the oral mucosa after mucositis is established.
• Systemic analgesic therapy of mucositis pain with narcotic medications is well established and recommended.
• Antibiotics and/or antifungal medications should be given to patients with evidence of infection.
• In the palliative setting, various mouthwashes are widely used in clinical practice based on provider preference and experience. These mouthwashes most frequently contain combinations of diphenhydramine, viscous lidocaine, magnesium hydroxide/aluminum hydroxide, nystatin, and corticosteroids. The efficacy of these measures has not been adequately evaluated to date.
• Baking soda mouth rinses appear to be the most economical solution, although efficacy is not clearly established.
• Low-level laser therapy has also shown promise in treating established mucositis lesions.
1. In the five-stage pathophysiology model of oral mucositis proposed by Sonis, which of the following statements is not true?
A Oxidative stress is responsible for the initiation phase of mucosal injury.
B Nuclear factor (NF)–κB plays an important role in the subsequent upregulation of proinflammatory cytokines.
C Microbial infections play an important role in the development of mucositis.
D Mucosal ulceration occurs late in the course of chemotherapy-induced mucosal injury.
2. Which of the following interventions is most strongly recommended by current guidelines based on prospective randomized controlled studies?
3. What is the most frequent and bothersome acute adverse effect experienced by patients receiving radiotherapy directed at the head and neck?
4. Which of the following interventions for prevention of radiotherapy-induced xerostomia is supported by multiple randomized, controlled trials?
A Conventional opposed lateral field radiotherapy
B Parotid-sparing intensity modulated radiotherapy
C Oral cavity–sparing intensity modulated radiotherapy
E PENTOCLO (pentoxifylline-tocopherol-clodronate combination)
5. Keratinocyte growth factor (palifermin) is recommended as a means to prevent mucositis with which of the following treatments?
1. Answer: C. Although microbial superinfections can complicate established mucositis, they are not thought to play an important role in the pathophysiology of mucosal injury. This view is supported by the general lack of efficacy of antimicrobial agents in preventing chemotherapy-induced mucositis. Oxidative stress is thought to be responsible for the first phase of mucosal injury (initiation phase), whereas upregulation of NF-κB occurs in the second phase and is thought to play an important role in the subsequent upregulation of multiple proinflammatory cytokines, such as tumor necrosis factor (TNF)–α, interleukin (IL)-1b, and IL-6. Mucosal ulceration occurs in the fourth phase, which is the symptomatic phase, characterized by erythema, plaque formation, pain, and bleeding. Healing (the fifth phase) generally occurs after leukocyte recovery begins, especially in patients undergoing myeloablative chemotherapy.
2. Answer: C. Cryotherapy is supported by multiple randomized controlled studies that have proven efficacy in the settings of 5-fluorouracil chemotherapy, edatrexate, and high-dose melphalan conditioning. Oral care protocols, although recommended by current guidelines, are not supported by randomized controlled studies but rather by principles of good practice and common sense. Antimicrobial agents in general have failed to demonstrate efficacy in the prevention of mucositis. Glutamine supplementation either by the intravenous or the oral route requires further testing before efficacy is established. Finally, low-level laser therapy has shown efficacy in randomized controlled studies, but the technical expertise required and the expense associated with the procedure limits current recommendations only to institutions that have the technology available.
3. Answer: D. Most patients undergoing radiotherapy directed at the head and neck experience some degree of painful oral mucositis. Hyposalivation can occur during radiotherapy, resulting in thick, sticky oral secretions. Appetite is usually unchanged or decreased because of loss of taste, nausea, and/or painful oral mucositis. Osteoradionecrosis and trismus are late adverse effects experienced by a minority of patients after radiotherapy.
4. Answer: B. Phase 3 randomized controlled trials conducted in Asia and Europe have demonstrated that parotid-sparing intensity-modulated radiotherapy (compared with conventional radiotherapy) results in increased posttreatment salivary flow, decreased patient reported xerostomia, and improved quality of life. When intensity-modulated radiotherapy is used, oral cavity sparing is recommended on the basis of retrospective analyses demonstrating that xerostomia is correlated with the dose to the oral cavity; however, this has not been specifically evaluated in randomized controlled trials. Low-level laser therapy has been evaluated in the prevention and treatment of oral mucositis. PENTOCLO has been evaluated for the treatment of refractory osteoradionecrosis in a pilot trial format.
5. Answer: C. Palifermin is a recombinant keratinocyte growth factor that has been approved by the United States Food and Drug Administration and recommended by guideline committees to be used in association with high-dose chemotherapy regimens with a high mucositis incidence prior to stem cell transplantation. Although some studies support its use to decrease radiation therapy–associated mucositis, it has not been recommended for this situation by guideline committees.
