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Chemotherapy or Radiation-Induced Oral Mucositis
Dental Clinics of North America, 2, 58, pages 341 - 349
Keywords: Oral mucositis, Stomatitis, Cancer, Chemotherapy, Radiation therapy.
- Oral mucositis is a significant toxicity of systemic chemotherapy and of radiation therapy to the head and neck region.
- The morbidity of oral mucositis can include pain, nutritional compromise, impact on quality of life, alteration in cancer therapy, risk for infection, and economic costs.
- Management includes general symptomatic support and targeted therapeutic interventions for the prevention or treatment of oral mucositis.
- Evidence-based clinical practice guidelines are available to guide clinicians in the selection of effective management strategies.
Introduction, epidemiology, and pathogenesis
An estimated 1.6 million people receive cancer therapy in the United States each year and worldwide numbers are much higher. 1 Although advancements in cancer therapy improved survival rates for many tumor types, these treatments also cause several side-effects, including some in the oral cavity. One of the more significant oral complications of cancer therapy is oral mucositis, which refers to inflamed erosive or ulcerative lesions of the oral mucosa. Oral mucositis can result from systemic chemotherapy, from radiation therapy (RT) to the oral mucosa, or a combination thereof. It affects approximately 20% to 40% of patients receiving conventional chemotherapy regimens for solid tumors, depending on the dose and cytotoxicity of the drug. 2 In patients receiving very high doses of chemotherapy before a hematopoietic stem cell transplant (HSCT), oral mucositis is seen in about 80%. 3 Almost all patients receiving therapeutic radiation for head and neck (H&N) cancer will develop oral mucositis. 4 Collectively in the United States, it is estimated that about 400,000 patients suffer from oral mucositis each year. 5
Historically, mucositis was thought to result only from damage to basal epithelial cells due to chemotherapy or RT. It is now understood that the pathogenesis is much more complex and involves the generation of damaging reactive oxygen species, activation of transcription factors such as nuclear factor-κB and inflammatory pathways such as the cyclooxygenase pathway, and the upregulation of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β. 6 The various factors involved have been integrated into a five-step pathogenesis model ( Fig. 1 ). 7
Morbidity of oral mucositis
The primary morbidity of oral mucositis is the intense pain usually associated with ulcerative lesions. Most patients with ulcerative mucositis need systemic opioids for pain management. In one study, a 1-point increase in peak mucositis scores in patients with HSCT was associated with 2.6 additional days of injectable narcotic therapy. 8 Systemic opioids have several side-effects, including risk of dependence, altered mental state, and constipation.
Because of the pain, patients with severe oral mucositis may be unable to continue eating by mouth. Therefore, they are fed intravenously via total parenteral nutrition (TPN) or through a gastrostomy tube. A 1-point increase in peak mucositis scores in HSCT patients was associated with 2.7 additional days of TPN. 8 Patients who have H&N cancer with oral mucositis are significantly more likely to have weight loss of 5% or more. 9 Impaired nutrition affects healing and resistance to infection, and leads to a general failure to thrive.
Quality of Life
The pain and nutritional compromise adversely affects quality of life. This is especially prominent in patients receiving H&N RT 10 and in patients receiving high-dose chemotherapy for HSCT. 11 Patients undergoing HSCT report oral mucositis as the most debilitating complication of transplantation. 11
Impact on Cancer Therapy
Severe mucositis can necessitate undesirable dose reductions or interruptions in cancer therapy. In patients receiving chemotherapy for solid tumors or lymphoma, a reduction in the next dose of chemotherapy was twice as common after cycles with mucositis than after cycles without mucositis. 12 Eleven percent of patients receiving RT for H&N cancer had unplanned breaks in RT because of severe mucositis. 13 Such modifications in cancer therapy can negatively affect cancer prognosis.
Ulcerative oral mucositis is colonized by oral microflora and is sometimes complicated by local infection such as herpes simplex virus (HSV) infection and candidiasis. In patients who are immunosuppressed due to chemotherapy, these ulcerative lesions can provide a route for systemic sepsis, which is potentially life threatening.14, 15, and 16 For example, in patients receiving conventional chemotherapy for solid tumors or lymphoma, the rate of infection during cycles with mucositis was more than twice that of cycles without mucositis and was proportional to its severity. 12 Infection-related deaths were more common during cycles with mucositis. In patients receiving high-dose chemotherapy for HSCT, moderate to severe oral mucositis has been correlated with systemic infection and transplant-related mortality. 17 Increased severity of oral mucositis has been associated with increased incidence of significant infection, number of days with fever, and a 3.9-fold increase in 100-day mortality risk. 3
Impact on Oral Health
Patients with painful oral mucositis may have difficulty carrying out routine oral hygiene measures such as brushing and flossing. In addition, transient or permanent hyposalivation is a frequent finding in patients receiving cancer therapy. 18 In combination, these factors can increase the risk of dental caries and periodontal disease. Furthermore, as mentioned above, lesions of oral mucositis can be secondarily infected with oral candidiasis or HSV, in the setting of possible immunosuppression. Thus, oral mucositis has a significant negative impact on oral and dental health.
Oral mucositis results in increased costs associated with pain management, TPN or gastrostomy tubes with liquid diet supplements, secondary infections, and hospitalizations. In patients receiving H&N RT, oral mucositis was associated with an increase in costs ranging from $1700 to $6000 per patient, depending on severity of mucositis. 9 In patients receiving conventional dose chemotherapy for solid tumors, average duration of hospitalization was significantly longer for cycles with mucositis and cost of hospitalization was 60% higher in cycles with oral mucositis. 12 In patients receiving high-dose chemotherapy for HSCT, increased severity of oral mucositis was associated with increased time in hospital, and increased total inpatient charges. 3 A single-point increase in oral mucositis severity was associated with 2.6 additional days in hospital and more than $25,000 in additional hospital charges. 8
Diagnosis of oral mucositis is usually made clinically, based on clinical appearance and a history of cytotoxic cancer therapy within the expected timeframe. It initially presents as erythema of the oral mucosa, which often progresses to erosion and frank ulceration. The ulcerations are typically covered by a pseudomembrane ( Fig. 2 ). The nonkeratinized mucosa is more often affected. Chemotherapy-induced oral mucositis presents 7 to 14 days after initiation of chemotherapy and typically heals within a few weeks after end of chemotherapy. In patients receiving the typical 6 to 7 week regimen of RT for H&N cancer, onset of oral mucositis occurs by the second or third week of RT, and the severity worsens with increasing dose of RT. The areas affected are defined by the field of radiation ( Fig. 3 ). The duration typically extends for several weeks after the end of RT, depending on the size of the lesions. In cases in which the clinical appearance or duration is not consistent with mucositis, secondary infection or an alternative diagnosis should be considered. The most common clinically relevant secondary infections of oral mucositis lesions involve Candida species fungi 19 and HSV. 20 These are more likely to be seen in patients who are immunosuppressed due to chemotherapy or in patients with hyposalivation due to RT.
Several measurement scales are available for oral mucositis. The most commonly used scales for clinical practice are the World Health Organization (WHO) scale ( Box 1 ) and the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) ( Box 2 ).
- Grade 0 = No oral mucositis
- Grade 1 = Erythema and soreness
- Grade 2 = Ulcers; able to eat solids
- Grade 3 = Ulcers; requires liquid diet (due to mucositis)
- Grade 4 = Ulcers; alimentation not possible (due to mucositis)
- Grade 1: Asymptomatic or mild symptoms; intervention not indicated
- Grade 2: Moderate pain not interfering with oral intake; modified diet indicated
- Grade 3: Severe pain interfering with oral intake
- Grade 4: Life-threatening consequences; urgent intervention indicated
- Grade 5: Death
Management of oral mucositis
The goals of mucositis management are to prevent or reduce the severity of the toxicity and to manage the associated symptoms. This, in turn, will allow the continued delivery of cancer therapy without interruption or dose reduction, improving the overall prognosis. General symptom management and targeted therapeutic interventions are discussed in the context of evidence-based clinical practice guidelines developed by the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). These guidelines include recommendations (based on higher level evidence), suggestions (based on lower level evidence), or a determination of “no guideline possible” in cases of inadequate or conflicting evidence.21 and 22
Pain is the most prominent symptom of oral mucositis. Thus, pain control plays a central role in mucositis management. Many centers use a mouth rinse containing a topical anesthetic such as lidocaine, often in combination with other agents such as diphenhydramine, and a coating agent such as Maalox. Due to inadequate evidence, no MASCC/ISOO guideline was possible for such combination rinses. However, the evidence did support suggestions in favor of 0.5% doxepin mouthwash and 2% morphine mouthwash in patients receiving RT for H&N cancer. 23
Although such rinses can provide short-term relief, most patients also need systemic opioid analgesics for adequate pain control. In patients receiving conventional or high-dose chemotherapy, a suggestion in favor of transdermal fentanyl was possible. A recommendation in favor of patient-controlled analgesia with morphine was made for treating oral mucositis pain in patients undergoing HSCT. 23
Several topical coating agents are marketed for oral mucositis, with the rationale that covering the ulcerated area will protect the nerve endings and reduce pain. Although there was inadequate evidence to formulate a guideline on any of the commercial agents, a large number of studies were reviewed related to sucralfate, which is a generically available coating agent. The evidence demonstrated a lack of efficacy for sucralfate and supported recommendations against its use for prevention or treatment of oral mucositis secondary to chemotherapy or RT. 23
Maintenance of good oral hygiene is considered a good clinical practice and can be helpful in alleviating symptoms of oral mucositis. In addition, there is some evidence that maintaining good oral hygiene may reduce the severity of oral mucositis. Therefore, a suggestion was made in favor of using oral care protocols to prevent oral mucositis across all cancer treatment modalities. 24
Severe oral mucositis can compromise oral intake. Such patients need nutritional support from a dietician, including advice on the use of a soft diet and/or liquid diet supplements. Hospitalized patients may be fed via TPN. A gastrostomy tube may be necessary in outpatients, such as patients receiving RT for H&N cancer.
Targeted Therapeutic Interventions
Oral cryotherapy, or oral cooling, involves the placement of ice chips in the mouth. It has been demonstrated that oral cryotherapy, during the administration of chemotherapy drugs with a short half-life, can reduce the severity of oral mucositis. The oral cooling causes vasoconstriction, which decreases the amount of chemotherapy drug delivered to the oral mucosa. The MASCC/ISOO includes two guidelines in favor of cryotherapy: (1) a recommendation for 30 minutes of oral cryotherapy to prevent oral mucositis in patients receiving bolus 5-fluorouracil chemotherapy and (2) a suggestion for oral cryotherapy to prevent oral mucositis in patients receiving high-dose melphalan as conditioning for HSCT. 25
Low-level laser therapy
Treatment of the oral mucosa with low-level laser therapy (LLLT) has been demonstrated to have an antiinflammatory effect and promote healing.26 and 27 The MASCC/ISOO mucositis guidelines recommend the use of LLLT with a wavelength at 650 nm, power of 40 mW, and each square centimeter treated with the required time to a tissue energy dose of 2 J/cm2 to prevent oral mucositis in patients receiving HSCT, conditioned with high-dose chemotherapy. A suggestion was also made for the use of LLLT (wavelength around 632.8 nm) to prevent oral mucositis in patients undergoing radiotherapy, without concomitant chemotherapy, for H&N cancer. No guideline was possible in relation to LLLT in other populations. 28
Growth factors that promote epithelial proliferation can be beneficial in ulcerative oral mucositis. The only drug approved by the Food and Drug Administration for oral mucositis is palifermin, a recombinant human keratinocyte growth factor-1. The MASCC/ISOO guidelines include a recommendation for the use of intravenous palifermin to prevent oral mucositis in patients receiving high-dose chemotherapy and total body irradiation, followed by autologous stem cell transplantation, for a hematological malignancy. 29 On the other hand, granulocyte-macrophage colony stimulating factor was found not effective. Therefore, a suggestion was made against its use for prevention of oral mucositis in patients receiving high-dose chemotherapy for HSCT. 29
Because the inflammatory response to cancer therapy is thought to play an important role in the pathogenesis of oral mucositis, several antiinflammatory agents have been evaluated. Benzydamine is a nonsteroidal antiinflammatory drug that inhibits the production of proinflammatory cytokines, including TNF-α and IL-1β. Benzydamine also has topical analgesic and anesthetic effects. The MASCC/ISOO guidelines include a recommendation in favor of benzydamine mouthwash to prevent oral mucositis in patients with H&N cancer receiving moderate-dose radiotherapy (up to 50 Gy) without concomitant chemotherapy. 30 Benzydamine mouthwash is not commercially marketed in the United States but can be available from a compounding pharmacy. It is worth noting that most patients receiving definitive RT for H&N cancer receive greater than 50 Gy, often with concomitant chemotherapy. Due to lack of efficacy, a suggestion was developed against the use of misoprostol mouthwash (prostaglandin E1 analog) for prevention of oral mucositis in patients with H&N cancer receiving RT. No guideline was possible for any other antiinflammatory agent. 30
Several antimicrobial agents have been tested for oral mucositis based on the rationale that secondary colonization of oral mucositis ulcerations may aggravate their severity. However, results of studies testing antimicrobial agents have been mostly disappointing. The MASCC/ISOO guidelines include a recommendation against the use of polymyxin, tobramycin, amphotericin B (PTA) lozenges and paste; or bacitracin, clotrimazole, and gentamicin (BCoG) lozenges for the prevention of oral mucositis in patients receiving RT for H&N cancer. In addition, a suggestion was made against the use of chlorhexidine mouthwash for mucositis prevention in the same population. 23 It should be noted that this, and all the other MASCC/ISOO mucositis guidelines, apply only to the use of the intervention for the prevention or treatment of mucositis (or mucositis-related pain). Thus, providers may choose to use chlorhexidine for other indications unrelated to mucositis, such as oral decontamination.
Oral mucositis is a significant toxicity of systemic chemotherapy and of RT to the H&N region. The morbidity of oral mucositis can include pain, nutritional compromise, impact on quality of life, alteration in cancer therapy, risk for infection, and economic costs. Management includes general symptomatic support and targeted therapeutic interventions for the prevention or treatment of oral mucositis. Evidence-based clinical practice guidelines are available to guide clinicians in the selection of effective management strategies.
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a Section of Oral Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1605, USA
b Department of Dental Oncology, Northeast Cancer Centre, Health Sciences North, Northern Ontario School of Medicine, 41 Ramsey Lake Road, Sudbury, ON P3E 5J1, Canada
∗ Corresponding author. MC1605 UConn Health Center, 263 Farmington Avenue, Farmington, CT 06030-1605.
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