Grade 1: erythema of the mucosa
Grade 2: patchy ulceration or pseudomembranes
Grade 3: confluent ulceration or pseudomembranes, bleeding with minor trauma
Grade 4: tissue necrosis, significant spontaneous bleeding

Mucositis usually develops two to three weeks after starting RT. The Incidence and severity are variable depending upon the field, total dose and duration of RT, as well as the concomitant administration of chemotherapy. In a retrospective series of 204 consecutive patients who received RT for HNC at M D Anderson in 2002, the incidence of mucositis was 91 percent overall; it was severe (grade 3 or 4, (table 1)) in 66 percent. The incidence in patients treated with RT alone or RT plus chemotherapy (predominantly concomitant) was 85 and 98 percent, respectively. The risk was higher in patients with oral cavity or oropharynx primaries, and in those treated with altered fractionation RT schedules. However, assessment of mucositis is frequently made by looking into the oral cavity when the worst mucositis may be observed in sites like the oropharynx and larynx that are not easily examined without a flexible fiberoptic laryngoscope or similar device.

Mucositis is managed symptomatically with scrupulous oral hygiene, dietary modification, and topical anesthetics. Topical anesthetics may be combined with an antacid suspension and/or diphenhydramine (for local drying effect) with or without nystatin in a "cocktail," commonly termed "Miracle Mouthwash". One such cocktail used for local pain control consists of 2 percent viscous lidocaine; diphenhydramine; and Maalox (sometime termed Miracle mouthwash and available commercially as FIRST®-Mouthwash BLM). Other "cocktails" add dexamethasone solution as an antiinflammatory, or antibiotics such as tetracycline. Care should be advised for patients using rinses containing lidocaine to avoid further trauma to the anesthetized mucosa.

Acidic or spicy foods, sharp foods (eg, chips), caffeine, alcoholic beverages and alcohol-containing mouthwashes should be avoided in symptomatic patients. In addition, secondary bacterial, fungal (eg, oral candidiasis), and viral (eg, herpes simplex virus) infections should be treated with appropriate antimicrobials. (See "Oral toxicity associated with chemotherapy".)

A variety of other agents have been evaluated either prophylactically or after the onset of symptoms; their role in the treatment of radiation-induced mucositis is uncertain.

Sucralfate — The bulk of evidence from placebo-controlled trials suggests that prophylactic sucralfate mouth washing during RT does not reduce the degree of mucositis

Amifostine — In contrast to the situation with xerostomia, the benefit of amifostine in terms of mucositis is uncertain, particularly among patients receiving chemoradiotherapy; the results of randomized trials with mucositis as an endpoint are conflicting . Published guidelines from ASCO do not recommend amifostine to prevent RT-related mucositis, but do recommend its use be considered to decrease the incidence of acute and late xerostomia

Helium-neon laser therapy — Several controlled trials have provided evidence that pretreatment with low energy helium-neon laser therapy (LEL) reduces mucositis associated with chemotherapy. In a double-blind, multicenter study, 30 patients with carcinoma of the oropharynx, hypopharynx and oral cavity that was treated with RT alone were randomized to LEL or placebo light treatment, starting on the first day of RT and before each session [34]. LEL therapy was associated with significant reductions in the frequency of both grade III mucositis (8 versus 35 percent) and severe pain (2 versus 24 percent). (See "Oral toxicity associated with chemotherapy".)

While the results of this single-institution study are encouraging, the general application of LEL for prophylactic treatment for RT-induced mucositis cannot be advocated until its safety and efficacy are verified in a multiinstitutional trial. Furthermore, a better understanding of the mechanism of action and the potential interaction with RT is necessary. Limitations of LEL treatment include the need for specialized equipment and lack of information on treatment-related complications.

GM-CSF and G-CSF — In pilot studies, recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), given either subcutaneously (5 microg/kg for five days) or topically (400 microg/day) beginning with the experience of oral pain or after the administration of a portion of the RT dose, significantly reduced the severity of mucositis However, three of four subsequent randomized trials failed to demonstrate any benefit for either subcutaneous or topical GM-CSF in this setting

The only trial to suggest a possible benefit for subcutaneous administration of granulocyte colony-stimulating factor (G-CSF) was a small double-blinded trial in which 41 patients undergoing postoperative RT after HNC resection were randomly assigned to a daily subcutaneous injection of G-CSF (3 microg/kg) or placebo during RT (63 Gy in daily 1.8 Gy fractions). There was a nonsignificant trend toward lower mucositis severity, shorter mean duration of RT, and less need for gastrostomy tube placement in the G-CSF group.

The role of G-CSF in mucositis prophylaxis remains uncertain, particularly in view of the results of a large randomized German trial which showed less mucositis but significantly worse locoregional control and survival in patients with advanced HNC treated with hyperfractionated radiotherapy or chemoradiotherapy plus G-CSF, compared to those receiving the same treatments without G-CSF

KGF — Other growth factors including keratinocyte growth factor (KGF, palifermin) may accelerate epithelial restoration. Completed and ongoing trials of palifermin, recombinant human keratinocyte growth factor show promise that this drug may ameliorate both the incidence and duration of severe mucositis [42].

Topical protectants/anesthetics — A mucosa-adhesive, water-soluble film, containing topical anesthetics and antibiotics (tetracaine, ofloxacin, miconazole, guaiazulene, and triacetin) may be beneficial for symptom control. Others have shown efficacy for topical application of tetracaine gel alone Neither of these products is available in the United States.

Two nonprescription products, Oratect® gel (which contains benzocaine) and Gelclair® gel, may provide a temporary protective barrier for inflamed mucosal tissues, especially the lips, especially if applied prior to eating. Polaprezinc (zinc L-carnosine), a gastric mucosal protective drug, appeared to reduce oral mucositis associated with chemoradiation therapy in a small trial

Benzydamine is an NSAID with topical antiinflammatory, analgesic, anesthetic, and antimicrobial activity. In a double-blind placebo-controlled trial, benzydamine oral rinse (15 ml for 2 minutes, 4 to 8 times daily) during RT was associated with significantly better freedom from ulceration (33 versus 15 percent), and a delay in the use of systemic analgesics during conventional (≤ 50 Gy), but not accelerated fractionation (≥ 2.2 Gy daily) RT.

Updated clinical practice guidelines developed by the Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology recommend the use of benzydamine for prophylaxis of radiation-induced mucositis in patients with head and neck cancer receiving moderate dose RT (≥50 Gy). However, this agent is not available in the United States. A confirmatory placebo-controlled trial is assessing its value as a mucosal protectant in patients undergoing RT for head and neck cancer, which if positive, may lead to the availability of this drug in the United States.

Glutamine — A small pilot trial randomized 17 patients with HNC who were receiving primary or adjuvant RT to oral glutamine (2 g in 30 mL normal saline four times daily) or placebo during therapy [47]. The glutamine group had a shorter duration and severity of objective mucositis (maximum grade 1.6 versus 2.6).

A benefit for intravenous l-alanyl-l glutamine was suggested in a second randomized double-blind placebo-controlled trial, conducted in 32 patients undergoing CRT for HNC [48]. Fewer patients who received a daily dose of intravenous glutamine had severe objective mucositis (14 versus 67 percent), and these patients also experienced significantly less pain, and need for feeding tubes (14 versus 60 percent, respectively).

Confirmation of these results in larger controlled trials is needed. Until then, updated guidelines for prevention and treatment of mucositis from the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology recommend that systemic glutamine not be used for the prevention of gastrointestinal mucositis in any setting

Zinc sulfate — Oral zinc sulfate may be beneficial in treating and preventing mucositis In one trial, 30 patients were randomly assigned to zinc sulfate (220 mg [50 mg elemental zinc] three times daily) or placebo, during and for six weeks after RT. The severity of mucositis was significantly less in the zinc group (grade 3 or 4 in 0 versus 8 patients); furthermore, mucositis developed later, and started to improve earlier with zinc. These results require additional confirmation.

Pain control — Despite local measures, pain may be significant during and shortly after the course of RT. Long acting opiates should be used as needed during the treatment period. For patients who cannot swallow long-acting morphine or oxycodone pills, transdermal fentanyl may provide good pain relief. Short acting opiates should be used for breakthrough pain. Long acting opiates should not be crushed and put in feeding tubes.

Limited evidence suggests that gabapentin may be useful for the treatment of pain associated with radiation-induced mucositis

Nutritional disturbances — A variety of factors can contribute to nutritional deficiency in patients with HNC who receive RT. Many patients present with weight loss related to dysphagia and/or odynophagia. This problem is often compounded by significant nutritional deficiencies associated with lifestyle before diagnosis, and treatment-related dysphagia if RT is delivered to large areas of the oral-pharyngeal mucosa or salivary glands.

Nutrition and swallowing should be assessed prior to starting RT in order to determine the need for intervention and to provide instructions about appropriate food choices and methods to promote mastication and deglutition. In general, frequent, small portion meals consisting of soft solids and liquids are recommended. Patients experiencing significant weight loss (ie, greater than 5 to 10 percent) or recurrent episodes of dehydration require alternative methods of feeding such as a gastrostomy tube.

Nutritional support during RT — Retrospective series suggest that head and neck cancer patients who receive nutritional support have less weight loss and fewer hospitalizations for treatment-related complications. As an example, in an observational series of 88 patients with locally advanced HNC treated with accelerated twice daily RT (n = 59) or concurrent chemoradiotherapy (n = 29), 36 had undergone prophylactic percutaneous gastrostomy (PEG) tube placement prior to starting therapy. Enterally supplemented patients had significantly less average weight loss during therapy (3.1 versus 7.0 kg), required significantly fewer hospitalizations for dehydration and malnutrition, and fewer patients had interruptions in their cancer treatment (0 versus 18 percent).

On the other hand, a randomized trial failed to demonstrate that the benefits attributed to enteral nutritional support definitely translate into improved outcomes among patients with HNC undergoing RT. In this study, 40 patients with inoperable squamous cell carcinoma of the nasopharynx and oropharynx were randomly assigned to oral nutrition or intensive nasogastric tube feedings during RT  Despite the significantly higher caloric intake of the NG-supplemented group, and less weight loss during treatment in this group, radiation response rates and overall survival were similar. Slightly more patients who received tube feedings returned to their regular activities after six months of follow-up, compared to controls (62 versus 45 percent).

Aggressive oral nutritional support may provide similar benefit to gastrostomy feedings, as illustrated by the following two trials:

In one trial, patients undergoing RT for HNC were randomly assigned to aggressive oral feeding with nutritional supplements or no additional nutritional support . Treatment-related toxicity necessitated interruption of RT in significantly more patients not receiving nutritional support (5 of 12, compared to 0 of 11). However, radiation outcomes were not reported.

A benefit for dietary counseling was suggested in a trial in which 75 head and neck cancer patients undergoing RT were randomly assigned to dietary counseling with regular foods (n = 25), usual diet plus supplements (n = 25), or usual diet only [37]. At three months, patients who received dietary counseling improved their oral intake while those in the other two groups returned to, or below, baseline. This group also had the greatest improvement in anorexia, xerostomia, and dysgeusia at three months. QOL outcomes also favored dietary counseling

One area of oncology in which PEGs appear to have a relatively proven track record is in patients with head and neck cancer. Head and neck cancers are commonly diagnosed when they are already in advanced stages. Aggressive chemotherapy and radiotherapy can lead to dysphagia, odynophagia, dehydration, and malnutrition, which can result in interruption of treatment and frequent hospitalization [28].

The benefit of PEGs in this setting was illustrated in a retrospective study that included 88 patients of whom 32 (40 percent) received a prophylactic gastrostomy tube. Patients who received a PEG tube had an average of 3.1 kg of weight loss compared to a loss of 7.0 kg in patients without a PEG tube. In addition, the PEG group required significantly fewer hospitalizations for dehydration and malnutrition and had no interruptions in their cancer treatment compared with interruptions in 18 percent of patients in the non-PEG group.

An additional study confirmed the positive impact of early PEG and enteral nutrition on maintaining weight and preventing cancer treatment interruptions in a group of 151 head and neck cancer patients undergoing radiochemotherapy

Long-term quality of life may be affected by the presence of PEG tubes following primary surgery for oral and oropharyngeal cancers Follow-up of 243 patients who had surgery for oropharyngeal cancer noted that those patients with PEG tubes still in place (median 34 months) had a poorer quality of life than patients who had their PEG tubes removed (median seven months) . The major PEG tube-related problems were not leakage, blockage, or discomfort, but interference with family life, intimate relationships, social activities, and hobbies.

A secondary analysis of 1073 patients receiving pretreatment, intratreatment, or posttreatment nutrition support during chemo-radiation therapy of head and neck cancer found that providing nutrition support before treatment resulted in a poorer five-year survival and locoregional control. However, the poorer survival may have been due to selection bias; patients who received nutrition support before therapy also had a worse pretreatment cancer staging, Karnofsky performance status, and degree of weight loss. Patients receiving pretreatment nutrition therapy experienced less weight loss during therapy and less severe mucositis.