Mucositis

The most troublesome acute reaction for patients receiving radiation therapy to the oral cavity is radiation-induced mucositis. Acute mucositis results from the loss of squamous epithelial cells owing to the sterilization of mucosal stem cells and the inhibition of transit cell proliferation. This leads to a gradual linear decrease in epithelial cell numbers. As radiation therapy continues, a steady state between mucosal cell killing and mucosal cell regeneration may occur because of an increased cell production rate from the surviving cells. Usually, however, cell regeneration cannot keep up with cell killing, and partial or complete denudation develops. This presents as patchy or confluent pseudomembranous mucositis. Healing eventually occurs when cells regenerate from the surviving mucosal stem cells. The loss of the epithelial barrier enhances insults from physical, chemical, and microbial agents. It has been reported that the oropharyngeal flora may contribute to radiation therapy-induced mucositis. However, which flora are involved and which step in the mucositis process may be preventable from eliminating the offending flora remains unknown. One hypothesis is that endotoxins produced by gram-negative bacilli are potent mediators of the inflammatory process.

The oral cavity mucosa, having a relatively high turnover rate, changes early during a course of fractionated external-beam radiation therapy. With 200-cGy fractions per day, 5 d/wk, mucosal erythema is typically noted within the first week of treatment. By approximately 2 weeks, the erythematous mucosa develops small whitish yellow patches called patchy pseudomembranous mucositis. These pseudomembranes represent collections of dead surface epithelial cells, fibrin, and polymorphonuclear leukocytes on a moist background. This acute reaction is typically accompanied by oral discomfort. In many patients, the patchy mucositis becomes confluent by the third week of radiation therapy and can be associated with significant pain.

The severity of mucositis is related to the daily dose of radiation therapy, the total cumulative dose, and the volume of irradiated tissue. At 170- to 180-cGy daily fractions, 5 d/wk, the maximal reaction is typically intense erythema with occasional patchy mucositis. In this situation, the cell killing and repopulation of epithelial stem cells are in near equilibrium. If the daily dose is increased to 200 cGy or more and the treatment volume is large (the entire oral cavity), cell killing will exceed the proliferative capacity of the epithelial stem cells, and almost all patients will develop confluent mucositis by the third week of radiation therapy. Mucositis first appears and is often most severe on the mucosa of the soft palate, tonsillar pillars, buccal mucosa, lateral border of the tongue, and pharyngeal walls. By contrast, mucositis less frequently involves the hard palate, gingival ridges, and the dorsum of the tongue during a course of radiation therapy or, alternatively, only after very high doses. Patients with metallic dental restorations frequently develop a prominent mucositis on the adjacent buccal mucosa and/or the lateral border of the adjacent tongue due to backscattering of low-energy electrons.

Symptoms of oral discomfort are usually maximal 2½ to 3 weeks into the course of radiation therapy. Thereafter, symptoms usually plateau and may even diminish, even though treatment is continued. Following external-beam radiation therapy, the mucous membranes normally heal within 2 to 4 weeks, although an occasional patient may require several weeks or months. The mucositis produced by an interstitial radioactive implant typically appears 7 to 10 days after removal and is maximal approximately 2 weeks after removal. The mucositis generally heals by 6 weeks, unless the implanted volume was large, in which case complete healing may require several months.

Radiation-induced oral mucositis can result in intense pain, which may substantially limit adequate hydration and nutrition, prevent proper oral hygiene, serve as a portal for infection, and affect speech. All these effects can significantly interfere with the general well-being of the patient and may tempt the treating physician to interrupt the course of treatment to permit resolution of the acute symptoms. At times the treatment may be discontinued altogether before delivery of a potentially curative dose of radiation therapy. Rapidly accumulating clinical and radiobiologic evidence shows that the protraction of overall treatment time adversely influences the radiocurability of certain human tumors, particularly squamous cell carcinomas of the head and neck region. In a retrospective study of nearly 500 patients with squamous cell carcinoma of the oral cavity and oropharynx, overall treatment time was found to influence significantly the probability of local tumor control. The additional dose needed to compensate for a protracted course of radiation therapy has been attributed to an accelerated tumor clonogenic growth rate. Several retrospective studies and randomized clinical trials have demonstrated improved local control and survival using altered fractionation schemes that deliver conventional or higher doses of radiation therapy over a shorter-than-conventional period.  Therefore, a break in radiation therapy because of mucositis may lead to treatment failure.

Prevention and Treatment

In light of the serious deleterious effects that radiation-induced oral mucositis may have on a patient's well-being and the potential loss of tumor control that may result from an interruption or prolongation of treatment because of mucositis, measures for preventing mucositis are being investigated. One small trial studied the use of a benzydamine hydrochloride rinse for preventing radiation-induced mucositis.  Benzydamine hydrochloride, a nonsteroidal drug, possesses analgesic, anesthetic, anti-inflammatory, and antimicrobial properties. Its action may be mediated by the prostaglandin system. Forty-three patients undergoing radiation therapy to the oropharyngeal region (4,500 cGy in 15 fractions in 3 weeks, or 6,000 cGy in 25 fractions in 5 weeks) were randomized (double-blind, placebo-controlled) to use either benzydamine hydrochloride or a carrier base "placebo" consisting of 10 percent alcohol and artificial flavor and color. All 25 patients randomized to benzydamine hydrochloride were evaluable, while 6 of 18 placebo patients did not comply with the protocol and were thus removed from the study and not included in the statistical analysis. The total mucositis score was less in the benzydamine group than in the placebo group. The average area of mucositis during radiation therapy and the maximum mucositis score were also reported to be significantly less in the benzydamine group. In addition, maximum size of ulceration and total area of ulceration  were significantly less in the benzydamine group. While not statistically significant, trends were seen in favor of the benzydamine group for less pain reported at rest , less pain with eating, greater pain reduction ( P = 0.07), and improved anesthesia . Thus, this study provided preliminary evidence suggesting that benzydamine might be beneficial in patients undergoing radiation therapy to the oral cavity.

In another small trial, 25 patients receiving radiation therapy (6,000 cGy in 30 fractions over 6 weeks, or 5,400 cGy in 18 fractions over 6 weeks) to the oral cavity were randomized to use mouthwashes consisting of benzydamine or chlorhexidine. This trial reported similar average pain scores, average mucositis grades, candidal carriage rates, and coliform bacteria carriage rates in the two treatment groups. However, patients randomized to receive the chlorhexidine mouthwash tolerated that rinse better. Furthermore, fewer patients using chlorhexidine required a prolongation of radiation therapy because of oral symptoms. These authors concluded that chlorhexidine and benzydamine showed little difference in controlling overall pain and mucositis, or the oral carriage of Candida species and coliform bacteria. Since patients better tolerated the chlorhexidine mouthwash, its use was preferred.

Four recently reported trials used the combination of three relatively nonabsorbable antibiotics (tobramycin, polymyxin E, and amphotericin B) in patients undergoing radiation therapy to the oral cavity. A prospective study reported by Spijkervet  compared data from 15 patients receiving this antibiotic lozenge to data from 15 patients in each of two groups that had previously been randomized to receive a chlorhexidine mouthwash or a placebo mouthwash. In all patients using the antibiotic lozenges, eradication of gram-negative bacilli was achieved within 3 weeks, whereas no effects on these flora were observed in the chlorhexidine or placebo groups . The severity and extent of mucositis were also significantly reduced in the 15 patients receiving the antibiotic lozenge. All patients in the antibiotic lozenge-treated group developed erythema only, whereas 80 percent of the placebo- and chlorhexidine-treated patients suffered severe mucositis with extensive pseudomembranes starting in the third week of a conventional radiation therapy protocol. No nasogastric tube feedings were required in the antibiotic lozenge-treated group, compared to 30 percent of patients in the chlorhexidine- and placebo-treated groups. Another small pilot study, performed by Mulkens et al.,  involved 25 patients. The maximum degree of mucositis noted was grade 2 (World Health Organization [WHO] scoring system), and no treatment interruption or nasogastric tube feedings were required.

The results of a randomized, placebo-controlled, double-blind study have been reported by Symonds  A total of 275 patients were randomly allocated to suck four times daily a pastille containing amphotericin, polymyxin, and tobramycin  or an identical-appearing placebo . A large number
of patients were inevaluable ( n = 54) and there was a slight imbalance in the site of the disease. No statistically significant difference was found in the primary study endpoint (percentage of patients who developed intermediate changes or pseudomembranes, 36 percent vs. 48 percent; ). The comparison of the worst recorded mucositis grade was statistically significantly different favoring the active pastilles  indicating a beneficial effect, the magnitude of which was probably smaller than the trial was designed to detect. There was a reduction in mucositis distribution , mucositis area , dysphagia ), and weight loss  in the active arm.

Members of the NCCTG also performed a randomized, placebo-controlled, study in which patients receiving radiation therapy to the oral cavity were randomized to receive a placebo, a chlorhexidine mouthwash, or an antibiotic lozenge. Fifty-eight patients were randomized to receive placebos (mouthwash or lozenge), 25 received a chlorhexidine mouthwash, and 54 received antibiotic lozenges. There was a trend for more mucositis and there was substantially more toxicity on the chlorhexidine arm, so it was discontinued after a planned interim analysis. It appeared that the chlorhexidine mouthwash was actually detrimental. In addition, there were no substantial differences or trends in mucositis scores between the antibiotic lozenge and placebo arms as measured by health care providers. However, the mean patient-reported mucositis score and the duration of patient-reported grade 3 to 4 mucositis were both lower in patients randomized to the antibiotic lozenge arm . Thus, these four trials (two pilot and two randomized, placebo-controlled) suggest that nonabsorbable antibiotics can decrease mucositis modestly. These trials, however, do not provide convincing enough data of sufficient clinical magnitude to make them recommended as part of standard practice.

The inability to control mucositis-related pain can be frustrating for both the patient and the treating physician. In a small trial, 18 patients were randomized in a double-blind study to test the efficacy of (1) viscous lidocaine with 1 percent cocaine; (2) dyclonine hydrochloride 1.0 percent; (3) a mixture of kaolin-pectin solution, diphenhydramine, and saline; and (4) a placebo solution. Four of the patients did not complete the study. No significant difference was found among the four solutions when pain relief and duration of relief were compared, but the power to detect any statistical difference was poor because of the small patient number. Janjan  recently reported improved pain management in patients undergoing radiation therapy for head and neck cancer with daily nursing intervention consisting of instructions on the use of mouthwashes and a three-step analgesic protocol consisting of acetaminophen; acetaminophen with codeine suspension; and liquid morphine for mild, moderate, and severe pain. Patients were seen daily by a radiation oncology nurse, who serially reviewed a 15-question pain survey completed by the 19 study patients before each radiation treatment. A physician promptly changed the prescribed analgesic regimen when the patient's symptoms changed. Marked differences in the control of pain related to radiation mucositis were observed when compared with patients from a prior study who used the same daily survey but had sporadic nursing intervention and no analgesic protocol. Patients having daily nursing intervention reported fewer days of moderate and severe pain; had less pain throughout the day; and noted less disturbance in sleep, eating, and energy level. Weight loss of greater than 5 kg was noted in only 3 of 19 patients. Analgesics were used on 77 percent of treatment days and relieved all or most of the pain on 94 percent of these days. Thus, daily review of a symptom survey by a radiation oncology nurse combined with a well-defined strategy for mouth care and analgesics appeared to improve pain management of radiation-induced oropharyngeal mucositis because of prompt attention to patient needs.

New ways of preventing or minimizing radiation-induced mucositis are being evaluated. One such idea involves the use of a sucralfate suspension, an agent that appears to provide a protective barrier and may also have a cytoprotective effect. The latter may be mediated through prostaglandin release, resulting in increased mucosal blood flow, increased mucous production, increased mitotic activity, and a surface migration of cells.  However, results from small double-blind, placebo-controlled, randomized prospective trials are contradictory. Epstein  found that prophylactic oral rinsing with sucralfate did not prevent radiation-induced oral ulcerative mucositis. Franzen  noted a significantly lower proportion of patients with severe mucosal reactions in their sucralfate group than in the placebo group. One report suggested that a combination of sucralfate and fluconazole may be effective in diminishing oral discomfort and pain associated with radiation and chemotherapy. In total, however, the randomized trials of sucralfate for therapy-induced mucositis do not establish a role for sucralfate in clinical practice.

To evaluate another intervention, Maciejewski  reported that painting the buccal mucosa with a 2 percent silver nitrate solution for several days before radiation therapy stimulates normal mucosa repopulation during radiation therapy, producing significantly less acute mucosal reaction and faster mucosal healing after completion of radiation therapy. This unique approach to the problem of acute mucositis deserves further study. Other preliminary data have investigated (1) the direct application of a prostaglandin E2 gel,  (2) the use of a combination of beclomethasone dipropionate and sodium alginate,  and  daily subcutaneous GM-CSF.  Based on preliminary data, the Radiation Therapy Oncology Group is about to open a Phase II study to evaluate the radioprotection of oral and pharyngeal mucosa by the prostaglandin E1 analog misoprostol used as an oral rinse. Perhaps one of the most promising avenues of research in this field is the investigation of the radioprotector amifostine. One small  and one large   randomized clinical trial have been reported suggesting that amifostine reduces the incidence and severity of acute mucositis and xerostomia  and late xerostomia and loss of taste without a detrimental affect on tumor control or survival.

One should not forget the role that sophisticated radiation therapy treatment planning can have in limiting the volume of normal tissues irradiated and thereby reducing the severity of normal tissue reactions. Kaanders  recently reported that normal tissue reactions can be reduced in a substantial number of head and neck cancer patients with the use of simple, custom-made, intraoral devices designed to exclude uninvolved tissues from the treatment portals or to provide shielding of tissues within the treatment volume. Patients with primary cancers of the oral cavity, oropharynx, paranasal sinuses, and salivary glands are most suitable for the use of such devices. These intraoral stents can be very useful in excluding the mucosa of the tongue and floor of mouth when treating hard palate, nasal cavity, and paranasal sinus malignancies. These same stents can be useful in excluding the palate mucosa when treating the tongue or floor of the mouth. Shielding stents using a lead alloy were found to be useful when treating well-lateralized tumors of the oral cavity, parotid gland, lip, and skin of the cheek. These shielding stents can decrease the amount of radiation delivered to the contralateral mucosa. More frequent use of electron beam and/or sophisticated multibeam, wedged-pair, or oblique treatment plans will also help exclude or minimize radiation dose to uninvolved mucosa. Packing gauze between metallic dental restorations and mucosa of the lateral tongue and buccal area appear to be very beneficial in minimizing dose from scattered radiation.

Given the data presented above, what measures should be taken to prevent/treat mucositis in patients receiving radiation to the oral cavity? Standard practice often includes aggressive, good oral hygiene consisting of teeth brushing after each meal, using a soft toothbrush and baking soda toothpaste, and rinsing the mouth every 2 hours throughout the day using a half-strength hydrogen peroxide or alkaline solution. Patients should be instructed to avoid the use of irritating or abrasive substances such as commercial toothpastes and mouthwashes; tobacco; alcoholic beverages; extremely hot or cold drinks or foods; very spicy foods; acidic foods such as citrus fruits and their juices; and foods that are hard and coarse, such as pretzels, raw vegetables, potato chips, crackers, or hard bread. When discomfort develops, topical anesthetic agents can be used. As the pain progresses, systemic analgesics including acetaminophen with codeine suspension or oral morphine sulfate elixir may become necessary. Suspensions are preferred over elixirs, since they are formulated without alcohol. As suggested by Janjan   daily intervention by a radiation therapy nurse or physician with prompt escalation of systemic analgesics appears to result in improved pain control, better patient feeling of well-being, and less weight loss. Whether the use of prostaglandin gels, or rinses, or amifostine will help prevent or minimize mucositis awaits further study in randomized, controlled clinical studies.

The mucosa of patients undergoing radiation therapy to the oral cavity should be examined at least once a week and antibiotic or antifungal medications prescribed as infections are documented. Clotrimazole troches, one dissolved in the mouth five times a day for 14 days, generally works well for oral candidiasis. However, if significant mucositis or xerostomia has developed, it may be very difficult to dissolve lozenges in the oral cavity. In this situation, nystatin oral suspension or fluconazole tablets or liquid are often effective.