Oropharyngeal Mucositis in Cancer Therapy
Oropharyngeal Mucositis in Cancer Therapy
Oropharyngeal mucositis is the most common distressing and disabling acute complication of cancer chemotherapy and radiotherapy,[ 2] as reported by patients, and is among the most significant dose-limiting toxicities of cancer therapy.[3-5] The condition is characterized by mucosal changes including erythema, ulceration, and oropharyngeal pain. Oropharyngeal mucositis is caused by numerous cancer therapies, including common treatments for head and neck cancer and for epithelial cancers at other body sites (eg, gastrointestinal, lung); mucositis is also common in patients receiving intensive chemotherapy- with or without total-body irradiation-associated with neutropenia and hematopoietic cell transplantation (HCT).
Few interventions have proven effective for prophylaxis of mucositis. Review of the literature reveals that most studies are of limited value due to scientific design deficiencies and/ or small patient populations in many trials. Currently, there are no universally accepted treatment protocols that allow for the prevention of oral mucositis. Future studies, however, will be aided by our increasing understanding of the pathogenesis of mucositis, and controlled randomized trials are leading to the development of guidelines for management. As our understanding of what truly causes mucositis improves, new approaches can be developed to specifically target steps in the evolution of mucositis and to repair the involved mucosal surfaces.
This paper is based on a review of Medline and CancerLit and presents an overview of current management and an outline of developments in oral mucositis research and patient care.
Review of the literature reveals a wide range in the frequency of oropharyngeal mucositis following cancer therapies. This side effect occurs in 30% to 75% of chemotherapy patients, up to 90% of patients receiving HCT, and essentially 100% of patients receiving head and neck irradiation in doses over 5,000 cGy. Ulcerative mucositis is the most common cause of severe pain in HCT and treatments for hematologic cancer. Although advances in HCT have led to a modest reduction in the frequency of severe oral ulcerative mucositis in these patients, changes in the treatment of head and neck cancer (including combined chemotherapy and irradiation and changes in radiation therapy dosing schedules) have increased the severity and duration of mucositis in these patients.
Oropharyngeal mucositis typically develops within 7 to 14 days after the initiation of chemotherapy or radiotherapy. Pain associated with mucositis can be intense and interfere with normal oral function, including speech and oral intake of food and medication; such pain also significantly affects quality of life,[1,2,6,7] frequently requiring opioid analgesics and possibly leading to hospitalization and interruption of the planned cancer therapy (Table 1). Radiation-induced mucositis is the result of progressive and repeated damage associated with the cumulative dose. Typically oropharyngeal mucositis begins at doses of approximately 10 to 20 Gy of standard fractionated head and neck radiation therapy but is limited to the field of radiation. Initial mucosal whitening due to transient hyperkeratinization may occur prior to erythema, or oropharyngeal mucositis may first manifest as erythema, followed by mucosal ulceration, which often arises at more than 30 Gy. Advanced mucositis presents as ulceration with or without a pseudomembrane and surrounding erythema. Mucosal lesions that extend beyond the field of radiation often represent secondary infection due to candidiasis or herpes simplex virus (HSV) reactivation. It generally takes 3 to 6 weeks for oral tissues to heal following the end of radiation therapy. In contrast, chemotherapy-associated oropharyngeal mucositis presents initially on the nonkeratinized (movable) mucosa of the soft palate, ventral tongue/floor of mouth, and buccal and labial mucosa. Neutropenia may complicate recovery and increase the risk of bacterial and fungal invasion and infection. Healing typically occurs in 2 to 3 weeks following completion of cancer chemotherapy, although, with more aggressive cancer treatment protocols, mucositis may persist more than 4 weeks after therapy.
Mucositis has been hypothesized to include several phases: (1) an initial phase characterized by changes in the submucosal connective tissue and vasculature (2) an epithelial phase, (3) an ulcerative/bacteriologic phase, and (4) a healing phase.[8, personal communication, S. Sonis, 2003]
Early changes occur in the connective tissue associated with the production of reactive oxygen species and proinflammatory cytokines such as interleukin (IL)-2, IL-6, and tumor necrosis factor (TNF)-alpha. Biopsies from patients prior to and during radiation therapy with resulting mucosal inflammation have shown early changes in cell surface molecules, with an increase in RM3-1 and ICAM-1. It has been proposed that epidermal growth factor (EGF) may increase the risk of mucositis if it is expressed when keratinocytes are at risk for direct cytotoxicity, and cytokines that reduce epithelial cell proliferation (eg, transforming growth factor [TGF]-beta-3) may decrease the severity of tissue damage when expressed during the early phases of mucositis. Clearly, a large number of pathways are likely involved, with activation of a nuclear transcription factor (NF-kappaB) leading to gene activation and expression. These processes can ultimately result in increased apoptosis and inflammation. The oral microflora may further complicate ulcerative lesions and be associated with increased ulceration/pseudomembrane formation. The outcomes of mucosal infection following mucosal damage are conditioned by the potential impact of systemic therapy upon the hematopoietic system and subsequent immune dysfunction. Resolution of mucositis is dependant upon the production of growth factors, angiogenesis, and epithelial cell regeneration/ migration, which may be enhanced by white blood cell function.[10-12]
Recent studies have suggested the influence of genetics on the course and severity of chemotherapy-induced mucositis. Methotrexate, an antifolate, interferes with nucleotide synthesis to produce its anticancer effect. However, it has also been shown to be very damaging to oral mucosa. Researchers have proposed that the activity of the folate enzyme, 5,10- methylenetetrahydrofolate reductase (MTHFR), modifies the toxicity of methotrexate. Activity of the MTHFR gene varies between the wild genotype (CC), the heterozygous CT (with 60% of the activity of CC genotypes), and the homozygous TT (30% of the activity of CC types). In a study of allogeneic HCT patients receiving methotrexate prophylaxis of acute graft-vs-host disease (GVHD), mucositis severity was found to vary significantly between the various genotypes, with the TT genotypes having more mucositis than the CC genotypes. This study is an example of how pharmacogenomics may lead to the ability to identify how different genotypes react to different chemotherapeutic agents, perhaps resulting in the ability to predict mucositis susceptibility and to customize doses of agents to not only reduce mucositis, but also improve the effectiveness of cancer therapies.
Pain associated with mucositis depends upon the degree of tissue damage, sensitization of pain receptors, elaboration of inflammatory and pain mediators, and individual variation. Pain scores associated with oral mucositis have been shown to closely parallel the severity of mucosal damage.
General Risk Factors
The risk factors for oropharyngeal mucositis have not been well established, although some cancer treatment protocols are known to put patients at high risk. Clinical experience has demonstrated a clear propensity for certain chemotherapy agents to cause oral mucositis. As dose intensity is increased, generally so does the severity of mucositis. Numerous non-cancer therapy variables have been suggested to increase the risk of mucositis, including such factors as poor oral hygiene, tobacco use, xerostomia at baseline and during chemotherapy, as well as lower baseline neutrophil counts, blood urea nitrogen, creatinine, older age, and use of total-body irradiation for HCT conditioning.[ 14-16] However, study design deficiencies similar to those that have hampered mucositis prevention trials also affect acceptance of the results of these studies. The potential for nonlinked factors must be considered for many previously reported associations. In HCT and intensive chemotherapy that results in severe immunosuppression, mucositis can be complicated by reactivation of HSV and candidal colonization of the mouth. The role of the "normal" oral flora and microbial end-products in oral mucositis is not clear, although many suggest that dental plaque affects the severity of mucositis.[14-19] In one study, intensive oral hygiene was shown to reduce the observed risk of oral mucositis by 70% in HCT patients, delaying the time to onset of mucositis and decreasing the duration of moderate/ severe mucositis. Moreover, septicemia was not increased in patients maintaining intensive oral care. Although HSV prophylaxis clearly has reduced the frequency of severe ulcerative mucositis in HCT patients, oral ulcerative mucositis is still found in more than 75% of HCT recipients conditioned with high-dose chemotherapy, with or without total-body irradiation. Reduced plasma levels of glutathione (GSH) have been shown to predict the severity of acute radiation mucositis, suggesting a radioprotective role of GSH either due to protection against membrane lipid oxidation or DNA damage. Immunoglobulins, EGF, and antimicrobial proteins in the saliva are decreased following conditioning for HCT, which may be a factor in the increased risk of mucosal infection and mucositis.
Diagnosis is currently clinical, based on oral examination findings, and supported by the timing, nature, and location of oral lesions. Sequential examination reveals progressive erythema and atrophy of involved tissues. The tissues at greatest risk for oropharyngeal mucositis are the nonkeratinized tissues. Ultimately, if inflammation and epithelial damage are severe enough, ulceration can occur. Many of the oral sites involved with ulcerative mucositis may have a traumatic component due to secondary damage caused by trauma associated with oral function. Ulcerations associated with oropharyngeal mucositis are usually covered by white to light yellow fibrin-exudate pseudomembranes. In patients who are also thrombocytopenic, bleeding can complicate the ulcers. Early fungal and viral infections and-in the case of allogeneic HCT recipients-acute GVHD can complicate the diagnosis in patients at risk for mucositis. In patients receiving radiation therapy, oropharyngeal mucositis is confined to radiation portals. As noted earlier, damage extending beyond irradiation fields is usually associated with secondary infections. Whereas HSV infections typically involve keratinized oral tissues (gingiva, palate, dorsal tongue) in immunocompetent patients, immunocompromised cancer therapy patients are at risk for lesions on both keratinized and nonkeratinized mucosal surfaces. Viral lesions in immunosuppressed hosts may present initially as clusters of rounded 1-to 2-mm ulcers that can quickly coalesce to cause extensive areas of ulceration. In the neutropenic patient who is at risk for viral infection, viral culture or use of direct immunofluorescence with exfoliative cytology at the time of lesion presentation is prudent. Candida presents most commonly as white adherent patches and/or erythema, most often involving the hard and soft palate, tongue (dorsal and lateral borders), and buccal mucosa.
GVHD develops following hematologic recovery following HCT. Acute GVHD occurring within the first 4 weeks post-HCT may overlap with resolving mucositis and complicate diagnosis. Oral GVHD involves tissue sites similar to those affected by mucositis, but if conditioning- induced mucositis appears to be worsening 18 to 28 days post-HCT, especially as peripheral blood counts recover, acute GVHD should be suspected.
Assessing the severity of mucositis is important in diagnosis and management. The measurement scale used to record the severity of mucositis should be chosen based upon the examiner's purpose.
If the mucositis evaluation is being conducted to support patient care, a global index such as the World Health Organization (WHO) or National Cancer Institute- Common Toxicity Criteria (NCI-CTC) mucositis scales may be used (Tables 2 and 3). These scales provide overall grades that include tissue assessment and assessment of oral function and pain. However, when mucositis is being assessed as part of a clinical trial, a tissue-derived score based on a validated scale such as the Oral Mucositis Assessment Scale (Table 4) or Oral Mucositis Index should be used.
Management and Prevention of Oropharyngeal Mucositis
Much of the current literature devoted to the prevention or management of oral mucositis comprises small single-center, often nonblinded and/or nonrandomized studies, with poorly defined measures of outcome. In some studies for which end points are defined, nonvalidated mucositis measures have been used, resulting in difficulty in comparing study outcomes. Careful and critical review of the literature is necessary due to the wide variability in quality of the available literature. Controlled, multicenter, randomized, prospective double-blind studies are needed for further progress to be achieved.
Good oral hygiene may reduce the severity of oral mucositis and does notincrease the risk of bacteremia even in neutropenic patients. Moreover, such measures may reduce the risk of bacteremia by controlling periodontal disease and reducing bacterial carriage. Unfortunately, in many centers patients are discouraged from toothbrushing and flossing due to theoretical concerns about increased risk of bacteremia and bleeding-problems that have not been documented. Rather, patients should be encouraged to maintain oral hygiene throughout cancer therapy. Rough or irregular dental surfaces such as broken teeth, fillings, and calculus should be managed to reduce the risk of secondary mucosal trauma or irritation. Orthodontic bands should be removed, and reduced use of removable oral prostheses should be promoted-at a minimum, patients should leave such devices out at night. Oral prostheses should be kept clean, preferably with periodic soaking in appropriate antimicrobial solutions. Patients should be encouraged to consume a bland, soft diet as the risk of mucositis increases, avoiding flavored, acidic, or spicy foods as well as hard, rough-textured, irritating, and hot foods (Table 5). Highly flavored oral care products (especially spearmint or peppermint) and products containing alcohol (such as mouthwash) should be discontinued, as these can be highly irritating to damaged mucosa. Elimination or at least reduction in tobacco and alcoholic beverages should be strongly recommended, and frequent use of protective lip-lubricating products should be promoted. Oral rinsing with bland solutions (eg, 0.9% saline, sodium bicarbonate solutions) and adequate hydration with high fluid intake may help to maintain mouth wetting and clear debris from the oral cavity.
Antimicrobial Approaches-Although viral infections do not cause oral mucositis, they can clearly complicate the course and severity of the condition. As noted earlier, HSV reactivation is common in immunosuppressed patients receiving cancer therapy. HSV prophylaxis for HSV seropositive patients receiving neutropenia- inducing chemotherapy is generally considered standard therapy. In patients given acyclovir or valacyclovir (Valtrex) prophylaxis, reactivation and shedding of HSV and thus clinical infection is prevented in most cases. Oral ulcerations due to cytomegalovirus (CMV) have become uncommon in HCT recipients with the increased use of strategies to prevent CMV infections and reduce the risk of CMV reactivation; nevertheless, shedding of CMV is detected in 13.3% of CMV-seropositive patients. Bacteremia due to Streptococcus viridans may occur in up to 70% of HCT patients when severe mucositis is present, and blood cultures may be positive before fever in approximately one-third of cases, providing evidence that mucosal ulceration predisposes to systemic infection by oral flora. Clindamycin prophylaxis has not been successful in preventing systemic infection by streptococci, suggesting that it may be more important to minimize mucosal damage than to treat secondary infection. No relationship has been found among Candida species, antifungal prophylaxis, and mucositis, suggesting that Candida organisms are not involved in the etiology of mucosal damage but can lead to oropharyngeal and systemic infection in neutropenic patients.[27,28] However, there is some suggestion of an increased risk of candidemia in patients with severe oropharyngeal and gastrointestinal mucositis. Systemic infection by Candida albicans, C krusei, C glabrata, and C dublinensis is a significant cause of morbidity and mortality in neutropenic cancer patients; unfortunately, prevention of colonization remains elusive. Fluconazole (Diflucan) has been reported to prevent oropharyngeal infection and systemic fungal infections (which, in one study, developed in 7% of fluconazole recipients vs 18% of placebo recipients). Although antifungal prophylaxis is frequently provided for Candida species in the setting of HCT, patients must still be assessed on a regular basis to identify signs of clinical candidal infection, especially with the increasing emergence of azole-resistant species (eg, C glabrata, C tropicalis, C krusei).
Anti-inflammatory Approaches-Anti-inflammatory approaches to the prevention of mucositis have received preliminary study, but no convincing benefits have been seen with agents used to date. Agents that have been studied include both prostaglandin E2 (dinoprostone, Prostin E2) and misoprostol (Cytotec), a synthetic prostaglandin E1 analog. Systemic prednisone provided to patients with head and neck cancer resulted in a trend to reduced severity and duration of mucositis, but overall results have not been encouraging. Pentoxifylline has been assessed in mucositis because it may decrease production of TNF-alpha. However, when used as a single agent, it has failed to prevent chemotherapy-induced oral mucositis in numerous controlled studies.[ 32-34] In a subsequent study, while pentoxifylline, ciprofloxacin (Cipro), and prednisone provided to HCT patients resulted in a lower incidence of mucositis, increased positive blood cultures were documented. Therefore, current evidence does not allow a recommendation for the use of pentoxifylline, steroids, or prostaglandin E1 or E2 products to reduce the frequency or severity of mucositis.
Radioprotectors-Amifostine (Ethyol) is a thiol compound shown in animal studies to protect a variety of tissues including mucosa, salivary gland, cardiac, renal, bone marrow, neuro-, and ototoxicity when administered prior to irradiation. It is currently indicated for salivary gland protection during radiation therapy. The drug is administered intravenously and requires good hydration; it is associated with side effects including nausea, vomiting, and hypotension, and commonly requires concomitant use of antinausea medications. Subcutaneous injection is being evaluated due to lower cost of administration than by the intravenous route, and because nausea may be less severe. A significantly reduced xerostomia rate has been reported with amifostine therapy in radiochemotherapy recipients,[ 37] although the clinical significance and long-term benefits are less clear. Evidence of mucosal protection is inconsistent; two studies in HCT patients have shown no benefit for amifostine in preventing mucositis, and one study has been supportive. A recent trial of amifostine to prevent oral mucositis in head and neck irradiation patients was supportive, and no tumor protection has been reported to date.[36,37]
'Xerostomic' Agents-Some investigators have suggested that if a chemotherapeutic agent is excreted in saliva, this could result in worse mucositis due to increased mucosal exposure to the drug. These researchers have proposed that an anticholinergic "xerostomic agent" could be used for prophylaxis of oropharyngeal mucositis. Although initial studies of propantheline in patients receiving etoposide resulted in less frequent and less severe mucositis,[38,39] considerably more study is needed. Additionally, propantheline had no effect upon esophagitis and enteritis. If salivary EGF is found to speed recovery of the epithelium, the use of sialogogues may be of value in accelerating healing of oral mucosa; careful study is required to confirm this possible approach for mucositis.
Biologic Response Modifiers-A large number of studies have looked at the potential benefit of the hematopoietic growth factors granulocyte- macrophage colony-stimulating factor (GM-CSF, Leukine) and granulocyte colony-stimulating factor (G-CSF, Neupogen) to prevent mucositis. Trials in a variety of clinical settings (chemotherapy, radiation, and HCT) have shown inconsistent results.[11,12,40-45] A placebo-controlled trial of topical G-CSF in patients receiving chemotherapy for non-Hodgkin's lymphoma reported a trend toward less severe mucositis, and number of days of hospitalization was reduced.[ 46] Other preliminary studies in cancer patients have assessed the effect of GM-CSF on oral mucositis,[ 11,12,40,46-50] and several trials have shown less severe or reduced duration of mucositis.[47,48,50] However, a double-blind, placebo-controlled study of GM-CSF mouth rinse conducted in 45 patients receiving chemotherapy showed no reduction in mucositis. The mechanism of action has not been elucidated but may involve a local mucosal effect or more rapid recovery of granulocytes that promote healing. Keratinocyte growth factor (KGF) is a member of the fibroblast-growth factor (FGF) family that binds to specific FGF receptors and is capable of accelerating wound healing. KGF modifies proliferation and differentiation of epithelial cells when administered systemically and may protect cells from damage by reducing apoptosis and promoting more rapid healing. Animal studies have shown the potential of KGF to reduce radiation- and chemotherapy-related mucositis.[ 51,52] KGF used prior to chemotherapy and irradiation in mice caused an increase in mucosal thickness and integrity in the small intestine. A phase I clinical trial of KGF in 81 patients with metastatic colorectal cancer with fluorouracil (5-FU) showed fewer patients developed ulcerated mucositis (43% vs 67%, P = .06) and patients overall experienced less oral pain. A recent study in recombinant human KGF vs placebo in HCT patients receiving total- body irradiation reported a statistically significant reduction in incidence (63% vs 98%), duration (3.7 vs 10.4 days), and severity of oral mucositis (all P < .001) and reduced the requirement for supportive care-ie, reduced opioid use (212 vs 552 mg morphine equivalent) and less need for parenteral nutrition (11% vs 40%)- in the KGF group, as compared to the placebo group.
Miscellaneous Systemic Approaches- Azelastine (Astelin) may suppress neutrophil respiratory burst activity and cytokine release from lymphocytes. A study of this agent in chemoradiotherapy patients with oral carcinoma reported reduced severity of mucositis. Further study of azelastine for the treatment of mucositis is indicated.
Topical Anti-inflammatory/Analgesic Agents-Benzydamine is an anti-inflammatory analgesic that has anti-TNF activity. The rinse has been shown to reduce the severity of mucositis during radiation therapy and to reduce oral pain.[57,58] Consistent reduction in oropharyngeal mucositis and reduced analgesic use have been shown in single-center and multicenter, double-blind, placebo-controlled clinical studies. Benzydamine is available in Europe and Canada (as Difflam and Tantum, respectively) and is currently in a pivotal phase III trial in the United States.
Topical Antimicrobials-Chlorhexidine has been assessed in HCT patients,[59-62] but the initial benefits reported for its prophylactic use in reducing oral mucositis have not been substantiated by the majority of studies carried out subsequently.[60,61] The effects of chlorhexidine rinsing on plaque levels, gingival inflammation, and caries risk have not been the primary end points in these studies. However, the true value of chlorhexidine during extended cancer therapy may be the control of dental plaque levels- thus contributing to reduced gingivitis, caries risk, and oropharyngeal candidiasis- rather than the prevention of oropharyngeal mucositis.[63-65] In a prospective study of patients treated with chemoradiotherapy for head and neck cancer, oral application of povidone-iodine, compared to sterile water rinses, reduced the onset, severity, and duration of mucositis. Pediatric patients treated for acute lymphoblastic leukemia were provided oral hygiene instruction, chlorhexidine, povidone-iodine, and nystatin; compared with historical controls, study patients had improved oral hygiene, less severe mucositis, and fewer cases of candidiasis. However, the impact of oral hygiene may be a confounding factor in these studies. Single-center studies of a nonabsorbable antimicrobial lozenge combining polymyxin, tobramycin, and amphotericin B reported that ulcerative mucositis was prevented in patients receiving head and neck radiation therapy. The effect was attributed to a reduction in oral colonization by gram-negative bacteria. A double-blind placebo-controlled trial of 112 patients found patient self-report of severe mucositis was lessened with the antimicrobial lozenge, but, mucositis scores were not significantly different, and the authors felt that the benefit was not sufficient to recommend this treatment in standard practice. Another large single-center study using a nonabsorbable lozenge of polymyxin, tobramycin, and amphotericin B employed an unusual mucositis assessment. This trial demonstrated a statistically significant reduction in mucositis in the lozenge arm, but further study is clearly warranted.
Topical Biologic Response Modifiers- These agents are in early phases of study but provide hope for future therapy. Animal models have been used to assess the potential of growth factors to protect against oral mucositis. Topical EGF increased the severity of mucosal damage when given concurrently with chemotherapy. TGF-beta-3 (which reduces epithelial cell proliferation) decreased the incidence, severity, and duration of mucositis.[70,71] Clinical trials with this agent suffered from dosing concerns, and results were not positive.[ 72] IL-11 (oprelvekin, Neumega) has been shown to cause a dosedependent and statistically significant reduction in oral mucositis and in inflammatory bowel in animal models. However, clinical trials of the agent in HCT patients failed to show any mucositis-related benefits and were associated with unacceptable systemic toxicity. EGF may be a marker of mucosal damage; it also has the potential to promote resolution of radiationinduced mucositis. In patients receiving head and neck irradiation, the quantity of EGF in saliva decreased due to both a reduced volume of saliva and a reduced concentration of EGF in saliva as mucositis increased.[ 9] Other studies in head and neck cancer patients have shown conflicting results: A preliminary study showed increased mucositis in patients with higher levels of EGF in saliva[ 73]; in a larger study, however, higher EGF levels were associated with less severe mucositis. A double-blind trial of EGF mouthwash in patients treated with chemotherapy showed no differences in the healing of established ulcers but a delay in onset and reduced severity in recurrent ulceration, suggesting that topical EGF may protect the mucosa. Growth factors may have pluripotential effects, whereby dose, concentration, and duration of contact in the oral environment may affect the outcome. This may explain, in part, the varied results of studies to date, and will complicate the future studies of these interventions.
Miscellaneous Topical Approaches- Current clinical recommendations for the management of mucositis are frequently not supported by clinical trials. Although there are no studies demonstrating a prophylactic benefit against oropharyngeal mucositis with the use of saline or bicarbonate rinses or coating agents (eg, milk of magnesia, Amphojel, Kaopectate), these solutions are commonly included in oral care protocols. Indeed, they clearly can have palliative effects that may improve patient comfort. A study comparing saline and hydrogen peroxide rinses in patients receiving radiation therapy found no significant differences in mucositis, although oral sensitivity and discomfort was greater in those using peroxide. Oral cooling (cryotherapy) produced by holding ice chips in the mouth for 30 minutes beginning 5 minutes prior to bolus administration of 5-FU has been shown to reduce mucositis associated with 5-FU chemotherapy in clinical trials.[77,78] It has been hypothesized that by decreasing blood flow to mucosal tissues while chemotherapy is being administered, there is a decreased delivery of drug to the mucosa and therefore less mucosal toxicity. Sucralfate suspension has been studied in mucositis associated with chemotherapy, radiation therapy, and HCT. Sucralfate is thought to adhere to gastric ulcer bases, thus creating a surface barrier in the gastrointestinal tract. This agent may have antibacterial activity and also binds to EGF, which may accelerate wound healing. Although less severe mucositis has been reported in some trials, numerous others have observed no benefit.[ 79-82] Reduced oral pain was also reported in some sulcralfate trials[ 79,80] but not all. Another hypothesized benefit of sucralfate use is reduced mucosal adherence of potentially pathogenic oral organisms in patients with mucositis, but no proof of this effect on infectious outcomes has been reported. A phase III randomized, doubleblind controlled study of oral chamomile mouthwash was conducted in 164 patients receiving 5-FU chemotherapy; no differences in the incidence, severity, and duration of mucositis were seen. Therefore, this mouth rinse is not recommended. Topical anesthetics have long been recommended to reduce the pain of oropharyngeal mucositis, and there are many agents to choose from, including true anesthetics, antihistamines, and a variety of miscellaneous drugs that can produce local pain relief by producing local anesthesia. However, no comparative trials have been reported to compare these agents. Viscous lidocaine is frequently prescribed for oropharyngeal pain management, although no studies have assessed its benefit, nor its potential for toxicity in cancer patients. Numerous authors have conjectured that lidocaine may not be appropriate to use in this setting because it causes a burning sensation when initially applied, eliminates the sense of taste, can diminish the gag reflex, and may have cardiovascular and central nervous system effects if absorbed systemically. However, a recent study reported by Elad et al would seem to support the contention that there is minimal potential toxicity when used in cancer patients. Dyclonine (Dyclone) may be better accepted than lidocaine. As noted above, benzydamine's anesthetic properties may decrease the severity of mucositis pain due to local effects.[57,58] Local applications of topical anesthetic creams or gels may be useful for local painful mucosal ulcerations. In a preliminary trial, doxepin rinse has shown evidence of prolonged action (> 4 hours) when used for pain relief in cancer patients.[ 85] The action of doxepin may be similar to that reported for benzydamine; ie, patients initially experience anesthesia, but there is a lingering analgesia that persists after the anesthetic has worn off. Glutamine has been demonstrated to have an effect upon mucosal maintenance and protection. However, both parenteral and topical glutamine have been assessed in patients receiving HCT and intensive chemotherapy, and no impact upon mucositis was observed. Studies of oral glutamine in a new delivery vehicle are ongoing. A gel film-coating agent based on hydroxypropylcellulose with ethyl alcohol (MGI 209) combined with anesthetic and antimicrobial agents was assessed in patients receiving radiation therapy (to fields including oral tissues) compared with lidocaine and/or systemic analgesics. No difference in pain severity was seen between groups, although the duration of pain was shorter in those using the gel film. Gelclair, a commercial product containing polyvinylpyrrolidone and sodium hyaluronate, has been reported in preliminary open trials to reduce mucositis and the pain of oral ulcers.[ 88,89] While preliminary pilot reports on the efficacy of this compound have been encouraging, overall efficacy has not been adequately studied to date. Oral capsaicin in a taffy-candy produced temporary pain reduction in 11 patients with oral mucositis pain. The findings suggest that some of the pain of mucositis is mediated by substance P. However, the practicality and acceptance of this approach to mucositis pain relief have not been demonstrated and are, at best, questionable. Intraoral radiation shields are often suggested during radiation therapy and were shown to be effective, with study patients experiencing less weight loss, fewer hospitalizations for nutritional support, and a trend toward fewer treatment interruptions than control patients.
Low-energy laser therapy has been studied for its ability to prevent oropharyngeal mucositis and reduce symptoms associated with HCT.[91,92] Initial results have been encouraging, suggesting the need for further controlled studies. The mechanism of action has been hypothesized to be related to effects on mitochondria or possibly effects on intracellular reactive oxygen species.
1. Pre-Cancer Therapy Oral Assessment and Management
Oral/dental evaluations and treatment should be conducted by knowledgeable dental providers. Management should include pretreatment periodontal therapy and dental extractions to prevent infection during neutropenia and, for patients receiving radiation therapy, to reduce the risk of osteonecrosis. Rough and irregular dental surfaces should be smoothed or removed, and a careful dental cleaning should be conducted. If dental prostheses are present, they must be assessed and modified as indicated to improve stability and retention; patients should be given instructions for reduced use and cleaning of dentures. Oral hygiene instruction should be given, and basic oral care instructions including rinsing with bland solutions (eg, 0.9% saline) should be given.
2. Avoidance of Mucosal Irritation
Patients at risk for mucositis should avoid tissue irritation (eg, from physically irritating and high-temperature foods, tobacco, alcohol, or spices). They should be encouraged to consume a soft, bland diet.
3. Prophylaxis of Oropharyngeal Mucositis
Oral cooling with ice chips for 30 minutes, beginning 5 minutes prior to bolus 5-FU, has been shown to reduce mucositis, which suggests that this approach may be useful for patients receiving other chemotherapeutic agents (with similarly short half-lives) that are given through bolus injection. If available, benzydamine should be recommended for prophylactic use in patients receiving radiation therapy. At this time, no recommendation can be made for using benzydamine in patients treated with chemotherapy; preliminary studies have shown potential benefit, but further research is necessary to support its use in this population.
4. Treatment of Mucositis
Of the many other agents assessed for the treatment of mucositis, chlorhexidine rinses and topical sucralfate have been studied extensively in clinical trials. The potential value of chlorhexidine in controlling chemotherapy-associated oral mucositis is reported in some studies but not in others. Chlorhexidine has been shown to have no effect upon radiation-induced mucositis. However, chlorhexidine can be considered for use in cancer patients to help reduce plaque levels and thus reduce risk of gingivitis and caries. The tolerance of chlorhexidine oral rinses in patients with mucositis is limited, because the alcohol and flavoring agents generally used in these rinses can be very irritating and painful. Sucralfate is a cytoprotectant that was initially thought to have potential efficacy for the management of chemotherapy- and radiation-induced mucositis. Unfortunately, results from investigations have been inconsistent. Sucralfate primarily appears to be able to help decrease oropharyngeal pain.
5. Treatment of Oral Infections
Oral infections may be seen during cancer therapy, with Candida and HSV infections being common when appropriate prophylactic therapy is not employed. Additionally, neutropenic patients are at increased risk for systemic infection, particularly due to alpha-hemolytic streptococci, Candida species, and gram-negative bacteria. Therefore, prophylactic antimicrobials are often used in neutropenic patients, although the ability to prevent systemic infection due to potential oral pathogens may be more predictable if mucosal damage (ie, oral mucositis) could be prevented. Candidal infection does not appear to have a significant impact on the severity or course of oropharyngeal mucositis in radiation therapy, and treatment with topical and/or systemic antifungals will not prevent mucositis. Nevertheless, candidiasis is the most common oral infection in cancer patients and may increase oral symptoms. Moreover, infection can involve the esophagus, leading to dysphagia. Prevention of oral infection may reduce the risk of systemic infection in neutropenic patients. Xerostomia, dental prostheses, antibiotic therapy, alcohol use, and tobacco smoking are risk factors for oral candidiasis. Antifungal prophylaxis is therefore recommended for patients who are receiving remission-induction chemotherapy or are undergoing HCT, ie, those in whom neutropenia is anticipated. Meta-analysis shows the prophylactic value of clotrimazole or fluconazole, although topical nystatin has not been shown to be effective. Chlorhexidine mouthwashes may reduce colonization by Candida species but should not be considered for actual treatment of established infections. The significantly increased frequency and severity of oral herpesvirus infections after intensive chemotherapy and HCT is well known. Risk of HSV reactivation is greatest early following the development of neutropenia. Acyclovir and valacyclovir are the most commonly used antiviral agents for HSV or varicella-zoster virus prophylaxis and treatment.
6. Symptom Management
Pain due to oropharyngeal mucositis frequently necessitates the use of systemic analgesics, adjunctive medications, physical therapy, and psychological therapy in addition to oral care. Strategies utilized to manage acute pain, in general, are applicable to the management of oral mucositis. Because oropharyngeal mucositis-related pain is amenable to topical anesthetics/ analgesics, these agents should be utilized initially at the onset of oral mucosal sensitivity, and if pain progresses, continued while adding nonopioid and opioid analgesics when pain becomes more severe. Oropharyngeal pain is a major distressing complication of oropharyngeal mucositis that can interfere with eating, speaking, wearing removable dental prostheses, and taking medications by mouth-all of which can greatly affect quality of life. Pain may be addressed with systemic analgesics. The WHO analgesic ladder is recommended as a guideline, with nonsteroidal agents and other nonopioids used first, and combined with mild opioids such as codeine and potent opioids including morphine and hydromorphone when pain becomes severe. It is important to recognize that numerous nonsteroidal agents are contraindicated in patients who are thrombocytopenic or who have coagulopathies. Topical oral medications can reduce the need for systemic analgesics and should be considered prior to the use of systemic analgesics; these drugs should be continued when the WHO ladder is initiated. Patient-controlled analgesia can also provide an effective method of pain control; studies have shown that this strategy can result in better pain control while utilizing lower total doses of opioids and causing fewer opioid side effects. The search for a topical drug with long duration is ongoing. Topical anesthetics have been used clinically, although clinical studies of such agents are limited. Anesthetic agents such as lidocaine and dyclonine or antihistamines such as diphenhydramine may provide symptomatic relief from the pain of mucositis, but these agents can be irritating when initially applied to ulcerated mucosa. Other side effects that can be encountered include anesthesia- induced loss of taste, oral sensitivity, and a negative effect on the ability to eat and swallow. Topical anesthetic agents have often been combined with coating agents, such as milk of magnesia, aluminum hydroxide gel, or calcium carbonate to produce a "magic mouthwash." Studies of these combination rinses have generally found no benefit for these combined agents over saline rinses, and when combined with the significantly increased cost of these compounded rinses, there is reasonable evidence to support the use of bland rinses and single topical anesthetics over these mixtures. Benzydamine has been shown to cause topical analgesia and reduce pain in studies of radiation-induced mucositis, in addition to reducing the severity of mucositis in this population, and is recommended for patients receiving radiation therapy. An initial trial of topical doxepin rinse has been shown to provide prolonged analgesia in cancer patients and may be a useful addition to local pain management. Adhesive mucosal-coating agents such as hydroxypropyl cellulose- based agents (eg, Zilactin) have been shown in preliminary trials to reduce oral pain in cancer patients. Adjunctive agents including centrally acting pain medications such as the tricyclics, gabapentin (Neurontin), and possibly anticonvulsants, as well as muscle relaxant medications, may be considered. The choice of adjunctive medication should account for patient comorbidities such as anxiety and depression. However, there has been limited study of the use of adjunctive approaches to pain management in patients with acute oral mucositis. Relaxation, imagery, biofeedback, hypnosis, and transcutaneous electrical nerve stimulation are other adjunctive approaches to the management of cancer pain. Indeed, the use of hypnosis has been shown to be a valuable adjunct. One controlled clinical trial of psychological interventions in HCT patients with oral pain studied four groups: standard treatment, therapist support, relaxation and imagery training, and cognitive-behavioral coping skills combined with relaxation and imagery; it was shown that relaxation and imagery reduced pain and that adding cognitive-behavioral skills to relaxation and imagery did not improve pain relief.
Given the pathobiology of mucositis with the abundant up- and downregulation of genes and gene products, an increasing number of potential targets for therapy should become possible. Furthermore, because oral mucositis is clearly expressed differently from therapy to therapy and even from patient to patient receiving the same therapy, it is likely that combined-modality approaches to preventing and treating oral mucositis may become necessary. For example, therapy may require the initial combination of an anti-inflammatory agent with an agent to prevent direct keratinocyte toxicity to be followed up by a keratinocyte growth factor to promote wound healing and resolution of mucositis. Indeed, KGF has been shown to have a significant effect on oral mucositis in HCT patients in a pivotal phase III study, and may be available soon for clinical use.
The current approach to the management of oropharyngeal mucositis is essentially palliative. Increased understanding of the pathogenesis of mucositis will provide opportunities for continuing study and the development of new and effective interventions. Similarly, improvements in study design and controlled studies, as well as new developments in biotechnology, will lead to novel, efficacious approaches in the future.
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