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Oral Complications
Summary of Key Points
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Incidence
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Mucositis is a major dose-limiting toxic effect of chemotherapy for solid tumors developing in 5% to 40% of patients.
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Mucositis develops in 70% to 100% of patients receiving high doses of chemotherapy with bone marrow rescue.
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Mucositis is the most troublesome acute reaction for patients receiving radiation therapy to the oral cavity.
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Radiation therapy to the oral cavity frequently causes a host of other oral complications including xerostomia, dental caries, tissue necrosis, and taste alterations.
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Etiology of Complications
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Oxidative stress and injury to oral cavity tissues by cytotoxic chemotherapy and radiation therapy lead to upregulation of inflammatory cytokines, additional signaling and amplification of inflammatory pathways, and subsequent ulceration and healing.
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Secondary infections occur from treatment-induced immunosuppression.
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Prophylactic Measures
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The importance of instituting oral hygiene protocols in patients receiving chemotherapy is well established.
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Cryotherapy is the most conventional and easiest-to-use preventive method, at least for 5-fluorouracil (5-FU)–based bolus therapy, and appears to have implications for other chemotherapeutic regimens also, such as edatrexate and high-dose melphalan therapy.
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Keratinocyte growth factor has been approved by the US Food and Drug Administration (FDA) for use with high-dose chemotherapeutic regimens associated with high rates of mucositis and has also shown promise in other settings.
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Low-level laser therapy has shown promise but is limited for now to centers able to support its use.
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Pretreatment dental care, good oral hygiene, and sophisticated treatment planning are recommended for patients receiving radiation therapy.
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Treatment
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There is overall lack of evidence regarding the efficacy of various agents in promoting healing of the oral mucosa after mucositis is established.
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Systemic analgesic therapy of mucositis pain with narcotic medications is well established and recommended.
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Antibiotics and/or antifungal medications should be given to patients with evidence of infection.
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In the palliative setting, randomized, placebo-controlled trials have demonstrated that two therapies are helpful for treating mucosal pain from radiation-induced mucositis: (1) a liquid doxepin “swish-and-spit” preparation, and (2) a “magic mouthwash” consisting of diphenhydramine, viscous lidocaine, and a magnesium hydroxide–aluminum hydroxide antacid suspension.
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Baking soda mouth rinses appear to be the most economical solution, although efficacy is not clearly established.
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Low-level laser therapy has also shown promise in treating established mucositis lesions.
The oral cavity is a common site for chemotherapy-induced and radiation-induced toxicity. Manifestations of this toxicity include alimentary tract mucositis; infectious complications induced by bacteria, fungi, and viruses; and graft-versus-host disease in patients receiving allogeneic bone marrow transplants. Although alimentary tract mucositis can involve the entire gastrointestinal tract, it is most frequently observed in the oral cavity as ulceration, pain, and bleeding. Mucositis leads to significant morbidity, limits the use of additional chemotherapeutic treatment, and causes considerable economic burden. This chapter discusses the etiology, incidence, risk factors, prevention, and treatment of oral toxic effects of standard chemotherapy, intensive marrow-ablative chemotherapy, and radiation therapy. The prevention and treatment of graft-versus-host disease is beyond the scope of this chapter.
Pathophysiology of Mucosal Injury and Clinical Manifestations
It is currently accepted that the process of mucosal injury, and subsequent healing, is not limited to the epithelium alone but involves all layers of the mucosa, including the extracellular matrix. A five-stage process has been postulated in order to explain the complex molecular, cellular, and histologic events associated with chemotherapy-induced mucosal injury ( Fig. 40.1 ). Oxidative stress related to chemotherapy is thought to be responsible for the first phase of mucosal injury (initiation phase). The second phase involves the upregulation of transcription factors and the generation of messenger signals (primary damage response phase). In this stage, upregulation of nuclear factor–κB (NF-κB) is thought to play an important role in the subsequent upregulation of multiple proinflammatory cytokines, such as tumor necrosis factor–α (TNF-α), interleukin (IL)-1B, and IL-6. NF-κB is also thought to upregulate cyclooxygenase 2 (COX-2), which in turn is implicated in the upregulation of matrix metalloproteinase. In addition, the sphingomyelinase and ceramide pathways, fibronectin breakup, and macrophage activation are other complex events that take place and lead to further mucosal injury and apoptosis. The third phase of mucosal injury involves additional signaling and amplification of the aforementioned pathways through biologic feedback, leading to generation of additional proinflammatory cytokines (signaling and amplification phase). Up to this point the biologically altered mucosa appears anatomically intact, but epithelial proliferation halts. The fourth phase consists of the symptomatic phase of mucositis, involving erythema, mucosal ulceration, plaque formation, pain, and bleeding (ulceration phase). Immune cell infiltration occurs in this phase. Microbial superinfection and reduction in salivary gland function can complicate and amplify the mucosal injury. Oral candidiasis and herpes simplex virus (HSV) infections are particularly common, comprising the majority of the infectious complications seen in patients with mucositis, although the increased risk of bacteremia in patients with mucositis also points to the role of bacterial superinfections of the ulcerative lesions. It is important to note that although microbial superinfections can influence the duration and severity of mucositis, they are not believed to be involved in the pathogenesis of mucositis. This is supported by multiple studies failing to show any benefit of antimicrobials in the prevention of mucositis. The fifth and final phase involves the healing of the mucosa, a process that depends on angiogenesis and on increased biologic activity in the extracellular matrix (healing phase). In patients undergoing myeloablative chemotherapy, the healing phase may not begin until leukocyte recovery. It is important to understand that these phases do not necessarily follow a linear progression but may occur simultaneously at different locations.
Mucositis Assessment
Multiple mucositis scales are used in clinical practice, differing in the level of objective and subjective information they provide. However, it is known that patient-reported data yield similar conclusions as clinician-determined data, and are probably more accurate. The National Cancer Institute Common Terminology Criteria have been commonly used to assess severity of mucositis based on clinical findings and symptomatology. The University of Nebraska Oral Assessment Score is another scale that has been validated for use in patients undergoing high-dose chemotherapy and autologous or allogenic stem cell rescue. Higher scores on this scale have been found to correlate with clinically significant events, including blood infections and transplant-related mortality.
Oral Complications From Chemotherapy, Including Myeloablative Chemotherapy
Incidence and Risk Factors
The type of chemotherapeutic agents used, the specific dose, the route and frequency of administration, and drug combinations significantly affect the degree of mucosal injury ( Fig. 40.2 ).
Antimetabolites such as methotrexate and 5-fluorouracil (5-FU), antitumor antibiotics such as doxorubicin, platinum agents such as cisplatin, purine analogues such as cytarabine, and topoisomerase inhibitors such as etoposide are most specifically associated with mucositis. Methotrexate and etoposide are secreted into the saliva, thus enhancing mucosal toxicity. Irinotecan, although notorious for causing gastrointestinal mucositis in the form of diarrhea, has limited oral toxicity.
Regarding the time course of mucosal injury, 5-FU–induced mucositis is usually first noticed anywhere from 3 to 7 days after initiation of therapy. Incidence peaks at the 7th to 12th day, and diminishes by around 2 to 3 weeks ( Fig. 40.3 ). With myeloablative chemotherapy for hematologic malignancies, mucositis severity can peak up to 18 days after initiation of therapy.
Chemotherapy for the treatment of solid tumors leads to the development of mucositis in 5% to 40% of patients (5% to 15% grade 3–4). Many modern treatment approaches have not solved this problem, and because of their aggressiveness, they are frequently more toxic. A vast experience exists with 5-FU, the most commonly used drug to treat gastrointestinal malignancies. Although there has long been the belief that continuous administration of 5-FU carries a higher risk of mucositis than bolus administration of 5-FU, a meta-analysis of trials failed to support this association.
When myeloablative chemotherapy is used, the incidence of mucositis increases to 70% to 100% (21% to 67% grade 3–4). This appears to be especially true for induction regimens containing high-dose melphalan. When chemotherapy is used in combination with radiation therapy to treat cancer of the head and neck, mucositis is experienced by 90% to 100% of patients (43% grade 3–4).
The role of age and gender in the development of mucositis has not yet been clearly defined owing to conflicting reports. There is also conflicting evidence regarding whether the type of bone marrow transplant (autologous versus allogeneic), the use of total body irradiation in the conditioning regimen, the use of granulocyte colony-stimulating factor (G-CSF), and the baseline nutritional status are related to the risk of mucositis. On the other hand, poor oral hygiene, dental caries, periodontal disease, high titers of HSV, and positive cultures for Candida tropicalis are generally accepted to be risk factors.
Finally, interpersonal variability in the development of mucositis been observed for years; this may be due to the differences in metabolism of the chemotherapeutic drugs from person to person. A prime example is the drug methotrexate, which results in much higher degrees of mucositis in patients with an inability to metabolize this drug. Another example involves polymorphisms in the genes coding for the activity of glutathione- S -transferases, which are important detoxification enzymes. Patients with reduced activity of these enzymes have near doubling of the risk to develop mucositis.
Biologic Therapies
Multiple targeted therapies, such as tyrosine kinase inhibitors (TKIs), epidermal growth factor receptor (EGFR) inhibitors, vascular endothelial growth factor (VEGF) inhibitors, mammalian target of rapamycin (mTOR inhibitors), and other drugs, have emerged in the treatment of various human cancers. Although these newer therapies can also cause oral complications, such side effects are less frequent, and generally milder. Mucosal ulcerations appear to be more consistent with aphthous ulcers. The mTOR inhibitors are the targeted therapies with perhaps the highest incidence of mucositis. In the BOLERO-2 trial, 29%, 22%, and 8% of patients had grades 1, 2, and 3 mucositis, respectively. It was usually apparent within 8 weeks of treatment initiation. In a meta-analysis of everolimus studies, 67% of patients had mucositis, and this was grade 3/4 severity in 9% of patients.
As single agents, the EGFR inhibitors panitumumab and erlotinib, known primarily for causing their characteristic skin rash, are responsible for approximately 20% of grade 1 to 2 mucositis, but only 1% of patients experience grade 3 mucositis or require treatment discontinuation for this reason. The rate of all-grade stomatitis appears to be as high as 72% (9% grade 3 or worse) in patients treated with afatinib, which inhibits EGFR, EGFR2, and erbB4. Regarding the TKIs, imatinib and sunitinib have been reported to have between 10% and 38% incidence of mucositis, but only 2% to 3% of cases are grade 3 or higher. Oral side effects with drugs such as bevacizumab, trastuzumab, or lapatinib are very rare. It is important to note that underreporting of oral side effects of biologic therapies has been identified as a possible reason for the low incidence reported in some of these trials.
When these newer therapies are combined with traditional chemotherapeutics, they can increase the usual severity of the individual chemotherapeutic drugs. Although some major studies have failed to show an increase in the incidence of mucositis when EGFR inhibitors are combined with radiation, a meta-analysis has shown that there is, indeed, such an increased risk (odds ratio [OR], 1.76; P < .001).
Prevention of Chemotherapy-Induced Oral Complications
Effective means of preventing chemotherapy-induced oral complications aim to provide an improved quality of life for patients receiving chemotherapy, as well as a reduction of the rate of life-threatening infections thought to be originating from the oral mucosa. Furthermore, prevention of oral complications might also improve the effectiveness of antineoplastic therapy by avoiding treatment modifications during subsequent cycles and permitting more dose-intensive therapies. Several different methods have been proposed for preventing chemotherapy- induced oral complications.
Oral Care Protocols and Oral Hygiene
Although there is insufficient evidence to suggest any one approach, the institution of comprehensive oral care protocols for patients receiving chemotherapy for solid tumors is generally recommended. Multiple oral care protocols have demonstrated feasibility and tolerability, and some have shown a reduction in the severity of mucositis and an improvement in the patient's ability to cope with the symptoms. Such oral care protocols are usually implemented by nursing staff and involve various degrees of patient education. They can include cavity screening and dental consultations; basic oral care with soft tooth brushing, flushing, and rinsing; regular inspection of the oral cavity; and avoidance of habits and substances such as smoking, alcohol, and spices. The cross-study differences seen in two similar treatment arms illustrated in Fig. 40.3 may be related to the use of nurse-directed oral care recommendations in the second study, which were not used in the first study.
Currently there is a wide heterogeneity in the approach to mucositis prevention in the United States, and multiple different oral care protocols are available. The need for a more standardized approach is evident, including the institution of multidisciplinary teams.
Regarding the oral care of myeloablative chemotherapy candidates, current guidelines, drafted in 2009 by multiple organizations in a global effort, recommend a formal dental evaluation and performance of any needed dental work before institution of conditioning regimens. This includes appropriate treatment of caries, proper fitting of dental prostheses, and extraction of teeth with significant periodontal disease. These interventions should ideally be performed 10 to 14 days before any conditioning therapy. During therapy, oral hygiene should be maintained with rinses four to six times a day with sterile water, normal saline, or sodium bicarbonate solutions, and patients should brush the teeth at least twice daily with a soft or ultrasoft toothbrush or a toothette (i.e., foam swab on a stick). Use of toothpaste is optional, and daily dental flossing should be done by patients experienced in the technique, if it can be done without trauma. Orthodontic appliances and space maintainers can be removed during therapy, although if good tissue integrity and satisfactory daily oral hygiene are maintained, their use can continue during the initial conditioning phase.
In a retrospective review of 140 patients undergoing autologous bone marrow transplantation at a single institution, patients received professional oral health care after the initiation of local institutional guidelines in 2005. Patients treated after the institution of guidelines (2005–2009) had a 66% incidence of mucositis compared with a 93% incidence in patients who did not receive professional oral health care according to guidelines (2002–2005).
Antimicrobial and Antiseptic Interventions
In the past, microorganisms were hypothesized to play a central role in the pathogenesis of mucositis. This no longer is thought to be true. This is in part because both topical and systemic antibiotics have failed to significantly affect the incidence and severity of mucositis.
One explanation for the general failure of antimicrobials in this setting may be their inability to significantly eradicate microbes from the oral cavity or the possibility that alterations in the microbial flora by antimicrobial agents might make no difference or cause more harm. Another explanation is that microorganisms play a more complex or possibly a more minor role than initially thought. It has been suggested that instead of being involved in the initiation phase, microbes intensify the inflammatory process associated with the later phases of mucosal injury. There is, however, an association between the severity of mucositis and the incidence of sepsis, suggesting that microbes may use the already damaged mucosa as a portal of entry.
Of all the antiseptics, chlorhexidine has been most extensively studied, with nine randomized controlled trials producing mixed results. When all trials are considered, there is no evidence for benefit of chlorhexidine, and its use is not recommended. Iseganan, a naturally occurring peptide with a broad antimicrobial spectrum, and a topical povidone-iodine preparation have similarly failed to show benefit after each compound was tested in two randomized clinical trials.
Reactivation of HSV can be a significant complication in patients receiving myeloablative chemotherapy and frequently manifests with oral ulceration. Despite this fact, HSV is thought to have a marginal role in causing frank oral mucositis. HSV infection should be suspected if mucositis persists, or appears to worsen, 2 or more weeks after transplantation. Guidelines for testing, prophylaxis, and treatment of HSV infection are well established.
Cryotherapy
Oral cryotherapy during administration of chemotherapy is hypothesized to work by cooling oral mucosal tissues and thereby causing local vasoconstriction during periods of peak chemotherapy blood concentration, thus decreasing the delivery of chemotherapy to the oral mucosa. It is currently recommended in three specific clinical settings and is considered to be investigational in several others.
5-fluorouracil–based chemotherapy
Initially, a North Central Cancer Treatment Group (NCCTG) randomized clinical trial demonstrated that oral cryotherapy can inhibit the development of bolus 5-FU–induced mucositis. This has been independently validated by multiple other investigators. This therapy is administered by having the patient suck on crushed ice, starting 5 minutes before 5-FU administration and continuing for a total of 30 minutes. Longer duration of oral cryotherapy (60 minutes) does not appear to provide any additional benefit in this setting.
Edatrexate
Four small nonrandomized phase I and II trials used 20 to 30 minutes of oral cryotherapy for prevention of mucositis in patients receiving edatrexate, a methotrexate analogue with improved preclinical antitumor activity. Three out of the four trials showed good tolerability of edatrexate when used with oral cryotherapy ; one study showed high toxicity despite this preventive strategy. Current guidelines recommend cryotherapy as an attempt to decrease mucositis in patients treated with bolus edatrexate.
High-dose melphalan
At least five small prospective nonrandomized studies in patients receiving high-dose melphalan therapy have tested the efficacy of oral cryotherapy as compared with historical controls. Grade 3 mucositis developed in only 0% to 11% of patients treated with oral cryotherapy as compared with the incidence of mucositis in historical controls (over 70% of patients). In the only randomized placebo-controlled study, with use of room temperature normal saline as placebo, 40 patients were treated with cryotherapy or placebo for 30 minutes before and 6 hours after chemotherapy with high-dose melphalan. Grade 3 mucositis was experienced in 14% of patients receiving cryotherapy versus 74% of patients receiving normal saline. Although the need for such prolonged administration of cryotherapy is questionable owing to patient noncompliance and the probably equivalent efficacy of shorter administration, cryotherapy appears to be a promising strategy in lowering mucositis in patients receiving high-dose melphalan therapy, and it is currently recommended in this setting. One randomized study in patients receiving methotrexate did not show a benefit. Overall, this evidence points to a possible role for cryotherapy in more diverse settings than previously thought.
Antioxidants, Anticholinergics, and Coating Agents
In general, insufficient evidence exists regarding the effectiveness of antioxidant compounds such as all- trans retinoic acid and vitamin E in preventing oral mucositis in patients receiving chemotherapy. Insufficient evidence also exists to support the prophylactic use of propantheline, an anticholinergic drug that is thought to reduce the amount of etoposide secreted in the saliva.
There are mixed results from at least nine different randomized clinical studies evaluating sucralfate for use in this setting. However, a 2011 meta-analysis suggests a 33% reduction in severe mucositis with this agent. Most of the studies involve patients treated with radiation therapy. Nonetheless, sucralfate is not currently recommended by any guidelines.
Antiinflammatory Agents
Because inflammatory mediators appear to play a central role in mucositis development, the use of antiinflammatory agents has been proposed as a method for preventing mucositis. Pentoxifylline, a TNF-α and IL-2 inhibitor, misoprostol (an analogue of prostaglandin E1), and prostaglandin E2 have failed to show benefit in randomized controlled trials. Benzydamine mouthwash is discussed in the radiation therapy section.
Stomatitis is a common side effect experienced by patients receiving mTOR inhibitors, such as everolimus. A dexamethasone-containing mouthwash was studied as a preventive agent in a phase II trial involving 92 women with metastatic, hormone-positive, HER2-positive breast cancer who were prescribed everolimus and exemestane. Patients were instructed to swish and spit the mouthwash four times daily for 8 weeks. Preliminary results indicate that grade 2 or worse stomatitis was experienced by 2.4% of women at 8 weeks compared with 33% in a historical control group. Another phase II trial found that a hydrocortisone mouthwash decreased stomatitis compared with a historical control. Although promising, the usefulness of a corticosteroid mouthwash ideally should be confirmed in a randomized placebo-controlled setting. Such a trial is in a planning phase.
Amino Acids
Glutamine is a nitrogen-rich nonessential amino acid with a critical role in nucleotide synthesis, muscle function, and overall metabolic homeostasis. However, during periods of stress it becomes a conditionally essential amino acid, and its stores can be significantly depleted, as is the case in patients with cancer. Multiple trials to date have attempted to investigate the beneficial potential of different glutamine preparations through both the parenteral and oral routes, with mixed results. Glutamine has been administered via the parenteral route, as part of total parenteral nutrition, or as intravenous infusions mixed with normal saline. It has also been administered as oral supplements and as swish-and-swallow mouthwash preparations. Overall, these trials have been small and conclusions have been difficult to draw; in the hematopoietic stem cell transplantation setting, the possibility of harm has actually been raised. None of these preparations are currently recommended, but further research is ongoing. An oral suspension form of l -glutamine (AES-14) was shown in a randomized controlled study of 326 breast cancer patients undergoing chemotherapy to reduce the rate of grade 2 or greater oral mucositis by 11% (50% to 39%; P = .03) and grade 3 or greater mucositis by 5% (1.2% versus 6.7%; P = .005). Further studies with this agent have not been reported.
Growth Factors
Growth factors, administered systemically or topically, are hypothesized to help prevent oral mucositis because of their potential to improve healing. Although the use of subcutaneous G-CSF and granulocyte-macrophage colony-stimulating factor (GM-CSF) mouthwashes has been associated with reduced mucositis in certain randomized trials, the data are, as of now, inconclusive. GM-CSF mouthwashes are currently not recommended for patients undergoing hematopoietic stem cell transplantation. In general, studies with G-CSF have been small; however, the largest study randomized patients to receive prophylactic G-CSF or placebo, involving 195 patients undergoing chemotherapy with cyclophosphamide, doxorubicin, and etoposide for small cell lung cancer. Patients treated with G-CSF had a significantly lower rate of oral mucositis (70% versus 53%). In addition, a study of adjuvant TAC (docetaxel, doxorubicin, cyclophosphamide) had to be amended after 116 patients with breast cancer were enrolled, because of a high incidence of febrile neutropenia. As a result, 423 additional patients who were treated with TAC received prophylactic G-CSF. The addition of G-CSF, in addition to reducing the rates of febrile neutropenia, was also associated with a reduced rate of grade 2 or greater stomatitis, from 32% to 23% ( P = .01). Although subcutaneous injections of G-CSF appear to reduce the rates of oral mucositis, this intervention is not recommended for mucositis reduction alone, and its use is restricted to patients with currently approved indications, such as high risk of neutropenic fever.
Topical keratinocyte growth factor (KGF), which is secreted by injured mucosal epithelium, was hypothesized to have efficacy in mucositis prevention. One such preparation, palifermin, has been approved by the US Food and Drug Administration (FDA) for use in preventing mucositis induced by myeloablative chemotherapy. The mechanism of action of KGF is thought to be complex, with both effects on stimulation of epithelial proliferation and antiinflammatory properties. The recommendation for approval was based on a study of 212 patients randomized to receive intravenous KGF or placebo for 3 consecutive days immediately before the initiation of conditioning therapy. Grade 3 or 4 mucositis developed in 63% of patients in the KGF group and 98% of patients in the placebo group. KGF has been tested in at least five more trials. Two of these studies were in patients undergoing myeloablative chemotherapy, two in patients with solid tumors (colorectal cancer and sarcoma), and one in patients undergoing chemoradiation for head and neck cancer. In all trials except one (in which a weekly instead of a daily dose was used), a benefit has been suggested. KGF is currently recommended for patients undergoing myeloablative chemotherapy but not in patients being treated for solid tumors because further studies are needed. Although effective, it constitutes an expensive option for mucositis prevention at this point. In addition, in these studies oral cryotherapy was not administered in either the patients who received 5-FU–based chemotherapy or the patients who received high-dose melphalan therapy, so it is unknown how KGF compares with oral cryotherapy.
Low-Level Laser Therapy
Accumulating evidence suggests that low-level laser therapy (LLLT) has the ability to promote wound healing and reduce pain and inflammation. Several trials have suggested a benefit for laser therapy for the prevention of oral mucositis. A recent meta-analysis of randomized trials found 11 randomized studies, 9 of which were in patients undergoing chemotherapy for solid tumors or hematologic malignancies. The results of these trials have been impressive, with a risk reduction for development of mucositis of 2.03 (95% confidence interval [CI], 1.11–3.69), a shortening of the duration of grade 2 or greater mucositis by 4.38 days (95% CI, 3.35–5.40), and significant reductions in mucositis severity and pain. A Cochrane review included five of these trials and also suggested significant benefit in mucositis prevention. However, the expense and the need for specialized training and equipment limit the widespread applicability of this approach. Guidelines recommend the use of this technology in specialized centers that have the appropriate expertise; further studies on the topic are needed. There has been some question as to what effect laser therapy might have on growth of cancer in the treatment fields. It is, however, true that the expense and availability of the technology are significantly improving and the technical specifications are being standardized, and thus it is possible that widespread clinical use may soon become a reality.
Other Interventions
A variety of protocols include the prophylactic use of oral rinses and mouthwashes, such as normal saline, sodium bicarbonate solutions, and other mixtures. Although there is insufficient evidence to support their use, they constitute parts of various standard oral care protocols. Evidence does exist that alcohol-containing rinses tend to worsen the symptoms of mucositis and therefore should be avoided.
Amifostine, a cytoprotective agent, has been primarily tested in patients undergoing head and neck chemoradiation. However, in at least three studies amifostine has been tested in patients undergoing high-dose chemotherapy or myeloablative chemotherapy with positive results. Although the newer subcutaneous formulation appears to address the toxicity and administration difficulties associated with daily intravenous amifostine, further studies are needed. Oral spray of intestinal trefoil factor, a peptide secreted by goblet cells and involved in mucosal protection, was tested in one randomized study of 99 patients undergoing 5-FU–based chemotherapy for colorectal cancer. There was a 75% to 81% reduction in the risk of mucositis, and further studies with the agent are underway. In two studies of patients undergoing bone marrow transplantation, a benefit was suggested for a neutral supersaturated calcium phosphate rinse (Caphosol).
Allopurinol mouthwashes, despite constituting “standard clinical practice” at some institutions in the early 1990s, are currently not recommended because several randomized clinical trials have convincingly shown no benefit. Traumeel S, a homeopathic remedy, and chamomile mouthwash have also failed to show any benefit.
Treatment of Chemotherapy-Induced Oral Mucositis
Scant data are available to guide the treatment of chemotherapy-induced mucositis, despite a plethora of prescribed remedies. Therefore initial treatment of established mucositis varies significantly among institutions, and different providers often prescribe remedies based on experience and preference. Among these many proposed treatments are various mouthwashes, coating agents, topical anesthetics or analgesics, antiinflammatory agents, systemic narcotics, and topical and systemic growth factors. These treatments are aimed at promoting the healing of the injured oral mucosa and limiting the severity and duration of ulcerations, as well as palliating the symptoms of oral mucositis.
General recommendations frequently given to patients with established mucositis include avoiding spicy, coarse, hot, cold, or acidic foods and alcohol-containing liquids. Physicians should also offer other means of support such as proper hydration, nutrition, infection surveillance, and psychological support, all of which can significantly affect the patient's well-being and quality of life.
Mouthwashes and Coating Agents
For patients with established mucositis, one of the first therapeutic measures frequently used is a salt and baking soda solution. Patients are instructed to rinse the mouth every 2 to 4 hours with a salt and baking soda solution ( 
tsp salt plus 
tsp baking soda in an 8-oz glass of warm water). Some centers use baking soda alone because the addition of salt is thought to be too drying to the mucosa. In one multicenter study, 200 patients receiving standard chemotherapy who followed a carefully planned oral hygiene protocol (PRO-SELF) were randomized to one of three different mouthwashes: salt and soda, chlorhexidine, or “magic mouthwash” (lidocaine, Benadryl, and Maalox). No significant differences were observed in time to resolution of the signs and symptoms of mucositis among the different regimens, with salt and soda being the least costly.
Mouthwashes, often referred to as “magic mouthwash” or “miracle mouthwash,” are topical preparations of analgesic, anesthetic, and coating agents, the composition of which varies across institutions. The most common ingredients are diphenhydramine, viscous lidocaine, magnesium hydroxide or aluminum hydroxide, nystatin, and corticosteroids. Other ingredients include benzocaine, milk of magnesia, chlorhexidine, kaolin, and pectin. Despite their widespread use, the general lack of evidence supporting their efficacy and tolerability does not currently allow any of these preparations to be included in formal guidelines. Further study of these palliative mixtures, however, is strongly encouraged, given their availability, ease of administration, and low cost.
Chlorhexidine mouthwashes are not recommended because studies have failed to support the use of this agent for the treatment of established mucositis. Coating agents, such as sucralfate, have also failed to show any benefit for the treatment of established chemotherapy-induced mucositis when tested in small randomized trials. Other coating agents include Gelclair and MuGard, which are oral lubricating gels and are used by some institutions based on anecdotal reports. No well-conducted trials have been performed, and Gelclair did not show promise in small preliminary studies.
Antiinflammatory Agents
Anti-inflammatory agents do not currently have a role in the treatment of chemotherapy-induced mucositis.
Growth Factors
It is hypothesized that GM-CSF, used systemically or topically as a mouthwash, may stimulate proliferation of endothelial cells and promote keratinocyte growth, thus enhancing recovery of oral mucositis. However, studies have been limited and are of poor methodological quality.
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