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REVIEW |
1 Departments of Oral and Maxillofacial Surgery,
2 Epidemiology and Statistics, and
3 Medical Oncology, University of Groningen and University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
* corresponding author, m.a.stokman{at}kchir.umcg.nl
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONLITERATURE SEARCH STRATEGY AND...INTERVENTION STRATEGIESCONCLUSION AND PERSPECTIVESREFERENCES |
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KEY WORDS: mucositis • prevention • scoring • meta-analysis
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONLITERATURE SEARCH STRATEGY AND...INTERVENTION STRATEGIESCONCLUSION AND PERSPECTIVESREFERENCES |
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In a conventional radiotherapy scheme of fractionation, a first mucosal reaction in the form of mucosal hyperkeratinization can be observed, as a white discoloration, after a cumulative radiation dose of 10–20 Gy. This stage is often overlooked or cannot be objectively diagnosed. Therefore, a deepening erythema is clinically considered to be the first sign and is usually visible after 20 Gy cumulative dosage. Thereafter, ulcerations can occur which are often covered with a pseudomembranous layer. This more severe stage of mucositis will develop after about 30 Gy, usually after 3 wks of radiotherapy (Spijkervet et al., 1989c). After completion of the radiotherapy, the mucositis will decline after 2 to 6 wks.
The oral mucositis induced by chemotherapy is more acute than that due to radiotherapy (Dreizen et al., 1975). Around 5–8 days following chemotherapy, erythema occurs, usually followed, within 2 days, by edema and ulceration. Mucositis due to chemotherapy lasts for approximately 7 to 10 days. The sites of predilection of mucositis lesions induced by both radiotherapy and chemotherapy are the non-keratinized mucosa, such as the buccal and labial mucosa, the ventral and lateral surfaces of the tongue, the floor of the mouth, and the soft palate.
The incidence of mucositis is dependent on the cancer treatment regimen. The current head and neck radiotherapy protocols have a mucositis incidence of 85–100%. For altered fractionated radiation, the incidence is 100%, for chemoradiation 89%, and for conventional radiation 97% (Trotti et al., 2003). The incidence of mucositis can approach 90–100% in patients receiving aggressive myelo-ablative chemotherapy (Filicko et al., 2003). In solid-tumor patients, who have chemotherapy-induced myelosuppression, mucositis occurred during 37% of 1236 cycles of chemotherapy (Elting et al., 2003).
The severity of mucositis depends on different factors—e.g., anti-cancer treatment protocol, age and diagnosis of the patient, level of oral hygiene during therapy, and genetic factors (Dodd et al., 1999; Sonis and Fey, 2002; Barasch and Peterson, 2003).
Historically, mucositis was thought to arise as a consequence of direct and indirect toxic effects on epithelial cells. The colonization of the damaged mucosa by bacteria, fungi, and viruses can superimpose secondary infections (Rand et al., 1982; Makkonen et al., 1989; Spijkervet et al., 1989b). Furthermore, it was thought that the development of mucositis was facilitated by trauma, i.e., due to the effects of dentures on the oral mucosa or to oral hygiene habits (Berger and Kilroy, 1997; Dodd et al., 1999).
Today, mucositis is recognized as an epithelial and subepithelial injury and is thought to develop in a five-stage model: (1) initiation; (2) up-regulation with generation of messengers; (3) signaling and amplification; (4) ulceration with inflammation; and (5) healing (Sonis, 2004). Possible pathways of interventions for mucositis prevention can be shown in relation to this model (Fig. 1
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This review aims to evaluate the effectiveness of interventions for the prevention of oral mucositis in cancer patients treated with head and neck radiotherapy, chemotherapy, or chemoradiation. It focuses, whenever possible, on meta-analyses of randomized clinical trials of interventions for the prevention of oral mucositis.
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LITERATURE SEARCH STRATEGY AND STATISTICAL ANALYSES |
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TOPABSTRACTINTRODUCTIONLITERATURE SEARCH STRATEGY AND...INTERVENTION STRATEGIESCONCLUSION AND PERSPECTIVESREFERENCES |
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The literature search yielded 109 publications, but in 5 of these, prevention of oral mucositis was not the study objective. Of the remaining 104 studies, 13 were non-randomized, and 29 studies did not contain data in a comprehensive form. Each of 17 articles stood alone in terms of intervention. Therefore, the remaining 45 articles were included in the meta-analyses (Table).
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–5). The 95% confidence interval for each study is depicted by a horizontal line, and the point estimate is depicted by a square whose height is inversely proportional to the standard error of the estimate. The summary OR is drawn as a diamond with horizontal limits at the confidence limits, and width inversely proportional to its standard error. Meta-analyses were performed with the Rmeta package of the R Project for Statistical Computing (Build 2.0.1) (R development core team, 2004).
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INTERVENTION STRATEGIES |
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TOPABSTRACTINTRODUCTIONLITERATURE SEARCH STRATEGY AND...INTERVENTION STRATEGIESCONCLUSION AND PERSPECTIVESREFERENCES |
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Basic Oral Care
The NIH consensus (1989) states that, before the start of cancer treatment, patients who receive head and neck radiation or chemotherapy must be evaluated for potential risk factors for oral complications, by a thorough oral and dental evaluation, including a radiographic examination (NIH Consensus Conference, 1989). In two randomized clinical trials, various different oral care protocols were tested (Borowski et al., 1994; Shieh et al., 1997). In both studies, an intensive oral care protocol was compared with a standard oral care protocol. The intensive oral care protocol varied in the different studies. In one study, intensive oral care included treatment of dental lesions before chemotherapy, and tooth- and gum-brushing during aplasia (granulocytes < 0.5 x 109/L and/or platelet count < 20 x 109/L) (Borowski et al., 1994). In another study, radiotherapy patients were divided into three groups. In two groups, the protocol consisted of oral care instructions, toothbrushing, and rinsing with sterile water. One group started on day 1 of radiotherapy, and one group started 1 wk before radiotherapy. The control group received no instructions (Shieh et al., 1997). Both studies showed that additional oral care was important and had a positive attenuation effect on the development of oral mucositis. No meta-analysis was performed because, in one study, the data were not presented according to the inclusion criteria on the outcome variable, and therefore only one study was available for analysis.
Topical Antiseptic and Antimicrobial Agents
Studies with topical antiseptic and antimicrobial agents attempted to determine whether oral mucositis, due to colonization of the mouth with aerobic and anaerobic Gram-positive and Gram-negative micro-organisms or yeast, could be prevented.
Chlorhexidine, as an oral rinse, with concentrations of at least 0.12%, is an anti-plaque agent with potential antimicrobial activity. It has been evaluated in 10 randomized clinical trials for preventing oral mucositis, but the outcomes were different (McGaw and Belch, 1985; Ferretti et al., 1988, 1990; Spijkervet et al., 1989a; Epstein et al., 1992; Foote et al., 1994; Dodd et al., 1996, 2000; Cheng and Chang, 2003; Pitten et al., 2003). Of these studies, only seven fulfilled the inclusion criteria on the outcome variable for the meta-analysis (Table). One study was included in the database as two different studies, one for radiotherapy, and one for chemotherapy (Ferretti et al., 1990). Three studies used "presence of ulceration" as the outcome, one study used "presence of mucositis", and four studies used both. The meta-analysis, however, showed no effect of chlorhexidine in the prevention of mucositis in chemotherapy and radiotherapy patients (OR = 0.7 [CI: 0.43–1.12]).
Povidone-iodine is an antiseptic agent that is effective against oral bacteria. In the single randomized clinical trial in which povidone-iodine was used as a mouthrinse (Betaisosona® Mund-Antiseptikum, diluted 1:8), radiochemotherapy-induced mucositis was significantly decreased (Rahn et al., 1997).
Iseganan is a structural analogue of naturally occurring protegin-1. Protegins, initially isolated from porcine neutrophils, are antimicrobial peptides involved in local and systemic host defense. Iseganan has rapid microbicidal activity in saliva. It is a microbicidal agent against a broad spectrum of endogenous oral flora, including Gram-positive and Gram-negative bacteria and yeast, and it can be applied topically to the oral mucosa with no detectable systemic absorption (Giles et al., 2002). In the three published studies, there was no significant effect of iseganan on the prevention of oral mucositis induced by radiotherapy, chemotherapy, or chemoradiation (Giles et al., 2003, 2004; Trotti et al., 2004). Giles’ first study was not included in this meta-analysis, because of a major randomization flaw (Giles et al., 2003). The two included studies used the "presence of ulceration" as the outcome and evaluated both chemotherapy and radiotherapy patients. The meta-analysis showed no effect on prevention of ulcerations, OR = 0.75 (CI: 0.55–1.02).
Other studies investigated the effects of topical application of a combination of antimicrobials—consisting of polymyxin E, tobramycine, and amphotericin B (PTA) in a lozenge or paste—for selective elimination of the oral flora in radiotherapy patients. The goal of this combination was to eliminate aerobic Gram-negative bacteria and yeast (Spijkervet et al., 1990). Several randomized placebo controlled trials, with PTA, have been conducted, and the results were not in total agreement (Symonds et al., 1996; Okuno et al., 1997; Wijers et al., 2001; El-Sayed et al., 2002; Stokman et al., 2003). All five studies, all in radiotherapy patients, were included in the meta-analysis. All these studies used "presence of mucositis" and "presence of ulcerations" as the outcome. The meta-analysis found a preventive effect of PTA on the development of ulcerations, with an OR of 0.61 (CI: 0.39–0.96) (Fig. 2). However, no effect on the prevention of mucositis was found in radiotherapy patients.
Anti-inflammatory Agents
Benzydamine is a non-steroidal drug with analgesic, anesthetic, anti-inflammatory, and antimicrobial properties. Benzydamine inhibits the production and effects of inflammatory cytokines, particularly TNF-
. In particular, it has been evaluated for the prevention and reduction of radiation-induced oral mucositis with different outcomes (Kim et al., 1986; Prada and Chiesa, 1987; Samaranayake et al., 1988; Epstein et al., 1989; Cheng et al., 2004). In a large, multi-center, double-blinded randomized trial, benzydamine improved the ulcer-free rate and diminished the incidence of ulceration and erythema (Epstein et al., 2001). However, no study contained data that fulfilled the inclusion criteria on the outcome variable for the meta-analysis.
Topical prostaglandins are agents believed to possess anti-inflammatory and cytoprotective properties. Both prostaglandin E1 (misoprostol) and prostaglandin E2 have been evaluated in a small series of radiotherapy or chemotherapy patients, and there were conflicting outcomes (Pillsbury et al., 1986; Labar et al., 1993; Hanson et al., 1997). The manner in which the data were presented did not permit a meta-analysis to be conducted.
In one study, corticosteroids showed no reduction in the intensity or duration of radiotherapy-induced mucositis (Leborgne et al., 1998).
Cytokines and/or Growth Factors
The hematopoietic growth factors, granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF), can promote the accumulation of activated neutrophils in the mucosa, and can directly induce proliferation of endothelial cells and keratinocytes. The mucosal-protective effects of GM-CSF and G-CSF were tested in 13 randomized placebo-controlled trials, with systemic administration or local application by mouthwashes, in various chemotherapy, radiotherapy, or chemoradiation regimens (Cartee et al., 1995; Chi et al., 1995; Katano et al., 1995; Nemunaitis et al., 1995; Karthaus et al., 1998; Crawford et al., 1999; Schneider et al., 1999; Makkonen et al., 2000; Hejna et al., 2001; van der Lelie et al., 2001; Saarilahti et al., 2002; Valcarcel et al., 2002; Dazzi et al., 2003). Ten out of 13 studies could be included in the meta-analysis (Table). Six studies used GM-CSF/G-CSF for systemic administration (Chi et al., 1995; Katano et al., 1995; Nemunaitis et al., 1995; Crawford et al., 1999; Schneider et al., 1999; Makkonen et al., 2000), and 4 studies used GM-CSF/G-CSF as a mouthwash (Cartee et al., 1995; van der Lelie et al., 2001; Valcarcel et al., 2002; Dazzi et al., 2003). The "presence of mucositis" was used in 5 out of 6 studies (systemic intervention) and in 3 out of 4 studies (mouthwash) as the outcome. The meta-analysis found a significant effect of GM-CSF and G-CSF in preventing mucositis in the systemic intervention group, with an OR of 0.53 (CI: 0.33–0.87) (Fig. 3). No preventive effect was found for the topical administration of GM-CSF and G-CSF, OR = 0.32 (CI: 0.06–1.67).
Transforming growth factor-ß3 (TGF-ß3) is a cytokine that stimulates or inhibits cell proliferation, depending on cell type. The interim analysis of a randomized clinical trial showed no preventive effect on chemotherapy-induced oral mucositis (Foncuberta et al., 2001).
Probably the most promising growth factor is the recombinant human keratinocyte growth factor (rhuKGF; palifermin). In a phase III, randomized, double-blind, placebo-controlled study, intravenous palifermin significantly reduced the incidence (35%) and duration (3 days) of severe mucositis in patients with hematologic malignancies undergoing autologous peripheral blood progenitor cell transplantation after fractionated total-body irradiation (Spielberger et al., 2004). Palifermin seems promising for chemotherapy patients, but data on radiotherapy patients are not yet available.
Locally Applied Non-pharmacological Methods
Oral cooling of the mouth by sucking on ice cubes causes local vasoconstriction and reduces blood flow to the epithelium. Thus, it was thought that this approach would reduce the chemotherapeutic drug delivery to oral mucosa cells. In two randomized trials in patients receiving a 5-fluorouracil bolus, a 50% reduction in mucositis was observed when they sucked on ice (Mahood et al., 1991; Cascinu et al., 1994). These two studies were included in the meta-analysis. Both studies used "presence of mucositis" as the outcome for the prevention of 5-fluorouracil-induced mucositis. The meta-analysis for this outcome revealed a significant preventive effect, with an OR of 0.3 (0.16–0.56) (Fig.e 4).
Low-energy helium-neon laser has been reported to promote wound-healing and to reduce pain and inflammation. In three double-blind controlled studies, the severity and duration of oral mucositis in radiation and chemotherapy patients treated with low-energy helium-neon laser were reduced (Barasch et al., 1995; Cowen et al., 1997; Bensadoun et al., 1999). Unfortunately, the manner in which the data were presented did not permit a meta-analysis to be conducted.
Mouth-coating agents
Sucralfate is a basic aluminum salt of sucrose octasulfate, which, in the past, has been used in the treatment of gastric and duodenal ulcers. It is currently sometimes used in the treatment of radiation-esophagitis. Sucralfate acts as a protective coating by forming an ionic bond to proteins in the ulcer site. Furthermore, sucralfate stimulates prostaglandin production and mucosal cell renewal. To date, there have been 13 randomized trials that involved sucralfate, as an oral suspension, in various treatment protocols (Shenep et al., 1988; Pfeiffer et al., 1990; Epstein and Wong, 1994; Makkonen et al., 1994; Franzen et al., 1995; Lievens et al., 1998; Carter et al., 1999; Cengiz et al., 1999; Etiz et al., 2000; Castagna et al., 2001; Chiara et al., 2001; Dodd et al., 2003; Nottage et al., 2003). Nine out of 13 studies could be included in the meta-analysis (Table). Only two (Cengiz et al., 1999; Etiz et al., 2000) reported a significant reduction of radiation-induced mucositis. Five studies used "presence of mucositis" as outcome, one study used "presence of ulceration", and three studies used both. The meta-analysis found no effect of sucralfate on the prevention of mucositis or ulcerations in chemotherapy and radiotherapy patients, OR = 0.82 (CI: 0.05–1.33).
Radical Scavenger
Amifostine (WR 2721, Ethyol) is an organic thiophosphate compound that selectively protects normal cells from treatment-related toxicity. It is a drug that is active as a protective agent when dephosphorylated by alkaline phosphatase to its active metabolite, WR-1065. WR-1065 is preferentially taken up by normal, rather than neoplastic, cells, because of the higher alkaline phosphatase activity, better vascularization, and higher pH of normal tissue. Once inside the cell, WR-1065 protects against chemotherapy- and radiation-induced damage by scavenging free radicals, donating hydrogen ions to free radicals, depleting oxygen, and by direct binding to and inactivation of cytotoxic drugs (Hospers et al., 1999; Culy and Spencer, 2001). Nine randomized clinical trials have used amifostine intravenously or subcutaneously for the prevention of mucositis in various treatment regimens, with different outcomes (Buntzel et al., 1998; Bourhis et al., 2000; Brizel et al., 2000; Koukourakis et al., 2000; Hartmann et al., 2001; Antonadou et al., 2002; Thieblemont et al., 2002; Lorusso et al., 2003; Vacha et al., 2003). Seven studies could be included in the meta-analysis (Table). All studies used "presence of grades 3 and 4 mucositis" as the outcome and were performed in chemotherapy, radiotherapy, or chemoradiation patients. The meta-analysis found a significant effect of amifostine in the prevention of grades 3 and 4 mucositis in chemotherapy and radiotherapy patients, with an OR of 0.37 (0.15–0.89) (Fig. 5).
The Amino Acid, Glutamine
Glutamine is an amino acid required for the support and maintenance of intestinal growth and function. During episodes of catabolic stress, there is a marked intracellular depletion of glutamine (Savarese et al., 2003). Oral glutamine was tested in five studies, with different outcomes (Jebb et al., 1994; Anderson et al., 1998a,b; Okuno et al., 1999; Huang et al., 2000). Two studies could be used for the meta-analysis, and the "presence of mucositis" was the outcome variable (Okuno et al., 1999; Huang et al., 2000). The meta-analysis found no effect of glutamine on the prevention of mucositis in chemotherapy and radiotherapy patients, OR = 1.25 (CI: 0.61–2.59).
Anti-oxidants
The use of anti-oxidants such as azelastine hydrochloride (Osaki et al., 1994), vitamin E (Ferreira et al., 2004), and zinc sulfate (Ertekin et al., 2004) for the prevention of oral mucositis in radiotherapy or chemoradiation seems to be interesting, but needs further research.
Anti-neoplastic Agent Antagonists
Allopurinol is a structural isomer of hypoxanthine, which is used for the treatment of gout. Some pilot studies have shown that allopurinol mouthwash decreased 5-fluorouracil-induced mucositis. However, in the single randomized, placebo-controlled, double-blind study, no effect of allopurinol mouthwash on 5-fluorouracil-induced mucositis was observed (Loprinzi et al., 1990).
Immunomodulatory drugs
Pentoxifylline is a xanthine derivate, capable of down-regulating TNF- production and stimulating vascular endothelial production of prostaglandins I2 and E2. The two randomized clinical trials that studied the effect of oral administration of pentoxifylline for the prevention of chemotherapy-induced mucositis failed to show any benefit (Attal et al., 1993; Verdi et al., 1995). The manner in which the data were presented did not permit a meta-analysis to be conducted.
Anti-cholinergic Agents
Oral administration of pilocarpine hydrochloride is approved for treatment of radiation-induced xerostomia in several countries. It is a naturally occurring, cholinergic, parasympathomimetic alkaloid that has a broad range of pharmacologic effects, including increasing secretion from the exocrine glands (sweat, salivary, lachrymal, gastric, pancreatic, and intestinal glands). Only one randomized, double-blind, placebo-controlled cross-over study has been published, showing a significant decrease in the development of chemotherapy-induced oral mucositis (Awidi et al., 2001).
Miscellaneous
Traumeel S® is a homeopathic medication containing 12 botanical substances and 2 mineral substances. It has been sold over the counter in pharmacies for over 50 years, and it is available worldwide for use as an anti-inflammatory, analgesic, anti-edematous, and anti-exudative drug. In a randomized, placebo-controlled study, Traumeel S®, as a mouthwash, significantly reduced the severity and duration of chemotherapy-induced mucositis (Oberbaum et al., 2001).
The topical application of honey was investigated in a randomized, non-blinded study in radiotherapy patients (Biswal et al., 2003). In this study, a significant reduction of mucositis grades 3 and 4 was detected.
In a double-blind, randomized study, the efficacy of a calcium phosphate mouthrinse (Caphosol®) with fluoride treatments was tested for the prevention of mucositis in patients undergoing hematopoietic stem cell transplantation (Papas et al., 2003). The use of the mouthwash Caphosol® had a significant effect in decreasing the duration and severity of mucositis.
Aloe vera contains numerous vitamins and minerals, enzymes, amino acids, natural sugars, and agents that may be anti-inflammatory and antimicrobial. The aloe vera gel has been used for topical treatment of wounds, minor burns, and skin irritations. In a double-blind, randomized clinical trial for the prevention of radiation-induced mucositis, topical aloe vera did not show any benefit (Su et al., 2004).
Chamomile mouthwash is a solution prepared from the flower of the chamomile plant. This plant contains many different substances that have been suggested to have anti-inflammatory, antibacterial, and antifungal properties. However, the use of chamomile mouthwash in a double-blind, randomized clinical trial for the prevention of 5-fluorouracil-induced mucositis did not show any benefit (Fidler et al., 1996).
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CONCLUSION AND PERSPECTIVES |
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TOPABSTRACTINTRODUCTIONLITERATURE SEARCH STRATEGY AND...INTERVENTION STRATEGIESCONCLUSION AND PERSPECTIVESREFERENCES |
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In our meta-analyses, studies involving radiotherapy and chemotherapy patients on amifostine or GM-CSF/G-CSF were combined. There were insufficient trials by type of intervention to conduct subgroup analyses for different cancer types or cancer therapies. Moreover, it is currently commonly accepted in oncology literature to combine studies on radiation and chemotherapy for meta-analyses if needed.
GM-CSF and G-CSF have been shown to be effective in reducing the severity, and shortening the duration, of neutropenia after chemotherapy. Our meta-analyses showed that GM-CSF and G-CSF are the only interventions with some beneficial effect on the development of mucositis. However, in our meta-analyses, GM-CSF and G-CSF were combined, which is probably not absolutely correct, because GM-CSF also enhances, in addition to the granulocyte-stimulating effect, the phagocytic capacity of macrophages. Subgroup analysis was not possible because of insufficient trials by intervention type.
PTA and amifostine decreased the severity of mucositis. With regard to the potential of amifostine to limit mucositis, it is noteworthy, for clinical practice, that this evidence is based on variable doses of amifostine and the various cancer types in which the effect of amifostine was studied.
Oral cooling prevented mucositis in 5-fluorouracil-induced mucositis, with evidence based on two studies, in one of which only patient-reported mucosal damage was used, and in the other, both patient- and investigator-reported mucosal damage was used.
From the 14 single studies published, each on a different intervention type, 9 interventions showed some positive results in the prevention of mucositis. Most studies consisted of small sample sizes, were not double-blinded, or did not use a placebo-controlled design, except one study (Epstein et al., 2001) in which benzydamine improved the ulcer-free rate and diminished the incidence of ulceration and erythema, in a large, multi-center, double-blind randomized trial. Further research with well-designed studies is necessary for evidence of the effectiveness of any of these interventions in the prevention of mucositis.
Palifermin, the recombinant human keratinocyte growth factor, administered intravenously, seems to be the most promising intervention for the prevention of mucositis in patients with hematologic malignancies and undergoing autologous peripheral blood progenitor cell transplantation after fractionated total-body irradiation (Spielberger et al., 2004).
To date, it can be concluded that no single intervention is capable of completely preventing oral mucositis. Future studies should evaluate a combination of interventions for the prevention of oral mucositis. In contrast, novel therapies could be developed that will improve outcomes and be used as single agents.
Received March 31, 2005; Accepted January 17, 2006
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