To begin with, let me acknowledgethat Drs. Epstein andSchubert are experienced doctorsof dental medicine who have beeninvolved in the evaluation and therapyof cytotoxic therapy–related mucositisfor a long time. I fully agree withthem that cytotoxic therapy–associatedmucositis is a major clinicalproblem and that there is a dearth ofgood studies that address ways to alleviatethe condition. Drs. Epstein andSchubert do an excellent job describingthe incidence, causative factors, and etiology of cytotoxic therapy–relatedoral mucositis, and they are tobe congratulated for this. Nonetheless,I view a few points differently, as discussedbelow.
To begin with, let me acknowledgethat Drs. Epstein andSchubert are experienced doctorsof dental medicine who have beeninvolved in the evaluation and therapyof cytotoxic therapy-related mucositisfor a long time. I fully agree withthem that cytotoxic therapy-associatedmucositis is a major clinicalproblem and that there is a dearth ofgood studies that address ways to alleviatethe condition. Drs. Epstein andSchubert do an excellent job describingthe incidence, causative factors, and etiology of cytotoxic therapy-relatedoral mucositis, and they are tobe congratulated for this. Nonetheless,I view a few points differently, as discussedbelow.Mucositis Grading
First, I disagree with the authors'opinion on the grading of oropharyngealmucositis as illustrated by theirstatement that "when mucositis is beingassessed as part of a clinical trial,a tissue-derived score based on a validatedscale such as the Oral MucositisAssessment Scale or Oral MucositisIndex should be used."There are good data to demonstratethe congruence of several differentmucositis grading scales, regardless of whether these grading scales are basedprimarily on visualization of the oralmucosa by an expert or on patientreportedsymptoms. Indeed, one ofthe two treatments recommended byDrs. Epstein and Schubert-oral cryotherapyfor the prevention of bolusfluorouracil (5-FU)-resultant oral mucositis-was studied by looking atsymptom-related mucositis scores intwo clinical trials conducted by independentgroups of investigators.[2,3]This contention that symptombasedmucositis scoring is appropriatein clinical trials was recently confirmedin a trial of keratinocyte growthfactor (KGF) to alleviate cytotoxictherapy-related mucositis. Investigators reported that patient-derivedsymptoms correlated well with oralinspections of the oral mucosa.[4,5]These data, and the recognition thatpatient-described mucositis-relatedsymptoms are probably much moreclinically important than are the sizeof particular lesions in their mouths,support the conclusion that symptomderivedmucositis scores are quite appropriate,both in clinical practice andin clinical research.Keratinocyte Growth Factor
Drs. Epstein and Schubert referencea recently conducted phase Iclinical trial of KGF, noting that"fewer patients developed ulceratedmucositis (43% vs 67%, P = .06)."Although this statement is true, theauthors do not note that, in this sameclinical trial, substantially increaseddermatologic toxicities were seen inthe patients receiving KGF, comparedto placebo. Therefore, the reductionin mucositis was traded for substantialincreases in dermatologic toxicity.In order for KGF to be clinicallyuseful in this situation, a better therapeuticwindow will be necessary.In addition, they discuss anotherKGF trial in patients receiving highdosechemotherapy and total-body irradiation,for whom statistically significantreductions in mucositis were noted.The reference to this trial is currentlyonly available as an abstract from thisyear's meeting of the American Societyof Clinical Oncology. A full reportof this promising-sounding clinical trialis necessary before we can more fullyunderstand the potential risks and benefitsof KGF in this situation.Thus, based on the available publishedreferences the authors provide,I view KGF as a potentially promisingnew therapy for the prevention ofmucositis, as opposed to somethingthat should be used presently in clinicalpractice. Hopefully, further positiveresults will become available inthe near future to demonstrate thatKGF has therapeutic efficacy.Benzydamine
Drs. Epstein and Schubert proposethe use of benzydamine as an analgesic based on two referenced clinical trialsfor which they were coauthors,[6,7]stating, "If available, benzydamineshould be recommended for prophylacticuse in patients receiving radiationtherapy." They note that benzydamineis available in Europe andCanada but is not available in theUnited States, where it is currentlybeing studied in pivotal phase III trials.Based on the available data, I sidewith the Food and Drug Administrationconclusion that there is not currentlyenough proof to recommendthat benzydamine be used in clinicalpractice.The first of the two studies citedby Drs. Epstein and Schubert to supporttheir recommendation is a smalltrial that was published in 1989.This trial enrolled 43 patients. However,6 patients randomly assigned tothe placebo group were removed fromthe analysis because they reportedlydid not comply with the protocol,leaving only 25 evaluable patients. Inlooking at patient symptoms duringradiation therapy in this trial, the investigatorsfound no statistically significantdifferences between the placeboand benzydamine groups. Therewas, however, some evidence of decreasedoral mucositis-as visualizedby the investigators-in the benzydaminegroup.The second referenced trial, the resultsof which were published in2001, was considerably larger, involving172 patients. As the main outcomevariable of this study, oral mucositisscores were based on physicalexamination, looking for erythema,pseudomembrane production, and ulceration.Utilizing this methodology,the investigators noted approximatelya 30% reduction of mucositis in thebenzydamine group, compared to theplacebo group (P = .006). In addition,statistically significant reductions inthe use of analgesics were reported inpatients receiving benzydamine vsplacebo.There were, however, no statisticallysignificant differences betweenthe two study groups for the followingoutcomes: mouth pain, throat pain,pain during meals, weight loss, suspensionof radiation therapy because of oral mucositis complications, or theuse of nasogastric or percutaneousendoscopic gastrostomy tube feedings.In addition, it was noted that adverseevents were seen in 87% of thebenzydamine subjects and 91% of theplacebo subjects in this trial. The investigatorscomment that 58% of thesetoxicities were felt to have been "attributedto the expected local pharmacologicactions of the study drug andvehicle on inflamed mucous membranes(ie, oropharyngeal burning,numbness/tingling, taste loss, and tastealteration)."Another thing to note regarding theabove two trials is that a potentiallytoxic placebo was used for comparisonwith the active therapy groups. Theplacebo ingredients, similar to the activeagent, "included approximately10% alcohol by volume, methanol,peppermint oil, clove oil, and otherflavoring agents." It can easily behypothesized that this alcohol-basedpreparation actually caused increasedmucositis and increased toxic symptomsin the study participants. Thishypothesis is supported by anothertrial, which looked at a chlorhexidinemouthwash vs placebo. In this trial,for which an inert placebo (no alcoholin a bland placebo preparation)was used, the patients receivingchlorhexidine had substantially increasedtoxicity and a trend for increasedmucositis scores compared tothe placebo group.Thus, it can be argued that furtherinformation is necessary before wecan recommend benzydamine as aprophylactic therapy for patients receivingradiation treatments. Hopefully,such information will be forthcomingsoon.Chlorhexidine
Drs. Epstein and Schubert appropriatelynote that chlorhexidine shouldnot be routinely used for radiationinducedmucositis based on clinicaltrial results. In their recommendations,however, they note that "chlorhexidinecan be considered for use in cancerpatients to help reduce plaque levelsand thus reduce risk of gingivitis andcaries." Given the irritation of the alcohol and flavoring agents in chlorhexidine,it would be better to avoidchlorhexidine altogether in patients atrisk for mucositis.Miscellaneous Topical Approaches
Drs. Epstein and Schubert note thatcoating agents such as milk of magnesia,Amphojel, and Kaopectate"clearly can have palliative effects thatmay improve patient comfort." Nonetheless,I am unaware of any publishedclinical trial data to confirmsuch a statement. Given the largenumber of negative clinical trials thathave evaluated purportedly helpfulagents,[9-16] it must be noted thatthese agents may well not help decreasemucositis, might actually increasemucosal injury, and mightcause toxicity.[11,12,15]In the same vein, the authors nicelydiscuss the limitations of sucralfate,based on clinical trial results, but thengo on to state that "sucralfate primarilyappears to be able to help decreaseoropharyngeal pain." This seems to bea statement based on anecdotal experienceunsupported by clinical trialdata. Results of phase III clinical trialsshow that sucralfate does not decreaseoral mucositis from 5-FUtherapy, esophagitis from radiationtherapy, or proctitis from radiationtherapy. Indeed, in each ofthese studies, sucralfate caused moretoxicity than did the placebo. Accordingly,not only is sucralfate not recommended,its use is contraindicatedduring cancer therapy as a means ofreducing mucosal toxicity.Conclusions
In conclusion, I agree with Drs.Epstein and Schubert regarding themagnitude of the clinical problem associatedwith cytotoxic therapy-associated mucositis, for which patientsare certainly in need of effectivetherapies. Stronger evidence ofefficacy without major toxicity isneeded, however, before agents suchas benzydamine, chlorhexidine, orsucralfate can be recommended foruse in clinical practice. This is particularlytrue of agents such assucralfate and chlorhexidine, forwhich the balance of evidence suggestsnot only a lack of efficacy, butalso a harmful effect from treatment.
The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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