Oral Medicine

Efficacy of a synthetic polymer saliva substitute inreducing oral complaints of patients suffering fromirradiation-induced xerostomiaG. Regelink, MD*/A. Vissitik, DDS. PhD**/H. Reititsema, DDS, PhD***/J. M. Nauta, DDS, PhD**

Objective: A saliva substitute based on polyglyceijlmethacrylate, lactoperoxidase. and glucose oxidase (OralBalance) has been developed. The aim of this study was to evaluate ihe effect of Oral Balance on ihe dryness-related oral complaints in patients suffering from irradiation-induced xewstomia.Method and materials: The efficacy of Oral Balance on the dryness-related complaints of 28 patients wasas.'iessed hy means of self-administered questionnaires. Each patient completed an initial questionnaire aboutdryness-related symptoms and then was given the moistening gel. The patients were instructed to apply the gelas ofien as desired. Afier 2 weeks and 3 months, the patients were asked to complete a progress questionnaire.The severity of xerostomia was measured with a saliva absorption method.Results: All patients suffered from moderate-to-severe xerostomia, the severity of which did not change duringthe experimental period. Three patients did not complete the study. In the other 25 patients, the applicationof Oral Balance tended to diminish the sensation of oral dryness and improve oral functioning. Statisticallysignificant reduction of the dryness-related complaints was observed only in the patients suffering from severexerostomia.Conclusion: Use of Oral Balance is of potential benefit in patients suffering from severe xerostomia.(Quintessence Int 1998;29:383-388)

Key words: irradiaiion therapy. Oral Balance. saUva çubstitute, xerostomia

Clinical relevance

As a general nile. in patients suffering from severexerostomia, dryness-related complaints can be sig-nificantly ameliorated by use of a saliva substitute.In patients with slight-to-moderatc xerostomia, abetter effect can be expected from gustatory stimu-lation of the residnal secretion.

Radiotherapy is a significant treatment modality inliead and neck oncology. It is aimed at destroying

tnmor cells, but ionizing irradiation has an effect on

•* Postgraduate Studeiil, Depanineni uf Oral and Maxillofacial Surgery,

University Hospital Groningen, Groningen. The Netherlands.

»'Oral and Maxillofacial Surgeon. Department of Oral andMaxilJofacial Surgery, University Hospital Groningen, Groningen,The Netherlands.

""Maxillofaciai Prosthodontist, Depanment of Oral and MasillofacialSurgery, University Hospital Groningen. Groningen. The Netherlands,

Reprint requests; Dr A. Vissink, Department of Oral and MaxillofacialSuroery University Hospital Groningen, PO Bos 30.001, 97G0 RBGroningen, The Netherlands. E-mail: A.Vissink@kchir.azg.nl

normal tissue as well. Within the field of oral and max-illofacial oncology, radiation damage to the oral mucosa,í;alivar>' glands, and bone is of particular clinical signifi-cance.' Radiation injury to these tissues results in earlyeffects such as inucositis, taste disturbance.̂ , and hypo-salivation, and late effects such as hyposalivation andosteoradionecrosis.

From both the clinical and radiobiologic points ofview, the salivary glands are unique tisstje becao.se theyshow both early and late radiation damage. The drop insalivary flow rate develops as quickly as the changes inthe oral mucosa and taste, but nnlike the oral mucosa andsense of taste, salivary secretion usually demonstrates nosignificant recovery after completion of the radiationtreatment schedule.--' Radiation injury to the salivaryglands and the consequent changes in the amount andcomposition of saliva result in oral dryness (xerostomia),nocturnal oral discomfort, difficulties with swallowingand speech, and an increased susceptibility to oral infec-tions and dental caries. These changes impede oral func-tioning and severely restrict daily activities and thus havea large negative impact on the well-being of the patient."

Treatment of radiation-related xerostomia and its re-lated complaints is mainly symptomatic because at cum-

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ulative doses of more than 40 Gy, the radiation-relatedreduction of salivary gland functioning becomes irre-versible.'-' Doses of 40 Gy and less are mainly reservedfor the treatment of hématologie disorders, stjcb asHodgkin's lymphoma. while a conventional radiationtherapy for squamous cell carcinoma In tbe bead andneck region is 2 Gy/d. five times a week, for 5 to 7weeks. Thus, in tbe latter patients, postradiotherapystimulation of tbe residual salivary flow witb pilo-carpine, for example, is not a tberapy with a predictablelong-lasting success because the achieved effect will belost witbin a few tnonths after therapy is stopped.'-'- Apromising, still experimental idea is prevention of theradiation damage to the salivai^ glands with radiopro-tectors such as WR-2721'̂ or by stimulating tbe salivaryglands with pilocarpine before irradiation.''''^ Tbese twotberapies, respectively, are aimed at protecting tbe sali-vary tissue against radiation damage and at increasingand stimulating tbe number of surviving acinar cells.

Because the latter two preventive therapies are stillexperimental and many patients are already sufferingfrom irradiation-related xerostomia, several sympto-matic treatments have been developed. Good resultshave been reported for the use of saliva substitutesbased on either carboxymethylcellulose or hydroxy-propylmethylcellulose'"" or on mucins,"* among whichthe mucin-containing substitutes have been shown to besuperior.'''--^ Nevertheless, clinical experience hasrevealed that even the latter substitutes are not usedwith predictable success by many patients because oftbe inberent shortcomings of the saliva substitutes andoverly high expectations of the patients. Therefore, newsubstitutes based on a linseed extract-' or syntbeticpolymers such as xanthan gum and polyacrylic acidhave been developed. '̂' The latter study revealed tbatthese substitutes were as effective as a mucin-contain-ing saliva substitute but that each substitute has its ownsubpopulation of patients for whom it is the most effec-tive one.-"*

Another, not tborougbly studied, saliva substitutebased on synthetic polymers is Oral Balance (Biopole),a substitute containing pol y glyceryl methacryiate, lacto-peroxidase, and glucose oxidase as active components.Tbe potential efficacy of this substitute, as claimed bythe manufacturer, is predominantly based on tbe appli-cability of the lactoperoxidase system in supragingivalplaque control-^ and reduction of oral mucosal dis-eases.^'' Its efficacy in reducing the subjective sen-sation of oral dryness in xerostomic patients is merelybased on (unpublished) case reports. Therefore, the aimof tbe present study was to evaluate the effect of OralBalance on the dryness-related oral complaints ofpatients suffering from irradiation-induced xerostomia.

Method and materials

During a period of 5 tnontbs, all patients wbo visitedtbe oncology unit of the Department of Oral andMaxillofacial Surgery of tbe University HospitalGroningen and who fulfilled the inclusion criteriawere asked to Join tbe study. Tbe inclusion criteriawere:

1. It bad been at least I year after radiation therapy(with or without surgery) for a squamous cell car-cinoma of the oral cavity or pharynx. This periodwas chosen because the functional recovery fromradiation injury to the salivary glands is usuallycomplete by the end of the first year after radio-therapy.

2. All major salivary glands were within the treatmentportals.

3. The radiation dosage to the salivary glands was atleast 50 Gy (fractionated radiotherapy; 2 Gy/d, fivetimes a week).

4. The patient was suffering from oral dryness (sub-jective complaints).

5. The patient was able and willing to complete ques-tionnaires.

6. There was no change in prescribed drugs during thestudy period.

Oral dromes s

Because hardly any saliva could be collected from arather large number of the patients, the severity of oraldryness was estimated by a saliva absorption method.'*The saliva (ie, oral fluid) on the mucosa, teeth, anddentures was soaked up with a saliva-absorbing gauzesponge, which was weighed before and after the col-lection. AH tests were performed between l;00 and4:00 PM, and the patients were asked not to take fluids,food, or the moisturizing gel (Oral Balance) for 1 hourbefore the test. The increase in weight of the spongereflected the degree of oral dryness.

Saliva sub s titule

Oral Balance is a moisturizing gel based on polyglyc-ery I methacryiate (for moistening and lubrication of theoral mucosa), lactoperoxidase, and glucose oxidase (forprotection against orai infections). The gel was provid-ed in tubes of 50 g. For each application, the patient hadto take about 1 cm of gel on the fingertip and spread itall over the oral mucosa. The patients were instructed toapply tbe gel before sleeping and as desired throughouttbe day.

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Qiie.-ítionniiires

The efficacy of Oral Balance on the dr^-ness-related com-plaints was assessed by means of self-administered ques-fionnaires (Table I ) based on quesfionnaires developedby Vissink et al," "s-Gmvenmade and Vissink,-and Vander Reijden et al.-̂ Each pafient was asked to cotnpletean inifial questionnaire (I) about dry ne s.s-re lated symp-toms and then was given the moisturizing gel. The gelwas to be used according to instrtictions. After 2 weeksand 3 months, tbe patients were asked to complete a pro-gress questionnaire (II) on the efficacy of the oral gel.

Quesfionnaire I was used to score the initial status ofthe dryness of tbe tnouth, in particular its influence onoral futicfioning, sucb as changes in swallowing, chew-ing, speech, and the impact on daily life. Quesfionnaire 11specifically asked about the effect of the oral gel on thepattem of complaints. The perceived adequacy of theoral gel was indicated on a 5-point scale that ranged fromabsence of restricfion in oral function or no sensation oforal dryness (score 4) to frequent occurrence (score 0).

Tbe frequency of apphcation of the gel and the reten-tion fime in the oral cavity were also recorded. Retentiontime was deflned as die period during which the patientsperceived an effective action of the gel (moistening oforal surfaces).

TABLE 1 Summary of the major questions asked ofpatients in the study

Ouestionnaire I

tHow dry is your mouth?Are you suflering from orai dryness during daytime?Are you suffering from orai dryness at nighfDo you have a nasty taste in your mouth?is sleeping impeded?is swaiiowing impeded?is eating impeded?irnpact on daily activities:

Are you visiting peopie less frequentiy?Are you speaking less with people?Are you staying at home more often?Do you feei ionely?Do you feei apathetic?

Ouestionnaire IItiow frequeritiy do you apply the gei''For how long is your mouth moist afler applying the gel?Is the extent of orai dryness reduced when applying the gel?How dry is your mouth when applying the gel?How do you appreciate the taste of Ihe gel?What compiaints are reduced when using the gei''Dryness during daytime

Dryness at nightBurning mouthNasty tasteSleeping diffiouitiesDifficuities with speechDifficuities with swailowingDifficuities with eating

Study design

If the pafient fulfilled all inclusion criteria and decided tocooperate (informed consent), quesfionnaire I was com-pleted by the patient, and the severity of oral dryness wasmeasured by the saliva absorption metbod. A newappointment was made 14 days after tbis first contact:during these 2 weeks, the pafient had the opportunity totry the gel. At the second contact, quesfionnaire II wascompleted, and the mouth was swabbed again for estima-tion of tbe level of oral dryness.

At the third appointment {3-month evaluation) themouth was swabbed, and questionnaire II was com-pleted. The patients were then asked if they wished toconfinue using the gel. This quesfion was intended toassess the additional value of the oral gel in reducing tbedryness-related oral complaints when compared to thepatients" normal way of reducing these complaints,because there is currently no proper placebo gel avail-able tbat would allow a double-blind crossover trial.

Statistical analysis

The data were analyzed by paired t tests. The t distribu-tion was used as an approximation to the distribution oftest statistics involving means of individual scores. The

use of the approximation is based on the fact that theindividual scores—on a 5-point scale—were fairly sym-metrically distributed and on the sufficiently large num-ber of observations. This approximation to the ; test isknown as tbe test of Yates.-'

Results

Patients

Twenty-eigbt edentulous patients cooperated in thisstudy, 9 females and 19 males, with a mean age of 61 ±11 years (range of 47 to 82 years). The mean overallradiation dose was 64.5 ± 8.0 Gy (range of 30 to 70 Gy).Three patients did not complete the study, one patientbecause of recurrence of the tumor and two patientsbecause they did not sbow up at the recall vi.sits.

At the end of the 3-month study period, 9 of the 25patients (36%) who completed the study stopped usingthe gel hecau.se of lack of subjective improvement oftheir complaints. They mostly returned to their formersaliva substitute or their individual ways of alleviatingthe oral discomfort. The other 16 patients (64%) didwi.sh to confinue die use of the gel after completion ofthe study period. The patients who stopped using the gelall suffered from moderate xerostomia.

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Fig 1 Effect (mean ± SEM) of Oral Balance on the severity oforal dryness experienced by tfie patients (n = 25, f6, and 9 fcrtotal group, group I, and group il. respectively). The scale of they-axis ranges from very severe xerostcmia (2) to a completeabsence of dryness-related cornpiaints (4). ('P < .05,)

Total group Group I Group II

Fig 2 Effect (mean ± SEfvl) of Oral Balance on oral functioning(n = 25. 16, and 9 for total group, group I, and group II, respec-tively). The scale on the y-axis ranges from rnany restrictions inoral functioning (2) to a compiete absence of such restrictions (4),(•P<.O5.¡

Oral diyness

The subjects participatitig in this study suffered frommoderate-tu-severe xerostomia. The tiieati amoutit ofsaliva ¡oral fluid) in the otal cavities was 342 ± 306 mg(range of 50 to 1,420 mg). Healthy subjects who do nottise dmgs and who have tiot been exposed to radiationtherapy have 1,800 to 3,000 mg of saliva in their oralcavities.'^ No change in the severity of oral dryness wasobserved during the 3-month evaluation period.

Questionnaires

The application of Oral Balance tended to reduce thesensation of oral dryness and to improve oral function-ing (Figs I and 2), Previous studies have shown that theborderline betweett moderate and severe xerostomia is300 mg of saliva in the oral cavity.-- This group ofpatients was split into two subgroups, resulting in agroup I (severe) with 16 patients who had less than 300mg of saliva in their mouth (185 ± 109 mg, range of 50to 260 mg) and a group II (moderate), consisting ofnine patients who had more than 300 mg of saliva intheir tnouth (652 ± 339 mg, range of 330 to 1,420 mg).The data for ihese two groups were analyzed separately(Figs 1 and 2), The three patients (all within group I)who did not complete the study were excluded. Thedaily activities were the same in both groups, whileboth oral functioning and the dryness-related com-plaints were ,signifieantly improved in patients sufferingfrotn severe xerostomia (P < ,05, paired / test).

During the daytime, the moistening effect of oneapplication of the gel lasted, on average, up to 1 hour inthe patients with severe xerostomia and up to 30 min-utes in patients stiffcring from moderate xerostomia. Atthe 3-month evaluation period, the average moisteningtime had increa,sed to more than I hour in patients ingroup 1, while it hardly increased in the patients itigroup II, who, on the whole, did not experience muchbenefit from this substitute. The greater effect of OralBalance in the patients suffering from severe xerosto-mia was also reflected in the application frequency ofthe gel by the patients at the 14-day and 3-month evalu-ations, ie, 2,8 ± 1,3 and 3,5 ± 1,4 times a day, respec-tively, in the patients of group I and 2,0 ± 1,2 and 2.3 ±1,4 times a day, respectively, in the patients of group 11,

The application frequency and moistening time dur-ing the night could not be recorded in a reliable waybecause most patients applied the gel before sleepingand did not have to repeat it during the night other thanon the few occasions that they awakened because oforal dryness or had to go to the bathroom. This meansthat the average moistening time during the night ismore than 4 hours, the maximum of the rating scale.

Discussion

It is unfortunate that patients who are being cured of asquarnous cell carcinoma of the oral cavity or pharynxmay suffer from the side efïects of radiotherapy for theresi of their life. The main complaints of patients suffer-ing from irradiation-induced xerostomia are oral dry-

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tiess, impeded oral functioning (ie, difficulties with eat-ing, swallowing, and speech), nocturnal oral discomfort,and the increased susceptibility to oral itifections anddetital caries. Consequently, the quality of patients'daily activities atid social life is considerahly poorer,''Therefore, every effort to decrease the wide range ofdry ness-related cotnplaints is a significant one.

This study revealed that Oral Balance can be of somevalue in patients suffering from severe xerostomia. Par-ticularly, the good adhesion of the gel to the oral sur-faces, and the consequently rather long retetttion timeduring the night and during periods with tninimal activ-ity, are of great value in these patients, A relationshipbetween the efficacy of a saliva substitute and itsviscosity has also been detected in tbe studies of "s-Gravenmade and Vissink-- and Van der Reijden et al,-''As a general rule, tbe following recotnmendations fortreatment can be detected frotn tbe literature and thisstudy:

1. Severe xerostomia. A saliva substitute witb gel-likeproperties (eg. Oral Balance) and mucin-containinglozenges-2 sbould be used during tbe night and wbendaily activities are at a low level. During tbe day. asaliva substitute witb properties resembling tbeviscoelasticity of natural saliva, such as substitutesbased on polyacrylic acid, xanthan gum, and mucin(tovin submandibular mucin), sbould be applied,

2. Moderate xerostomia. If gustatory or pbarmacologicsiimulation of tbe residual salivary secretion does notprovide sufficient amelioration, saliva substitutes witba rather low viscoelasticity, such as substitutes basedon carboxymethylcellulose, hydroxypropylmetbylcel-lulose, mocin [porcine gastric mucin), or low concen-trations of xanriian gum and polyacrylic acid are indi-cated. During tbe nigbt or other periods of severe oraldryness, the application of a gel is worthwhile.

3. Slight xerostomia. Gustatory or pharmalogic stimula-tion of the residual secretion is the treatment ofchoice. Little ameboration is to be expected frotn theuse of saliva substitutes.

Although it has been sbown tbat continuous applicationof a mucin-containing saliva substitute has tbe potentialto reduce botb tbe pathogenic properties of the oralflora-** and the prevalence of stomatitis and oral candidi-asis,=' the application of lactoperoxidase and glucoseoxidase is apparently of limited usefulness for this pa-tient group, considering their large number of com-plaints. Perhaps, as in the mucin-containing substitutes,the addition of enzymes such as lactoperoxidase andglucose oxidase is of some potential in those xerostomicpatients who frequently suffer from oral infections.

Because in these patients candidal species are oftenthe underiying pathogenic microorganisms, the additionof histatines, which possess a much greater inhibitoryeffect on growth of Candidu albicans. sbould be consid-ered as a potentially better additive to a sabva substitute.The value of these and other additions to saliva substi-tutes is a stibject of current research as well as the mu-tual cornparison of the efficacy of the various developedsaliva substitutes. In dentuious patients, the addition ofboth fluoride and the lactoperoxidase system to a salivasubstitute or toothpaste has to be considered as well.

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Answers to Ql 3/98 Questions

^•"í^liíí^ 1.

2.3.4.

DCDD

5.6.7.8.

DCDD

9.10.11.12.

BBDB

13.14.15.16.

BDDA

388 Voiume 29. Number 6, 1998