Efficacy of the BioXtra dry mouth care system in the treatment of radiotherapy-induced xerostomia

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1 DOI /s y SHORT COMMUNICATION Efficacy of the BioXtra dry mouth care system in the treatment of radiotherapy-induced xerostomia Piet Dirix & Sandra Nuyts & Vincent Vander Poorten & Pierre Delaere & Walter Van den Bogaert Received: 7 September 2006 / Accepted: 20 December 2006 # Springer-Verlag 2007 Abstract Introduction Xerostomia is a common complication of radiotherapy for head and neck cancer. Symptomatic treatment consists of stringent oral hygiene to prevent oral infections and saliva substitutes to increase comfort. The aim of the study was to evaluate the clinical effectiveness of the BioXtra (BX) dry mouth care system. Materials and methods A xerostomia questionnaire consisting of 3 parts (xerostomia symptom score, quality of life (QoL) survey and visual analogue scale (VAS)) was completed by 34 patients suffering from radiation-induced xerostomia, before and after 4 weeks of treatment with the BioXtra moisturizing gel, toothpaste and mouthwash. Results The BioXtra products significantly diminished the most common symptoms of xerostomia. Mean VAS score at the start of treatment was After treatment, this decreased to 36.4 (p<0.001). Twenty-six patients (77%) responded to treatment, 11 of these patients (32%) reported a major improvement. Quality of life significantly improved under treatment: mean QoL score at the start was 59.4; this increased to 70.5 (p<0.001). None of the 34 patients reported any adverse effects and all but 1 patient found the BX dry mouth care system easy to use. P. Dirix (*) : S. Nuyts : W. Van den Bogaert Department of Radiation Oncology, Leuvens Kanker Instituut (LKI), University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium piet.dirix@uz.kuleuven.ac.be V. Vander Poorten : P. Delaere Department of Otorhinolaryngology-Head and Neck Surgery, Leuvens Kanker Instituut (LKI), University Hospital Gasthuisberg, Leuven, Belgium Conclusions The results of this study suggest that the BioXtra dry mouth care system is effective in reducing the symptoms of radiation-induced xerostomia and improving the quality of life of xerostomia patients, even if a proportion of the benefit is due to a placebo effect. However, further research is necessary to evaluate the efficacy of BioXtra on oral health. Keywords Radiation therapy. Xerostomia. Saliva substitutes Introduction Xerostomia is an almost ubiquitous long-term complication of radiotherapy (RT) for head and neck cancer (HNC). Saliva is necessary for lubrication and comfort of the oral cavity and oropharynx, modulation of the oral microbial flora, re-mineralisation of the teeth, maintenance of the mucosal immune system and preparation of the food bolus during mastication. Patients with hyposalivation suffer from oral discomfort or pain, find it difficult to speak, chew or swallow and run an increased risk of dental caries or oral infection. Ultimately, this leads to decrease in nutritional intake and weight loss. Xerostomia not only diminishes the quality of life (QoL) of a lot of patients who are potentially cured from their cancer, but also poses a major new health problem for them [4]. Currently, management of radiationinduced xerostomia includes stringent oral hygiene with fluoride agents and antimicrobials to prevent dental caries and oral infection, sialogogic agents to stimulate saliva production from remaining intact gland tissue and saliva substitutes to relieve symptoms [7, 13, 14]. Saliva substitutes are usually administered as a mouthwash, alone or in conjunction with toothpaste, moisturizing

2 gel, spray and/or chewing gum. Products based on carboxymethylcellulose (CMC) or mucin were studied for many years, albeit with mixed results [1, 15, 17, 20, 21]. A possible explanation for this observation is the fact that those saliva substitutes do not restore the immunological protection of saliva [6]. It is the activity of factors such as lysozyme, lactoferrin and lactoperoxidase in conjunction with immune system components such as immunoglobulins that maintains a healthy balance in the mouth. Based on these considerations, a new generation of substitutes was marketed. These formulations, e.g. Biotène Oralbalance (BO) and BioXtra (BX), contain naturally occurring salivary components to supplement the mouth s immune system [2, 8, 12, 16, 18, 22]. The purpose of this study was to assess the clinical effectiveness of one of such newer products: the BioXtra dry mouth care system, consisting of a moisturizing gel, antibacterial toothpaste and alcohol-free fluoride mouthwash. Materials and methods Patient selection Thirty-five patients, previously treated for HNC at the University Hospital Leuven, were asked to participate while waiting for their regular follow-up visit at the multidisciplinary out-patient clinic of head and neck oncology. The coordinator explained the protocol to each patient who read and signed an informed consent form. All 35 patients agreed to participate. The Ethics Committee of the University Hospital Leuven granted approval for the study. Patients eligible to participate in the study had a subjective complaint of dry mouth since completing curative radiotherapy treatment ( 50 Gy) for HNC with the fields of irradiation encompassing the major salivary glands bilaterally, at least 6 months earlier. None of the patients had received any measures to prevent xerostomia (e.g. salivary gland-sparing radiotherapy or concomitant amifostine). All patients were aged 18 years or older, and taking nutrition orally (i.e. not through a percutaneous endoscopic gastrostomy (PEG) tube). Patients who had evidence of persisting or recurrent malignant disease were not included; as were patients with diabetes, Sjögren s syndrome or other medical causes of xerostomia. Patients who were taking antidepressants or other drugs with known anti-cholinergic side effects were similarly excluded. Treatment protocol After entry in the study, patients were provided with the BioXtra products for home application during 4 weeks (28 days). Each dry mouth system consisted of a toothpaste, a mouthwash and a moisturizing gel, and included the following manufacturer s instructions for use: 1. Brush your teeth with the toothpaste. 2. Rinse with the mouthwash. 3. After approximately 15 min, or as soon as your mouth feels dry, apply the moisturizing gel to your tongue and gums with your fingertip or a cotton swab. The gel can be re-applied as many times as necessary. At night, repeat those steps, but apply a larger quantity of the gel to give a longer lasting comfort through the night. The use of other products for the treatment of xerostomia (i.e. saliva substitutes or stimulants) was not allowed during the study period, although patients could take frequent sips of water for their comfort. They were also permitted to use other mouth care products if indicated (e.g. topical analgesics, topical antiseptics, antifungal treatments). Xerostomia questionnaire (XQ) Participating patients were asked to complete a xerostomia questionnaire (XQ) on the first day (day 0), after 2 weeks (day 14) and at the end (day 28) of treatment, and to return the filled-in questionnaires either by mail or on the next follow-up visit. Some additional questions concerning side effects, ease and pleasance of use, speed and duration of effect and helpfulness of the three different products were attached at the end of the questionnaire. The XQ itself consisted of three parts (Table 1). First, patients were asked to estimate the degree (grade 0 to 3) of oral dryness, pain, taste loss and dysphagia they were suffering from. Second, participants answered 15 questions regarding the perceived impact of xerostomia on their quality of life. For each question, patients encircled a number from one to five, reflecting the measure of agreement with the statement. A QoL score was calculated (100 sum of all scores) to provide an impression of the general impact of xerostomia on QoL (Dirix et al., submitted for publication). Third, the questionnaire also included a 100 mm ( in.) visual analogue scale (VAS) on which patients could mark to which degree they suffered from xerostomia with one end representing no xerostomia (completely normal saliva) and the other end total xerostomia (no saliva at all). For analysis of the VAS score, the score at 4 weeks was subtracted from the baseline score to assess change. A patient with a decrease of 10 mm from baseline score on the VAS was classified as having responded to the treatment intervention, those patients with a decrease of 25 mm were classified as having a major improvement in their symptoms [7, 22].

3 Table 1 Xerostomia questionnaire (XQ) Items in the xerostomia questionnaire Xerostomia symptoms Oral dryness No oral dryness 0 Now and then, partial 1 Always, partial 2 Completely dry, disturbing 3 Oral pain No pain 0 Seldom, minimal 1 Always, strong 2 Unbearable 3 Taste loss No change 0 Seldom, minimal 1 Now and then, considerable 2 Always 3 Dysphagia No swallowing problems 0 Solid food 1 Soft food 2 Liquids 3 Quality of life (QoL) My dry mouth Not at all (1) A little (2) Moderately (3) Quite a lot (4) Very much (5) restricts the amount and type of food I eat. gives me an uncomfortable feeling in my mouth. makes me worry. restricts my social life. makes it awkward to eat in front of other people. makes it difficult to speak to other people. is the cause of considerable tension. makes me worry about the look of my teeth and mouth. makes me feel depressed. restricts me in my daily activities. troubles my intimate relation. gives my food less or a different taste. diminishes my will to live. invades every aspect of my live. cannot stay like this for the rest of my life. Visual analogue scale (VAS)

4 Statistical analysis Patient and tumor characteristics (age, gender, primary tumor site, tumor histology, TNM classification, clinical stage, radiation dose, treatment modality, interval since end of RT) were recorded. The data were analyzed using the software package Statistica 7 (StatSoft, Tulsa, OK, USA). Means and standard deviations of continuous variables were calculated and paired t-tests were applied to test for statistically significant differences between the baseline scores and the scores after 2 or 4 weeks of treatment. Results Between August and October 2005, a total of 35 patients were recruited for the study. However, one patient could not be included in the statistical analysis because he did not return the XQ and was furthermore lost to clinical followup. The remaining 34 patients used the products as instructed for the full duration of the study. Of the participating patients, 24 were male and 10 were female. The mean age of the population was 63.8 years (range years) and the median age was 63.5±9.4 years. All patients had completed treatment for HNC at least 6 months earlier: the mean interval was 37.3 months (range months) and the median interval was 40.8± 18.5 months. Treatment consisted of surgery followed by post-operative radiotherapy in 16 (47.0%) patients, definitive radiotherapy with a hyperfractionation schedule in 9 (26.5%) patients and concomitant chemoradiotherapy in 9 (26.5%) patients. The BioXtra saliva substitutes significantly diminished the most common symptoms of xerostomia (Tables 2 and 3). At the start of treatment, 19 patients suffered from severe xerostomia (oral dryness grade 3). After 28 days use of the BX dry mouth care system, 9 patients still complained from xerostomia grade 3 and 17 patients no longer reported any oral dryness (grade 0). In total, 18 patients (53%) responded to the treatment (9 patients decreased 1 grade, 5 patients dropped 2 grades and 4 patients went from grade 3 to grade 0). BX had no effect on the reported xerostomia grade in 16 patients (47%). The mean xerostomia grade decreased from 2.03 at day 0 to 1.12 at day 28; the mean difference was 0.91 (95% confidence interval (CI) [ 1.16 to 2.98], p<0.001). The effect on dysphagia was similarly large: 23 patients (68%) responded to the treatment (17 patients decreased 1 grade, 6 patients dropped 2 grades); 11 patients (32%) reported stable dysphagia in spite of the treatment. The mean difference was 0.85 (95% CI [ 0.52 to 2.23], p<0.001). The BX dry mouth care system had a smaller, but statistically significant impact on oral pain (mean difference 0.35, 95% CI [ 1.00 to 1.71], p=0.005) and on taste loss (mean difference 0.53, 95% CI [ 1.16 to 2.22], p=0.001). The impact of the BX dry mouth care system on xerostomia, as measured by the VAS scores, was similarly large (Fig. 1). The mean VAS score at the start of treatment was After 28 days, this decreased to 36.4 (mean difference was 23.4, 95% CI [ 17.5 to 64.3], p<0.001). After 1 month of using the BX products, 26 patients (77%) reported a significant improvement ( 10 mm) in the sensation of intra-oral dryness and 11 of these patients (32%) reported a major improvement ( 25 mm) compared with the baseline assessment. Eight patients (23%) were classified as non-responders (<10 mm difference). This decrease of xerostomia and its related symptoms translated into a significant improvement of quality of life, as reported by the patients (Fig. 2). The mean QoL score at the start of treatment was This increased to 70.5 after 28 days of BX (mean difference was 11.1, 95% CI [ 28.7 to 6.6], p<0.001). Only 2 patients had a QoL score at the end of treatment that was identical to the score at the start of treatment; the other 32 patients reported an improvement of their QoL. It should be noted that after 14 days of treatment, the efficiency of the BX dry mouth care system became already clear. No statistically significant change was seen between days 14 and 28, except for oral dryness itself (mean difference 0.23, 95% CI [ 1.05 to 1.52], p=0.04). The difference between QoL at days 14 and 28 was similarly small, although also statistically significant (mean difference 1.7, 95% CI [ 7.15 to 3.79], p=0.001). None of the 34 patients reported any adverse effects. Also, all but one patient found the BX dry mouth care system easy to use. This one patient complained that it was Table 2 Mean xerostomia symptom scores at days 0, 14 and 28 Mean score (day 0) Mean score (day 14) Mean difference (95% CI) p Mean score (day 28) Mean difference (95% CI) p Oral dryness ( 1.30 to 2.65) < ( 1.16 to 2.98) <0.001 Oral pain ( 1.00 to 1.71) ( 1.00 to 1.71) Taste loss ( 0.98 to 1.97) < ( 1.16 to 2.22) Dysphagia ( 0.66 to 2.31) < ( 0.52 to 2.23) <0.001

5 Table 3 Difference in xerostomia symptom scores between days 0 and 28 Xerostomia symptom Oral dryness Oral pain Taste loss Dysphagia No response 16 (47%) 26 (76%) 20 (58%) 11 (32%) Response 18 (53%) 8 (24%) 14 (42%) 23 (68%) 1 9 (26%) 4 (12%) 8 (24%) 17 (50%) 2 5 (15%) 4 (12%) 6 (18%) 6 (18%) 3 4 (12%) 0 (0%) 0 (0%) 0 (0%) too difficult to rinse the whole throat with the BX mouthwash. Most patients (n=22) applied the moisturizing gel 1 to 3 times a day; 12 patients used it 4 to 8 times a day. For most patients, the moisturizing gel worked quite some time (10 patients >1 h, 3 patients min, 7 patients min). In a minority, the effect lasted only a while (6 patients min, 4 patients <10 min, 4 patients described no effect). The majority of patients received the largest benefit from the mouthwash (n=15) or gel (n=13), only 6 patients preferred the toothpaste. For 20 patients, the BX dry mouth care system was the first treatment with saliva substitutes that they had received. Of the other 14 patients that had already used some earlier treatment, 10 patients found it better than the previous one and 4 found it just as good. Concerning the dichotomous questions: 26 patients (77%) found that the BX products improved their dry mouth and 28 patients (82%) would have preferred to continue the treatment after the 28 days. Discussion Xerostomia is a common and debilitating complication after radiotherapy for head and neck cancer, which generally lasts the patient s lifetime. Its impact on quality of life is considerable: in a survey of 75 HNC patients (>6 months after RT), 93% of the respondents reported oral dryness, 65% suffered from dysphagia, 63% complained of taste loss and 33% experienced oral pain (Dirix et al., submitted for publication). Mastication and oral manipulation of dry or hard food becomes uncomfortable or even painful, which forces patients to adjust their diet. Most patients need frequent sips of water while they eat and food gets stuck in their mouth or throat. Difficulty with speech is another common complaint, seriously inhibiting social contacts. Patients also run an increased risk of dental caries or oral infection [3, 19]. Treatment of xerostomia and its complications is mainly symptomatic [7, 14]. A variety of artificial saliva substitutes Fig. 1 Mean VAS score at the start of treatment was After 28 days of BX dry mouth care system, the mean VAS score decreased to 36.4 (mean difference was 23.4, 95% CI [ 17.5 to 64.3], p<0.001) Box and Whisker plot of mean VAS scores Day 0 Day 14 Day 28 Mean Mean±SE Mean±0.95 CI

6 Fig. 2 Mean QoL score at the start of treatment was This increased to 70.5 after 28 days of BX dry mouth care system (mean difference was 11.1, 95% CI [ 28.7 to 6.6], p<0.001) Box and Whisker plot of mean QoL scores Day 0 Day 14 Day 28 Mean Mean±SE Mean±0.95 CI were developed to supplement the reduced production of saliva, although few were appropriately evaluated [1, 13, 15, 17, 20, 21]. Because saliva is such a complex substance, it is difficult to replace. Artificial saliva substitutes are rarely effective in relieving symptoms and most patients find regular sips of water equally useful. What is more, older saliva substitutes do not replace the antibacterial and immunological protection of saliva and are therefore of little use in the prevention of oral infections. Recently, a new generation of dry mouth care systems became commercially available. These products contain the essential salivary lactoperoxidase system and other natural salivary components to help supplement the mouth s immune mechanisms. The purpose is to relieve symptoms, to increase comfort and to promote a healthy, balanced oral environment. The first of such new dry mouth care systems, Biotène (toothpaste, mouthwash, chewing gum) Oralbalance (moisturizing gel), can successfully improve many of the symptoms of xerostomia and increase oral health [2, 8, 12, 16, 22]. The BioXtra (BX) dry mouth care system is a comparable product as the Biotène Oralbalance (BO) system, consisting of an alcohol-free mouthwash, a mild toothpaste and a moisturizing gel. BX products contain lactoperoxidase, lactoferrin, lysozyme and xylitol as active components. In one small crossover study comparing the BO and BX systems, BX proved to be very effective in alleviating the symptoms of post-radiotherapy xerostomia and appeared to be slightly superior to the BO products in efficacy and ease of use [18]. This is the first study comprehensively evaluating the usefulness of the BX dry mouth care system for radiationinduced xerostomia in a large number of patients. The results show that the use of BX significantly improves the symptoms of xerostomia and reduces its impact on QoL. The most important effect was on the subjective feeling of xerostomia itself: the mean difference in oral dryness between the start and the end of treatment was almost one full grade (0.91) and highly statistically significant (p<0.001). At the start of treatment, most patients (n=23, 68%) suffered from severe xerostomia (grade 2 or 3), after 4 weeks of BX, this number had almost halved (n=12, 35%). A large majority of patients (n=26, 77%) responded to the BX products, as assessed by an improvement of more than one tenth on the visual analogue scale. The same number of patients (77%) stated that the BX dry mouth care system improved their xerostomia. The treatment with BX also significantly improved dysphagia in most surveyed patients. Radiation-induced xerostomia primarily impairs the patient s perception of swallowing, rather than the actual physiologic aspects of

7 bolus transport [9, 10]. With increased moisture of the oral cavity and pharynx, oral manipulation and swallowing of food becomes less painful and more comfortable. The impact of BX on oral pain was less pronounced, probably because of the smaller number of patients suffering from pain in the first place. There was also a modest, although statistically significant improvement in taste perception, possibly because taste loss after radiotherapy is only partially explained by radiation-induced xerostomia [11]. Post-radiotherapy xerostomia significantly affects quality of life (Dirix et al., submitted for publication). However, QoL questionnaires are seldom incorporated in protocols assessing the efficacy of new treatments for xerostomia. This is the first study to demonstrate a significant improvement in patient-reported quality of life through the use of saliva substitutes [12, 18]. The major disadvantage of most saliva substitutes is the temporary nature of the provided relief. With the BX moisturizing gel, however, the majority of patients (n=20) reported a long-lasting effect (>30 min) and most patients (n=22) needed to apply the gel only 3 times a day. While these results are encouraging, some caution is necessary in evaluating this study. It is likely that a placebo effect of treatment accounts for a proportion of the observed response. For example, in a double-blind phase III study of a sialogogue for radiation-induced xerostomia, 25% of those treated with placebo reported a significant benefit [7]. It is not clear to what point QoL scores are susceptible to a placebo effect, but the response is probably too large to be fully ascribed to placebo. Another flaw is the lack of correlation with shift in oral microbial flora or incidence of periodontal disease. The timescale of the study was too short to assess the effect of BX on oral health, supposedly one of the major advantages of the newer generation of saliva substitutes. Of the two trials evaluating the effect of the Oralbalance gel on colonization with Candida and cariogenic bacteria, one found significant decrease of the S. mutans and Lactobacillus species while the second registered no difference [2, 12]. The only other study with BX to date did not include any measurement of oral health [18]. A randomized phase III trial incorporating those endpoints should be initiated to properly assess the role of BX in the prevention of oral disease. Just as important as the apparent effectiveness of the BX dry mouth care system is the complete lack of side effects and the easiness to use the products. The BX toothpaste was designed to avoid irritation of the mucosa and was indeed well-tolerated by all the patients. Moreover, the toothpaste does not contain the foaming agent sodium lauryl sulphate (SLS), which in susceptible mouths can increase the incidence of mouth ulcers [5]. The manufacturers claim that SLS inhibits the activity of BX formulations by inactivating the enzyme system. It is therefore important not to use the mouthwash and gel in conjunction with a toothpaste that contains SLS. The BX mouthwash is alcohol-free to improve patient comfort and the BX gel was formulated with minimal sweetening. The results show that the three BX products are well-tolerated by xerostomia patients. Conclusion The results of this study indicate that the BioXtra dry mouth care system could be effective in reducing the symptoms of radiation-induced xerostomia and improving quality of life. Further research is necessary to evaluate its efficacy on oral health. Acknowledgements This work was supported by grants from the Vlaamse Liga tegen Kanker (VLK) and the Klinisch Onderzoeksfonds (KOF). The firm Bio-X Healthcare (manufacturer of the BioXtra dry mouth care system) provided all the products free of charge. References 1. 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