Journal of Cancer Research and Therapeutics Medknow Publications on behalf of the Association of Radiation Oncologists of India (AROI) ISSN: 0973-1482 EISSN: 1998-4138 Vol. 6, Num. 4, 2010, pp. 466-472

Journal of Cancer Research and Therapeutics, Vol. 6, No. 4, October-December, 2010, pp. 466-472

Original Article

Effectiveness of triclosan in the management of radiation-induced oral mucositis: A randomized clinical trial

PS Satheeshkumar¹, Moideen Sha Chamba¹, Anita Balan¹, KT Sreelatha¹, VN Bhatathiri², Tinky Bose¹

¹ Department of Oral Medicine and Radiology, Government Dental College, Trivandrum, Kerala, India
² Department of Radiotherapy, Regional Cancer Centre, Trivandrum, Kerala, India

Correspondence Address: P S Satheeshkumar, Department of Oral Medicine and Radiology, Government Dental College, Trivandrum, Kerala, India, drsatheeshkumar@gmail.com

PMID: 21358082

DOI: 10.4103/0973-1482.77109

Abstract

Keywords: Oral cancer, radiation mucositis, triclosan

Introduction

Oral cancer is the sixth most common cancers in the world and the most dominant cancer in India. ^[1] Oral cancer incidence in males in Indian population is 10.3-15.7/100,000 population whereas in females the cancer incidence is 3.8-7.9/100,000 population. ^[2] Surgery and radiotherapy have been the standard loco regional treatment modalities employed in oral cancer with a high cure rate. ^[1] In early stages of oral cancers, radiotherapy is used principally with curative intent. ^[3] It is of great concern that the majority of patients reporting for treatment are in the later stages of the disease and thus in a non-operable condition. Hence, radiation treatment becomes the only treatment option.

Mucosal injury remains an undesirable, painful, and expensive side effect of cytotoxic cancer therapy and is disheartening for patients and frustrating for caregivers. ^[4],[5] Mucositis and associated outcomes in patients receiving radiotherapy (RT) for head and neck cancer shows that the mean incidence was 80%. ^[6] Rates of hospitalization due to mucositis are reported to be 16% overall and 32% for RT-AF (altered fraction radio therapy) patients. ^[6] Patients in the high risk of developing oral mucositis group fall into the head and neck cancer population where the incidence of mucositis is high in this group. ^[6]

An oropharyngeal epithelial surface has a rapid rate of cell turnover and appears to be at high risk of injury from ionizing radiation. A healthy oral mucosa serves to clear microorganism and provides a chemical barrier that limits penetration of many compounds into the epithelium. A damaged mucosal surface increases the risk of a secondary infection. Acute mucositis results from the loss of squamous epithelial cells owing to the sterilization of mucosal stem cells and the inhibition of transit cell proliferation. This leads to a gradual linear decrease in epithelial cell numbers. Normally, cells of the mouth undergo rapid renewal over a 7-14 day cycle. Radiation therapy interferes with cellular mitosis and reduces the ability of the oral mucosa to regenerate.

There are conflicting data relating to the effects of age on the development of chemotherapy-induced mucositis. ^[7] In general, younger patients appear to have an increased risk of chemotherapy-induced stomatitis. This observation may be explained by a more rapid epithelial mitotic rate or by the presence of more epidermal growth factor receptors (EGFR) in the epithelium of younger patients. ^[8],[9],[10] In reports, patients with pre-existing poor oral hygiene had an increased incidence of oral complications following cancer therapy. ^{[11],[12],[13]} The present day management of oral mucositis is mostly palliative and or supportive care. Management includes good oral hygiene, avoiding irritating or abrasive substances, use of bland rinses, topical anesthetic agents, and systemic analgesics. Though, the newer guidelines are suggesting Palifermin, which is the first active mucositis drug as well as Amifostine, for radiation protection and cryotherapy for symptoms related to high-dose melphalan; the role of safe radiotherapy remains the ultimate goal in reducing the symptoms of radiation-induced oral mucositis.

Triclosan is a broad-spectrum antibacterial agent. It is the non proprietary designation pertaining to 2, 4, 4′ - trichloro-2′-hydroxydiphenyl ether. ^[14],[15] The primary site of antimicrobial action of triclosan is the cytoplasmic membrane of bacteria. It is also suggested to act by increasing the permeability of the bacterial cell wall. ^{[16],[17],[18],[19]} It is effective against a variety of both Gram-positive and Gram-negative bacteria and is widely used in most countries of the world as an antibacterial agent. ^[20],[21] The anti-inflammatory properties of triclosan have well been proved in the reports. ^{[22],[23],[24],[25]} Triclosan blocked the production of prostaglandin E ₂ (PGE ₂ ) in human gingival fibroblast cultures, which were stimulated by Interleukin - (IL-IB). ^[23] This suggested that the effect of triclosan was due to a pronounced effect on the production of specific mediators of inflammation, such as prostaglandin. ^[26] The aim of this study has been to determine the effectiveness of triclosan in the management of radiation-induced oral mucositis and to compare the effectiveness of triclosan mouth rinse with conventional sodium bicarbonate mouth rinse with weekly follow-up of grading of mucositis, evaluation of body weight, food intake, and assessment of pain during the radiation treatment period and post radiation treatment period.

Materials and Methods

The study was conducted in the Radiation oncology department of regional cancer centre, Trivandrum in association with the department of Oral medicine and Radiology, Dental College, Trivandrum during the period January 2000- June 2000. The patients reporting to the outpatient clinic of Radiation oncology department of regional cancer centre, Trivandrum and Oral medicine and Radiology Department, Dental College, Trivandrum were screened for oral cancer. Those with clinically suspicious lesions were subjected for a biopsy from the representative area. Histopathologically confirmed cases of squamous cell carcinoma, selected for external beam radiotherapy and those who were willing to give informed consent and ready to report for post treatment weekly review, were included in the study. Ethical clearance was obtained before starting the study.

The trial group comprised 24 patients who were randomly allocated into two groups of 12 patients each. Patients in Group I was administered sodium bicarbonate mouth rinse and constituted the control group. Group II was the study group who were given triclosan mouth rinse.

Subjects were selected into the study based on the criteria given below. The patients were briefed about the study and the probability of selection in to the interventional arm and the control arm were described. History and personal data were recorded in the proforma.

Inclusion criteria:

1. Histopathologicallly confirmed cases of oral squamous cell carcinoma, selected for external beam radiotherapy.
2. Those who gave informed consent.

Exclusion criteria:

1. Patients planned for post surgical radiation treatment.
2. Patients on chemotherapy or on concomitant chemo radiotherapy.
3. Patients continuing or not willing to stop the deleterious habits of smoking, pan chewing or alcohol intake.
4. Patients to be treated with palliative doses of radiotherapy.
5. Those patients who had a history of previous radiotherapy or chemotherapy.
6. Extensive oral lesions involving larynx or hypopharynx.

The patients are allotted either to the intervention arm or to the control arm with the help of a random number table. A two digit random number was selected with the help of a random number table on every entry to the study. An odd number would select the patient to the intervention group and an even number enrols the patient to the control arm. Study subjects were selected according to the criteria set and twenty four patients satisfied the criteria. Blinding was not followed in the study. Detailed extra oral and intra oral examination was performed. All patients were strictly advised cessation of habits and at each follow-up visit they were questioned as to whether they had totally stopped the same. Awareness was created regarding signs and symptoms of mucositis in the patients. A detailed clinical examination for signs and symptoms of radiotherapy-induced oral mucositis was done and a detailed chart regarding the nature of food intake (whether solid or semisolid or liquid food) and the body weight were noted in the first day of radiotherapy and on subsequent reviews on every Monday and Thursday OP days.

Preparation of mouth rinses: The patients in control group were advised to prepare sodium bicarbonate mouth rinse by dissolving 2 g of sodium bicarbonate powder, available with the chemist in Luke warm water. The triclosan mouth rinse used in the study group was provided to the patient as a readymade commercial mouth rinse marketed by M/S Colgate Palmolive India Ltd (Colgate Plax) containing triclosan 0.03% W/V.

Method and schedule of use: On noticing the early signs or symptoms of oral mucositis, the patients in the study group were advised to use triclosan mouth wash and those in the control group were advised sodium bicarbonate mouth rinse. Patients in both the groups were instructed to swish the mouth three times a day with the respective mouth rinse during the rest of the course of radiation treatment and continue the same regimen for a period of one and a half months following completion of radiotherapy.

WHO Grading for mucositis

Grade - Subjective and objective assessments of oral mucosa

Grade 0 - Normal, moist tissue

Grade 1 - Erythema present or absent, soreness, no ulceration

Grade 2 - Erythema present or absent, ulceration, ability to tolerate solid foods

Grade 3 - Erythema present or absent, ulceration, inability to tolerate solid foods

Grade 4 - Erythema present or absent, ulceration, inability to tolerate oral intake

A weekly follow-up of grading of mucositis (WHO grading), evaluation of body weight, food intake, pain (visual analogue scale) were made during the radiation treatment period and post radiation treatment period. Acute exacerbation of signs and symptoms, which could be attributed to reaction of the mouthwash, was also monitored during treatment.

Statistical analysis

Evaluation was based on subjective and clinical (objective) criteria with statistical analysis. Primary analysis was based on intention to treat analysis. Statistical analysis was done using SPSS package 10; descriptive statistics were calculated for base line characteristics. Means medians and SD were calculated for continuous variables and proportions were calculated for categorical variables.

The data collected were entered into a master sheet and statistical tables were constructed. The comparison of the two groups was done by computing the mean and standard deviation of the variables and also the percentage. The statistical hypotheses formulated were tested using Chi Square test (χ² ) in the case of qualitative data and by using Student ′t′ test in the case of quantitative data.

Results and Observatons

Grading of mucositis [Table - 1] [Figure - 1]

The mean number of days taken for a change in the grade of mucositis occurring due to radiotherapy was compared in the two groups [Table - 1]. Initially, it took an average of 10 days for the onset of grade 1 mucositis in both groups. Shift from grade 1 to 2 and 2 to 3 took about four days each in both the groups. Till the change from grade 2-3, there was no appreciable statistical difference between the study and control groups (P>0.05). While only one patient (8%) in the study group progressed on to grade 4 mucositis, in the control group, it was 10 patients (83%). Thus the control group was 10 times inferior to the study group if the occurrence of grade 4 mucositis is being considered. Thus, the effect of treatment in control of severity of mucositis was tested statistically by Chi square test and was found significant at a very higher level (P<0.001).

With regard to reversal of mucositis from grade 3 to grade 0, a difference was noted. The study group had taken only a mean of 23.6 days in place of 36.5 days in the control group. The Students′ test was significant at 5% level (P<0.05). The lone case in the study group and the 10 cases in the control group which progressed to grade 4 took more than 45 days to resolve. The remaining 11 cases in the study group with grade 3 mucositis took less than 28 days to resolve.

Food intake and duration [Table - 2] [Figure - 2] and [Figure - 3]

Both the study and control group took exactly the equal number of days following start of radiotherapy to switch over from solid to semisolid (11.17 days in the study group and 12 days in the control group) and semisolid to liquid respectively (5.67 days in the study group and 4.83 days in the control group). When considering the time taken for shifting from liquid to semisolid, it was 14.18 days in the study group and 27.17 days in the control group (P<0.05). The time taken to resume solid food from liquid was 25.1 days in the study group and 44.67 days in the control group respectively (P<0.01).

Pain [Table - 3]

Pain occurred in the study group at a mean of 10.17 days and 7.92 days in the control group. The severity of pain increased from mild to moderate in 3.73 days in study group and 5.92 days in the control group. Severe pain incidence occurred on an average of 7.67 days in the study group and 10 days in the control group.

Weight Loss [Table - 4]

The data were analyzed to see the extent of weight loss, if any, during the treatment and follow up period of one and a half months by computing the mean change in weight. In the control group, the mean loss of weight recorded was 3.1 kg at the end of one and a half months. On the other hand, the study group showed only a mean loss of 0.75 kg. The loss of weight in the control group was four times higher than the study group. The difference noted was highly significant (t=3.73; df = 22; P<0.01).

Discussion

In the present study, 24 oral cancer patients were randomized in two groups consisting of 12 patients each in the study and control group, respectively. Out of the total 24 patients, the male female ratio was 1:1. The age of the 24 patients who participated in the trial varied from 45 to 81 years with a mean age of 64.8 years (64.7 years in males and 64.9 in females, respectively). The mean age in the study group (63.67) and that of the control group (65.9) showed numerically marginal difference in the mean value. This could be attributed to sampling variation, since the ′t′ test was insignificant (P>0.05). Previous study shows that age does not relate to complications after radiotherapy. ^[27] In our study, as both groups were matched in respect to age, the influence of age on radiotherapy- induced mucositis cannot be assessed [Table - 5].

All the subjects in the study, except for one female patient, had the habit of pan chewing with or without associated smoking. This strongly supports the conclusive epidemiologic evidence of the role of tobacco in carcinogenesis. Out of the total 24 patients, only 8 (33.3%) consumed alcohol. This is probably due to the fact that alcohol consumption when compared to tobacco is lesser in our population with regard to the western population particularly in females. The demographic data including age, male to female ratio, deleterious habits and dietary habit were found to be statistically insignificant in the intervention and control arm, respectively. Patient factors such as systemic illness, the clinical findings at the time of presentation, the site of involvement, the size of tumor, nodal status and histopathologic findings were found to be comparable in the intervention and control arm [Table - 5].

Numerous authors have emphasized the importance of proper maintenance of good oral hygiene in alleviating the oral problems due to radiation. In addition, the fact that more than 70% of the patients were affected by periodontal diseases and hence considered to have a role in increasing the severity of mucositis. ^[28],[29] In our study, about 58.33% of the patients comprising the study and control group were having poor oral hygiene status. No specific oral hygiene measures were employed other than the mouth washes used. In our study, it is observed that the oral hygiene status has got much role in aggravating mucositis as the majority of our patients (83%) were edentulous, on the radiation field.

With regard to radiation technique employed, radiation were given with a wedge field technique for 10 (42%) patients, and single on field and lateral parallel pair technique were used in seven (29%) patients each. As we considered only the mucosal area in prescribed dose zone for grading mucositis, the different technique employed does not influence the outcome of our study. The protocol adopted in our trial was a total dose of 52.50 Gy in 15 fractions for a three week period, five sittings per week, one sitting per day.

The influence of total dose and dose per fraction on mucositis development has been noted in the literature by various authors. But a direct comparison with our trial is not worthwhile due to the variation in radiotherapy protocols adopted by different authors. The protocol adopted in our trial was a total dose of 52.50 Gy in 15 fractions for a three week period, five sittings per week, one sitting per day.

The main parameters compared in this trial were grades of mucositis attained and time taken for the development of different grades of mucositis. Invariably, all the patients in the study developed oral mucosal changes of varying degrees during radiotherapy. Till date, no study has been conducted to document the role of triclosan in the management of radiation-induced mucositis. In previous studies conducted by various authors employing a variety of mouth rinses, there has been no uniformity in the grading system followed. Hence, no attempt was made to compare the results of previous studies with our study. Therefore, an attempt has been made to compare the results obtained in the intervention and control group.

There was no significant difference in time taken for occurrence of grade 1 mucositis (erythema) in both the groups. Erythema was noticed in both the groups on 10 ^th day on an average. A similar study has also observed the same number of days for erythema to occur. ^[30] Triclosan and sodium bicarbonate, the mouth rinses used in our study, were employed only after the erythema had developed.

It was observed that there was no remarkable difference in the time taken for the change from grade 1 to 2 and 2 to 3 in both the groups. However, a definite change in the severity of mucositis was noticed in the study and control groups in the last day of radiotherapy. Grade 4 mucositis was noted in only one (8%) out of the 12 patients in the study group on the last day of radiotherapy whereas 10(83%) out of 12 patients in the control group had progressed on to grade 4 mucositis.

Triclosan exerts its action in the ulcerative phase. ^[31] The anti-inflammatory action of triclosan is well documented by several authors. ^{[22],[30],[32],[33]} Since triclosan was used only after the appearance of reaction, its effect in delaying and curtailing severe mucositis must be predominating on the phase 3 and 4. This is most likely due to antimicrobial and anti-inflammatory properties of triclosan. Decrease in the pathologic flora can be expected to reduce microbial injury to the proliferating mucosal cells, which are already in a state of compromise due to radiation effects. ^[16] It is therefore reasonable to assume that the synergistic anti-inflammatory and anti microbial activity of triclosan may account for the reduction in severity of mucositis. Eleven patients in the study group did not progress on to grade 4 mucositis, while 10 patients in the control group progressed to grade 4 mucositis. Time interval for reversal of mucositis in the study group was notably reduced and took only less than 28 days. It is interesting to note that the reversal of mucositis in the control group took more than 45 days.

Effectiveness of treatment by considering the time taken for switching over from one type of diet to the other was also compared. It was observed that both the groups took exactly the equal number of days following start of radiotherapy to switch over to semi solid from solid. (a mean of 11.17 days in study group and 12 days in the control group). Even in the case of time taken for switch over from semi solid to liquid, there was no appreciable difference noted between the two groups (In control group, it took 4.83 days in place of 5.67 days in the study group). While considering the total time taken for switching over from solid to liquid in both the groups the mean number of days worked out as 16.83. With gradual resolution of mucositis following treatment, in both the groups, there was reversal of nature of diet. While the study group took 14.78 days to change to semi solid diet, the control group took twice the number of days (mean = 27.17 days). This difference was found to be statistically significant (t = 3.02); df = 22; P<0.05).

The control group took about double the time taken by the study group to resume solid diet which was found to be statistically significant (t = 3.42; df = 22; P<0.01). The difference noted in the reversal of nature of diet from liquid to semi solid or solid, in the mucositis resolution period, could be probably attributed to the less severity and early reversal of mucositis noted in the study group. Thus it is concluded that triclosan mouth rinse helped the patients in the study group to maintain a better food intake in a shorter period. On analyzing the results, the loss of weight in the control group was four times higher than the study group. This may be explained by the fact that the severity of mucositis directly affects the consumption of food, which in turn reflects on the individual′s body weight. Hence it may be rationalized that the study group were able to rapidly switch on to a solid diet from liquid food and thereby accounting for the weight gain during the post treatment period.

Summary and Conclusion

The notable observation that the early reversal of mucositis in the study group can best be explained by the antimicrobial action of triclosan which hastened the healing phase by controlling the microbial flora which retard the wound healing. It was found that the patients in the study group were able to maintain better food intake in a shorter period consequent to the lesser severity of mucositis. This directly reflected in the significant lesser weight loss noted in the study group. The results of this study shows that triclosan mouth rinse is effective and better when compared to the sodium bicarbonate mouth rinse in the control of mucositis with regard to its severity and duration. However, this is a study with small sample size and by itself cannot prove the efficacy of triclosan in radiotherapy-induced mucositis. Further studies are necessary to conclusively prove the efficacy of triclosan in radiotherapy-induced oral mucositis.

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