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 » Introduction
 »  Materials and Me...
 » Results
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 » Acknowledgements
 » Conclusion
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  Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 52  |  Issue : 1  |  Page : 81-85
 

Phenytoin mouthwash to treat cancer therapy-induced oral mucositis: A pilot study


1 Department of Oral and Maxillofacial Medicine, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Department of Oral and Maxillofacial Medicine, Qom University of Medical Sciences, Qom, Iran
3 Department of Oncology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
4 Department of Pharmaceutics, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Date of Web Publication3-Feb-2016

Correspondence Address:
M Hamian
Department of Oral and Maxillofacial Medicine, Qom University of Medical Sciences, Qom
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.175597

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 » Abstract 

Background: Oral mucositis is one of the most common side effects of cancer therapy with no definite treatment. Phenytoin has positive effects on healing of mucosal and dermal wounds. In this study efficacy of 1% phenytoin mouthwash on severity of mucositis (on the basis of WHO scale), pain relief (based on Visual Analogue Scale), and improvement of patients' quality of life (on the basis of EORTC-QLQ-H and N35 questionnaire) was evaluated. Materials And Methods: In a pilot -double-blind randomized clinical trial, eight patients in study group were given 1% phenytoin mouthwash while eight patients in control group used normal saline. Data analysis was performed by Mann-Whitney and Repeated Measured ANOVA tests. Results: Reduction of mucositis severity was observed, but the difference was not significant. On the other hand, patients on phenytoin therapy had better pain relief (VAS# 6.75 ± 1.58 at the beginning of the study reached to # 3.75 ± 1.16 after 3 weeks in phenytoin group) and improvement in quality of life (score of QOL was 70.63 ± 5.5 that reached to 63.61 ± 6.39 in phenytoin group) than normal saline group significantly (P < 0.05). Conclusion: One percent phenytoin mouthwash caused pain relief and improvement of life quality significantly in patients with mucositis due to cancer therapy, but it did not reduce the severity of mucositis in a statistically significant scale.


Keywords: Cancer, chemotherapy, oral mucositis, phenytoin, radiotherapy


How to cite this article:
Baharvand M, Hamian M, Moosavizadeh M A, Mortazavi A, Ameri A. Phenytoin mouthwash to treat cancer therapy-induced oral mucositis: A pilot study. Indian J Cancer 2015;52:81-5

How to cite this URL:
Baharvand M, Hamian M, Moosavizadeh M A, Mortazavi A, Ameri A. Phenytoin mouthwash to treat cancer therapy-induced oral mucositis: A pilot study. Indian J Cancer [serial online] 2015 [cited 2019 Aug 23];52:81-5. Available from: http://www.indianjcancer.com/text.asp?2015/52/1/81/175597



 » Introduction Top


Oral mucositis (OM) is defined as inflammation and ulceration of the mouth mucosa with pseudomembrane formation.[1] It is a frequent and painful debilitating complication of radiotherapy and chemotherapy affecting over 80% of patients.[2] Currently, the world wide population with chemo radiotherapy-induced mucositis is estimated to be 400,000 to 600,000 receiving.[3] The initial presentation is erythema followed by white desquamating plaques, which are painful when touched.[1] Epithelial crusting and a fibrin exudate result in pseudomembrane formation and ulceration, which is the most pronounced form of mucositis.[4] This condition is usually seen 5-7 days following chemotherapy. Radiation-induced mucositis typically begins at cumulative doses of about 15 Gy (after around 10 days) and typically reaches full severity at 30 Gy.[1],[5] Patients invariably complain of pain; therefore, intake of food and fluids can be severely curtailed leading to dehydration and malnutrition.[1] The risk of infection caused by opportunistic pathogens is increased as well. Mucositis is a potential source of infection, which might lead to death and even be a risk for other more serious complications

such as hepatic veno-occlusion.[2] The consequences of oral mucositis, not only affect the patients' quality of life, but could also cause a limitation in the treatment of cancer, as well as an increase in hospital stay and therapeutic costs.[1]

Throughout the last two decades there have been many attempts to identify remedies to prevent or at least ameliorate OM with conflicting results.[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15] These interventions are various from bland rinses to growth factors.[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15] Phenytoin, an anti seizure medication, has been reported to promote wound healing when applied topically on the skin and mucosal lesions.[16],[17],[18],[19],[20],[21],[22] It has been proven to be effective on acute and chronic lesions with diverse etiologies such as decubitus ulcers, leprosy ulcers, pressure sores, diabetic ulcers, traumatic wounds, burns, epidermolysis bullosa (simplex type), aphthous ulceration, and oral lichen planus.[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27] Phenytoin promotes wound healing by a number of mechanisms including stimulation of fibroblast proliferation, facilitation of collagen deposition by inhibiting the activity of collagenase enzymes, and antibacterial activity. Furthermore, by stabilizing neural membranes and reducing the inflammatory response, phenytoin contributes to topical pain relief.[9], 17, [20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30]

Several previous studies have addressed treatment of oral mucositis by different modalities,[3], 4, [6],[7],[8],[9],[10],[11],[12],[13],[14],[15] but most of them did not consider the effect of treatment on patients' life quality.

The aim of this study was to evaluate the effectiveness of 1% phenytoin mouthwash on cancer therapy-induced oral mucositis in terms of pain relief, healing process, and quality of life.


 » Materials and Methods Top


In a randomized triple-doubledblind clinical trial, patients with head and neck cancer undergoing chemotherapy or radiotherapy were selected among those attending two major Radiotherapy Centers in Tehran, Iran. The research was approved by the Medical Ethics Committee of the authorized University of Medical Sciences.

The inclusion criteria were as follows: (1) Patients undergoing chemotherapy and/or radiotherapy;

patients under radiotherapy entered the study at their at least 10th day and patients under chemotherapy entered the study at their at least 7th day of treatment.[1] (2) Suffering from grade 1, 2, or 3 mucositis according to WHO scaling system;[2] (3) Not being affected by systemic diseases creating oral mucositis (such as connective tissue diseases and Sjögren syndrome), or interfering with healing process of tissues (such as diabetes); (4) Having informed consent of patients and their physicians, and no interference of the treatment with that of the primary disease/cancer; (5) Absence of severe psychological disorders, such as major depression, which would interpose the research process; (6) Estimation of at least a 6-months survival for the patient by the physician.

The exclusion criteria were: (1) Patients with mucositis grade 4 based on WHO classification; because in mucositis grade IV oral alimentation is impossible, patients are not able to cooperate with the procedure and gargle the mouthwash. (2) Appearance of unwanted side effects (such as allergy); (3) Being under brachytherapy treatment plan; (4) Lack of cooperation or tendency to continue the treatment process on behalf of the patient.

Sampling method was performed on a multi-central, non-probable (easy- to- access) basis. All patients with oral mucositis due to cancer therapy who met the inclusion criteria were randomly classified into two groups of phenytoin and normal saline. Randomization was performed by a 4-block stratified technique. Each patient signed a standard informed consent form. Sixteen patients were included in the study with eight patients in each group. The patient, the nurse who handed in the mouthwash and the examiner were not aware of the type of the medicine received by each patient. The groups were homogenous with respect to medical history, tumor characteristics, and treatment details. Radiotherapy schedule for all patients was a fractional treatment plan that completed between 18 up to 27 sessions with the mean dose of 3051.25 ± 1119.63 cGY in phenytoin group and 3656.25 ± 1067.52 for normal saline group. Medications used for chemotherapy were mostly Cisplatin, Cyclophosphamide, 5-Fluorouracil, Methotrexate and Busulfan. Type and dose of the medications were planned individually for each patient according to the overall cancer therapy treatment plan and tumor characteristics.

One percent phenytoin mouthwash was prepared by Pharmaceutics Department, School of Pharmacy. Because of bitter taste of pure phenytoin solution and probable reduction in patients' compliance and cooperation, the investigators decided to prescribe a commercially prepared suspension with an acceptable and pleasant taste. In order to prepare 1% phenytoin mouthwash, distilled water was added to dilute 2.5% phenytoin suspension of a pharmaceutical company. Phenytoin and normal saline mouthwashes were bottled in the same shape and volume. The bottles were coded as A or B by the supervisor of the study. It is worth mentioning that normal saline has not been considered as placebo, but it actually was the routine current therapeutic protocol administered in radiotherapy centers. Patients were instructed to gargle their mouthwash for 1 minute, three times a day for 3 weeks. Each patient was examined at the beginning of the study and three times afterwards with one-week intervals. The severity of mucositis was scored on the basis of WHO scale. Healing was considered complete when there was no evidence of mucositis. Severity of pain was measured using a 10-cm VAS (visual analogue scale), and quality of life was evaluated using the validated Farsi version of EORTC-QLQ-H and N35. Since phenytoin was used in the form of a mouthwash and without a dressing, the amount of systemic absorption was not considerable and there was no need to evaluate the blood concentration according to previous studies.[18] Statistical analysis was performed by Mann-Whitney and Repeated Measured ANOVA tests via 15th version of SPSS software.


 » Results Top


Descriptive information regarding gender, age, radiotherapy dose, and treatment protocol has been summarized in [Table 1]. Our patients suffered from different malignant tumors of the head and neck such as oropharynx SCC, tongue SCC, SCC of the larynx, mucoepidermoid carcinoma of the submandibular gland and supraglottic SCC. Although the area under radiotherapy differs among the patients, this will not cause any conflict with results because the criterion to include a patient in the study was the WHO classification for the severity of mucositis.
Table 1: General characteristics of patients

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At the beginning of the study according to Repeated Measured ANOVA test for quality of life and Mann-Whitney test for pain and grade of the mucositis, the two groups did not show any statistically significant difference in terms of three items of quality of life (P = 0.1), VAS (P = 0.1), and severity of mucositis (P = 0.4). Therefore, the comparison between two groups seemed reasonable and practical. In [Table 2], treatment plan of cancer therapy for each tumor has been shown.
Table 2: Information regarding patients' tumor characteristiscs and treatment details

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As it is shown in [Table 3], quality of life in both groups has improved, but this improvement was more obvious in phenytoin group than normal saline. So the difference between two groups was significant (P < 0.001).
Table 3: Patients' quality of life at the beginning and end of the treatment

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Regarding severity of pain, in [Table 4] there is a significant difference between phenytoin and normal saline in all three evaluations. Although in both groups pain relief was observed, it was more pronounced with phenytoin use.
Table 4: Severity of pain (based on VAS) at different intervals

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In [Table 5] mucositis grade at different intervals has been compared. The severity of mucositis has been decreased in both groups, but the difference was not found significant.
Table 5: Mucositis grade at different intervals

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There was no side effect such as gingival hyperplasia in phenytoin group, and phenytoin mouthwash was well tolerated by all patients.


 » Discussion Top


In this pilot study the efficacy of phenytoin mouthwash was investigated in three domains: Healing of mucositis, pain relief, and quality of life improvement.

Since “quality of life” reflects the whole therapeutic effect of the medication, it is one of the most suitable criteria used in this research. For this purpose we used the validated Farsi version of EORTC-QLQ-H and N35, a standard 35-query questionnaire designed for patients with head and neck cancer, which its validity and reliability has been proved and used in previous similar studies.[31] Despite zooming on oral condition, the results of the above-mentioned questionnaire reflect other improved parameters too.

Visual analogue scale (VAS) has been known as one of the most authentic and valuable criteria for measurement of pain severity.[32] Since it is determined by patients, it actually reflects their point of view, which is the main goal of the treatment.

The literature indicates that phenytoin appears to improve wound healing,[16],[17],[18],[19],[20] so the authors investigated whether it'sits various properties [9], 17, [20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30] might limit the severity of radiation and chemotherapy-induced oral mucositis. Regardless the underlying mechanism of mucositis (caused by radiotherapy or chemotherapy), the authors expected patients' benefit from healing properties of this medicine.

In a study accomplished by Baharvand et al.,[20] in 2010, patients under chemotherapy and/or radiotherapy received 0.5% phenytoin mouthwash and normal saline in experimental and control groups, respectively, for 2 weeks. They used the mouthwash for 1 minute four times a day. This procedure caused healing of the lesions, and improvement of life quality but had no significant effect on pain relief. There were no side effects of the trial drug in the study group and it was well tolerated by the patients throughout the study.

According to the results of Baharvand et al., study,[20] the concentration and dosage of the mouthwash was increased to 1%, frequency was decreased to three times a day for better patients' compliance, and the follow-up period was extended to 3 weeks. In our pilot study, 16 patients were included with eight patients in each experimental and control group. Findings of our study confirmed the results of Baharvand's study in the way that quality of life was improved. Furthermore, pain relief as a result of dose increase was observed. Lack of significant healing acceleration may be due to lesser frequency of drug usage and small group of patients.

In a similar study performed by Mehdipour et al.,[13] Zinc sulfate had no significant effect on healing of mucositis after 4 weeks. The authors have hypothesized that at final stages of treatment the prophylactic agent should be administered at a higher dose or at closer intervals. The same conclusion may be justified in the present study.

Other researchers have considered topical phenytoin as a healing and analgesic agent in their reports: Ghebanchi et al.,[16] Sobooti et al.,[18] Swamy et al.,[22] Holisaz et al.,[23], Jarrahi et al.,[25] Shaw et al.,[27] Habibpour et al.,[29] have confirmed and proved the therapeutic effect of phenytoin in different forms on wound healing. Sobooti et al.,[18] in 2002 applied 125mg/l phenytoin elixir on recurrent aphthous stomatitis every 2 hours for 5–10 days. In 38% of the patients, the healing time was reduced to half of the regular period, and in 24% of the patients healing time of oral lesions was reduced to one-fourth. Moreover, reduction in pain and burning sensation of RAS were reported. The latter findings are in concordance with the current study and healing acceleration might be due to the frequency of drug application, which was every 2 hours.

Ghebanchi et al.,[16] in 2009 applied phenytoin powder under periodontal surgical flaps in rats and afterwards in a 14-year old girl. The outcomes proved the positive effects of phenytoin on healing and pain relief. Again in this study, shorter healing time could be attributed to the drug form, which was used as a powder under the periodontal flaps in close contact with the underlying tissue during healing period. In terms of pain relief, the results were in agreement with our study.

Phenytoin shortens the healing time of dermal and mucosal ulcers via multiple mechanisms: Although does not stimulate epithelial proliferation directly, it promotes epithelial or epidermal healing by improving the underlying connective tissue. Other effective mechanisms are stabilization of neuronal membrane, eliminating bacterial contamination around the ulcers, PH compromising, improving regional blood circulation and finally anti-inflammatory effects.[9], 17, [20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30] The authors suggest usage of other possible forms of phenytoin-like oral paste that might result in a longer contact time. Considering the basic nature of all oral and mucosal ulcers, phenytoin could ameliorate other oral ulcers such as RAS or traumatic ulcers.


 » Acknowledgements Top


This article was based on a postgraduate thesis on oral medicine accomplished by Dr. Mina Hamian under the supervision of Dr. Maryam Baharvand, Dr. Ahmad Reza Moosavizadeh and Dr. Alireza Mortazavi in School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

The authors are sincerely appreciated for cooperation of Dr. Dinan, researcher of R and D Department of Loghman Pharmaceutical Company for providing phenytoin powder. We are greatly thankful to the staff members of School of Pharmacy, Shahid Beheshti University of Medical Sciences for preparing the mouthwashes. Special thanks are due to our patients for their cooperation.


 » Conclusion Top


Phenytoin mouthwash (in 1% concentration) brought about significant pain relief and improvement of life quality in patients with cancer therapy-induced oral mucositis, and although reduced the severity of mucositis, it was not considered statistically significant.

Ethical approval

This research has been approved by the Medical Ethics Committee of Shahid Beheshti University of Medical Sciences, and all study procedures were undertaken according to Helsinki Declaration.

 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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