Abstract
This prospective randomized 2-period crossover study aimed at comparing the efficacy of 2 oral care protocols differing in the type of mouthwashes: chlorhexidine versus benzydamine in alleviating oral mucositis symptoms for children undergoing chemotherapy. Forty subjects were randomly allocated to receive either chlorhexidine first then benzydamine protocols or benzydamine first then chlorhexidine protocols. Each protocol was started on the first day of chemotherapy and continued for 21 days. Subjects were evaluated in intervals of 3 to 4 days using the World Health Organization (WHO) grading for mucositis and 10-cm visual analogue scale for oral symptoms evaluations. Among 34 evaluable subjects, 26% and 48% of them using chlorhexidine and benzydamine had WHO grade II mucositis, respectively (P < .05). The results revealed a significant difference in mean area under the curve (AUC) of mouth pain (1.35 +/- 2.26 versus 3.09 +/- 3.21) (P = .05), and a trend of a lessening of mean AUC of difficulty in eating/chewing (2.49 +/- 3.74 versus 2.71 +/- 4.1) (P = .82) and swallowing (1.34 +/- 3.31 versus 1.91 +/- 4.03) (P = .53) for subjects receiving chlorhexidine compared to those receiving benzydamine. In conclusion, chlorhexidine may be helpful in palliating mucositis symptoms for children in chemotherapy. The beneficial effect, however, is small and needs to be confirmed in a larger trial.
The erythematous, erosive, and ulcerative lesions characterizing oral mucositis are one of the most debilitating complications of cancer therapy. 1 Children are at particularly higher risk of developing oral mucositis than are adults, which afflicts from 52% to 80% of children in chemotherapy. 2,3 There has, however, been little research conducted in pediatric cancer population in this area to guide clinical practice. A number of studies among adults have indicated that oral mucositis can result in considerable morbidity, including pain, bleeding, and infection. In severe cases, the progression of oral ulcerative lesions and the patient's general condition might require temporary interruption or modification of cancer treatment. 4-6 Clinically, ulcerative oral mucositis is the most symptomatic problem of patients in chemotherapy. 6,7 Oral dysfunctions including dysphagia and inability to eat/chew, drink, and talk are common accompanying symptoms with ulcerative pain and result in weight loss from compromised oral intake and nutritional status. 4-6 It is also important to note that oral mucositis is a major source of cancer treatment-related pain, necessitating the use of narcotic therapy and supplemental nutrition. 7 Miser and colleagues, in a prevalence survey of 139 pediatric and young adult cancer patients, reported that 40% had treatment-related pain, including 27% with acute pain due to oral mucositis. 8 Recent data revealed that 57.8% of pediatric cancer pain was secondary to chemotherapy-induced oral mucositis. 9 A multicentered study in North America and Europe demonstrated that the extent of oral mucositis was significantly positively correlated with the frequency of narcotic therapy and total parenteral nutrition. 10 Research also revealed that worsening mucositis correlated with a longer inpatient length of stay. 11 Apart from treatment outcomes, the symptomatology associated with oral mucositis is particularly significant because of its profound effect on the patient's well-being and quality of life. Borbasi et al indicated that quality of life was significantly compromised for patients with mucositis, in particular for patients who found eating difficult and painful. 12 Data from a study measuring the impact of oral mucositis on quality of life in adult population indicated that pain and social functioning scales in both generic and cancer-specific quality of life instruments significantly correlated with oral mucositis. 13 In another study, Dodd et al reported that patients with chemotherapy-related oral mucositis experienced a significant increase in mood disturbance compared to patients who did not experience mucositis. 14 From the patient's point of view, oral mucositis is the worst part of cancer treatment, and is considerably more distressing than other complications, including nausea and vomiting, diarrhea, and fatigue. 4,15 The clinical significance of ameliorating oral mucositis symptoms is therefore clear to patients and their families, as well as nursing and medical professions.
An increasing body of evidence has suggested that the biological basis of oral mucositis involves a complex interaction of the chemotherapeutic drugs or irradiation on mitosis of proliferating epithelium, as well as a number of cytokines and elements of oral microbial environment. 16 The risk factors for the development of oral mucositis are many and complicated. Although a few studies have reported the association of potential predictor variables with the occurrence of oral mucositis, the findings are conflicting. At present, only cytotoxic regimen, neutrophil count, age, and oral hygiene level were found to be significant determinants of oral mucositis in studies using multivariate regression analysis. 11,17,18 In particular, chemotherapeutic agents, which include antimetabolites such as methrotexate and fluorouracil, and antitumour antibiotics, such as doxoribicin and daunorubicin, are frequently associated with mucositis. 11,19
Currently, the range of preventive strategies and treatment options that have been tested for oral mucositis is extensive, including cytokines, inflammatory modifiers, cytoprotectants, anti-ulcer agents, vitamins, amino acid supplementation, topical antimicrobials, palliative rinses, cryotherapy, and laser treatment. Up until now, however, the optimal treatment is not known, and questions and controversies persist on different treatment approaches. Two recent reviews conducted by the Cochrane Oral Health Group 20 and the Joanna Briggs Institutes, 21 could identify only the application of ice-chips that can prevent bolus fluorouracil-induced oral mucositis, leaving few recommendations for mucositis. Nevertheless, given the role of oral microflora in the pathogenesis of mucositis is increasingly clear, prophylactic elimination of acute and potential dental and periodontal foci of pathologic conditions before cancer treatment and systematic oral hygienic care have emerged as an acceptable form of treatment in oral mucositis. A remarkable number of studies appear to describe comprehensive oral hygiene regimens, and to evaluate the safety and efficacy of agents used for prophylaxis and treatment of oral mucositis. Nevertheless, it is important to note that the vast majority of oral care studies primarily focused on the biomedical outcomes, such as incidence, severity, and duration of oral mucositis, as well as oral infection. Symptomatic outcomes including mouth pain and discomfort, mouth dryness, and difficulties in eating/chewing, swallowing, and speaking, which are equally important to determine the effectiveness of oral care treatment, did not receive adequate attention and are understudied.
The literature on mouthwashes in chemotherapy-induced oral mucositis is at best inconclusive and at worst confusing. Chlorhexidine has been introduced as an antimicrobial approach to aid in the control of oral mucositis in patients undergoing cancer treatment. It is the most commonly used agent in the clinical settings to treat oral mucositis in the United States 22 and Hong Kong. However, the relative efficacy of chlorhexidine has varied in different studies. While several clinical studies of pediatric and adult patients treated with chemotherapy showed reduced oral mucositis, 23-25 Dodd et al compared 222 adult outpatients treated with chemotherapy using chlorhexidine and water and found no significant differences in oral mucositis. 26 Nevertheless, some literature supports the prophylactic use of chlorhexidine in children receiving intensive myelosuppressive therapy to obtain optimum oral health. 24,27 Benzydamine, which contains anti-inflammatory, pain relieving, and antimicrobial properties, has been introduced as a method of reducing oral mucositis. 28 Benzydamine has not previously been studied in pediatrics. However, positive responses to benzydamine in reducing oral mucositis incidence and improving the oral symptoms were reported in studies for adult patients undergoing radiotherapy. 29,30 At present, there have been no studies in the literature comparing the use of chlorhexidine and benzydamine mouthwashes in reducing oral symptoms associated with chemotherapy, especially for pediatric patients with cancer. The aim of this study was therefore to compare the efficacy of 2 protocols on oral care, which are different in the type of mouthwashes: 0.2% w/v chlorhexidine gluconate versus 0.15% w/v benzydamine hydrochloride in alleviating oral mucositis symptoms for children undergoing chemotherapy.