Abstract
Radiation therapy for oral carcinoma is therapeutically useful in dose of at least 6000 cGy but causes mucositis that severely interferes with oral function. The literature indicates that honey appears to promote wound healing, so the authors investigated whether its anti-inflammatory properties might limit the severity of radiation-induced oral mucositis. A single-blinded, randomized, controlled clinical trial was carried out to compare the mucositis-limiting qualities of honey with lignocaine. A visual assessment scale permitted scoring of degrees of mucositis and statistical evaluation of the results was performed using the χ 2 test. Only 1 of 20 patients in the honey group developed intolerable oral mucositis compared with the lignocaine group, indicating that honey is strongly protective (RR = 0.067) against the development of mucositis. The proportion of patients with intolerable oral mucositis was lower in the honey group and this was statistically significant ( p = 0.000). Honey applied topically to the oral mucosa of patients undergoing radiation therapy appears to provide a distinct benefit by limiting the severity of mucositis. Honey is readily available, affordable and well accepted by patients making it useful for improving the quality of life in irradiated patients.
Oral carcinoma is the sixth most common malignancy worldwide , accounting for an estimated 4% of all cancers, of which 95% are squamous cell carcinoma . This invasive disease arises from the basal cells of the epithelial lining of the oral cavity. Surgery is the mainstay of treatment but radiotherapy is increasingly being used alone or as an adjuvant to surgery or chemotherapy . Radiotherapy is used for recurrences after surgery . Radiation may be delivered pre- or postoperatively as an adjuvant to surgery and is traditionally given as single daily doses, for 5 days a week, up to a total dose of 6000 cGy over 6 weeks.
Ionizing radiation causes damage to normal tissues located in the radiation portals. The most common acute complication of radiotherapy in the head and neck region is oral mucositis and its inevitability has been studied for decades . The traditional model held that purely epithelial damage resulted in mucositis, but recent research implicates reactive oxygen species in initiation. Several genes appear to be ‘switched on’ by radiation and chemotherapy leading to synthesis of tissue-injuring cytokines and apoptosis-causing enzymes. These mediators appear to induce, upregulate, activate and amplify more pro-inflammatory molecules even after the cessation of radiation and chemotherapy. Clinically, the result is ulceration, prolonged inflammation, and severe pain for a long duration and cell death, the latter leading to further inflammation and predisposing to bacterial infection . This newer hypothesis highlights the different steps in the development of mucositis opening up possibilities for better interventions.
Radiation damages epithelium and submucosal connective tissue and causes inflammation . Cell turnover decreases and the loss of mucosal barrier function increases the risk of oral infection . Gram-negative bacteria colonize the oral cavity, worsening the severity of mucositis. It is logical to seek an agent that when applied topically would reduce inflammation and decrease infection with minimal adverse reactions . At times it is necessary to discontinue radiation therapy because of the severity of these problems. Management of oral mucositis is critical to patient survival because an interruption of radiation therapy jeopardizes its cancer-destroying effect and increases the possibility of tumor cell repopulation .
Several interventions have been used to prevent or reduce the severity of mucositis but outcomes are inconsistent . Sucralfate, which is used to treat gastrointestinal ulceration, is well tolerated by the oral mucosa but demonstrates no significant advantage in the prevention or treatment of radiation-associated mucositis . Non-steroidal anti-inflammatory drugs (NSAIDs) and opioids that are usually prescribed for pain management are inappropriate for mucositis because the long duration of their administration increases the incidence of adverse drug reactions . Benzydamine mouthwash, an anti-inflammatory agent, significantly reduces erythema and ulceration but had little effect when accelerated radiotherapy was used. Interventional studies with antimicrobial therapy have shown conflicting results. Lozenges of polymyxin B, tobramycin and amphotericin B show promise in limiting radiation mucositis, but lozenges of clotrimazole, bacitracin and gentamicin did not reduce mucositis. At least one study contraindicated the use of lozenges in oral mucositis . Mouthrinses of chlorhexidine gluconate appear to prevent mucositis. Amifostine, a cytoprotective, appears to reduce mucositis but has adverse effects. Prostaglandins, low-level laser therapy, and proteolytic enzymes such as trypsin, papain and chymotrypsin can be beneficial .
Honey has been used as a medicament since ancient times . It has recently been rediscovered to have desirable properties on wounds . For chronic infected skin ulcers that do not heal with conventional treatment, honey renders wounds sterile . S ubrahmanyam et al. demonstrated that honey applied to burn wounds controlled infection early and relieved pain . Honey has been applied to ophthalmic mucosa and in extraction sockets after dental extraction to reduce pain and inflammation. C hiba et al. stated that the anti-inflammatory action and stimulating effect of honey on tissue repair could relieve the oral discomfort resulting from radiotherapy . Work done by Molan indicates that honey inhibits bacterial growth . Honey applied to the oral cavity reduces levels of plaque and decreases the severity of gingivitis .
The composition of honey is difficult to define since it is not a generic product, the ingredients and their relative amounts being dependent on the flora of the geographical area from which honey bees collect pollen. The composition of honey from an apiary is likely to differ from that obtained from beehives in the wild (the usual source of honey in India) . Honey typically contains <20% water, a high concentration of sugars, proteins, vitamins and enzymes .
In the management radiation mucositis, it is important to investigate whether preliminary reports suggesting the effectiveness of topical honey can be clinically validated through a randomized, controlled trial. It is especially desirable to avoid systemic anti-inflammatory agents such as corticosteroids to avoid immunosuppression and adrenal cortex suppression. Similarly, non-steroidal anti-inflammatory agents are avoided since gastrointestinal bleeding is a risk of prolonged usage . The enzymes contained in honey are invertase, diastase and glucose oxidase, the latter being metabolized to hydrogen peroxide . It is not known whether the antimicrobial property of honey is derived from its yield of hydrogen peroxide on exposure to catalase in wound fluid, or whether it is the result of its high osmolarity. What appears to be evident is that it has a definitive effect on wound healing. With this background of oral carcinoma, and mucositis as a complication of radiotherapy, the authors investigated whether honey has the potential to reduce the severity of mucositis and associated symptoms in patients undergoing radiation therapy for oral carcinoma as well as satisfy the additional objectives of promoting wound healing, availability, affordability and acceptability.
Materials and methods
This was a single-centre, randomized, controlled, multi-dose, investigator-blinded clinical trial. The study group comprised patients with oral carcinoma at the authors’ hospital, planned for treatment with radiation therapy. The exclusion criteria were: xerostomia; poorly controlled diabetes mellitus; chemotherapy; oral surgery within the previous 6 weeks; anti-inflammatory medications by oral, topical or parenteral route; and poor oral hygiene.
The study aimed to recruit subjects into two groups giving 80% power to detect an estimated 50% difference between the two groups. It was required to calculate the difference in proportions between two groups for which nMaster™ 1.0 software was used. Each group was calculated to require at least eight subjects.
At the commencement of the study all participants were verified to have no mucositis of the oral cavity. Subjects were randomized into either of two groups using opaque envelopes; a co-worker oversaw the randomization. It was agreed that patients in the test (honey) group and the control (lignocaine) group would receive 6000 cGy of radiation to the head and neck over 6 weeks. Radiation would be given once a day, for 5 days a week. Each patient would receive an intervention 15 min prior to radiation, 15 min after radiation and once before going to bed. Honey group participants would receive honey extracted from beehives of the Western Ghats forests, and lignocaine group participants would receive lignocaine gel. Either intervention consisted of a trained co-worker administering 20 ml of either honey or lignocaine gel which would have to be swished about the oral cavity for 2 min and expectorated.
The objective was to detect any difference in oral mucositis levels between the two groups. The null hypothesis (H 0 ) was that there was no significant difference between the two groups in the proportions of subjects with intolerable mucositis. The alternative hypothesis (H 1 ) would be that there was a statistically significant difference in the proportion of patients developing intolerable mucositis between the two groups. Visual assessment using the Radiation Therapy Oncology Group (RTOG) mucositis assessment scale was performed. The scale grades from 0 to 4, indicating progressively more severe degrees of oral mucositis. A blinded researcher, unaware of the intervention received by the subjects, assessed oral mucositis visually at the end of each week, for 6 weeks. The scores were entered into a data spreadsheet. Battery-powered torchlight was used to standardize illumination of the oral cavity during grading of severity of mucositis. When differing grades of mucositis were present in the same oral cavity, the highest score was recorded. Scores 0, 1 and 2 were grouped as ‘tolerable mucositis’ and scores 3 and 4 were termed ‘intolerable mucositis’. The co-worker administering the intervention did not participate in the assessment of mucositis. As only one blinded researcher evaluated all patients, calibration of assessors was not required. The researcher evaluating mucositis had no knowledge of the randomization allocation.
To compare the findings between the two groups descriptive statistics were used. To determine whether there was a statistically significant difference in proportions of patients in the groups with intolerable mucositis, the χ 2 test was applied. SPSS ® version 11.5 was used to perform all statistical analyses.
Results
Three patients were lost to the study, two due to diabetes mellitus and one did not consent. There were no deviations from the study protocol. Interventions began immediately after enrolment. The data were subjected to statistical analysis.
The patients were stratified according to whether they were less than 40 years or over 41 years of age ( Table 1 ). Analysis showed no statistically significant differences between the two age groups ( p = 0.89).
| Age | Mucositis | Total | |
|---|---|---|---|
| Tolerable | Intolerable | ||
| <40 years | 8 | 5 | 13 |
| 41 years and over | 16 | 11 | 27 |
| Total | 24 | 16 | 40 |
Several oral carcinoma sites were included in this study ( Table 2 ). The association between subsite of noted mucositis and its severity showed no statistically significant association ( p = 0.86).
| Site | Age (years) | Total | |
|---|---|---|---|
| <40 | 41 and above | ||
| Tongue/floor of mouth | 8 | 9 | 17 |
| Buccal mucosa/alveolar gingival | 2 | 9 | 11 |
| Retromolar trigone | 0 | 1 | 1 |
| Palate | 1 | 2 | 3 |
| Lip | 0 | 3 | 3 |
| Gland (tonsil/parotid) or other sites | 2 | 3 | 5 |
| Total | 13 | 27 | 40 |
Participants in each group (test and control) were evaluated at the end of the fourth week of irradiation. The oral mucosa was assessed for mucositis. Scores according to the RTOG scale were allotted for statistical analysis. Based on intervention, the scores observed are shown in Table 3 . The data were simplified into tolerable mucositis and intolerable mucositis ( Table 4 ).
