Abstract
Oral mucositis is characterized by erythema, inflammation, and ulcerations of the mucous membranes in the oral cavity. This common side effect from radiation and chemotherapy can have significant impacts on quality of life, including alterations in immunity, malnutrition, and weight loss. At present, treatment options for this condition are limited. This review highlights the current state of evidence regarding oral mucositis and treatments that may help prevent or reduce its occurrence.
Introduction
Mucositis is a common complication among patients receiving chemotherapy or radiation therapy, occuring in approximately 40% of this population (Raeessi 2014 A). It can be especially problematic during treatment of head and neck malignancies, as well as during treatment with concurrent chemotherapies, which include alkylating agents such as cyclophosphamide and various platinums, anti-tumour antibiotics such as bleomycin, adriamycin (doxorubicin) and epirubicin, and antimetabolites such as 5-fluorouracil (5-FU).
Uncontrolled mucositis can profoundly impact quality of life and treatment effectiveness for patients with cancer, as it may lead to dose limitations for cancer therapy. It can cause immense pain, increases the risk of infection and dysphagia, cause difficulty with food and fluid ingestion, affect nutrition and hydration status and lead to weight loss (Keefe 2007, Stubbe 2013, Worthington 2011).
Treatments
In addition to good oral hygiene, avoidance of spicy, acidic, hard, and hot foods and beverages, the use of mild-flavoured toothpastes, and repeated mouthwashes with suggested rinses from the patient’s local cancer clinic, the following have been shown to be effective in reducing oral mucositis induced by conventional cancer treatment.
CHAMOMILE
In a recent randomized phase II clinical trial, 40 patients undergoing hematopoietic stem cell transplantation (HSCT) received routine care plus a mouthwash containing a liquid extract of the botanical Chamomilla recutita at 0.5%, 1%, or 2% or standard care alone (control group). Use of the mouthwash ended when the oral mucosa was reestablished or the granulocyte count exceeded 500 mm3 for 3 consecutive days in patients who did not develop mucositis. Control patients received standard care without use of a herbal mouthwash. Patients were evaluated daily using the measurement scale for oral toxicity defined by the World Health Organization.
Of the three concentrations, the experimental group at the 1% dosage demonstrated the greatest reduction in incidence, intensity and duration of oral mucositis compared to the control group. Patients tolerated the herbal extract well and it was found to be safe with no moderate or severe adverse effects (Braga 2014).
DGL
Deglycyrrhizinated licorice (DGL) is an extract of licorice that has had the glycyrrhetinic acid component removed. This avoids the potential hypertensive properties of glycyrrhetinic acid. DGL is well-known to possess demulcent properties that promote the healing of mucus membranes (Dehpour 1994, Morgan 1982). DGL is available in multiple forms, easily dissolved and is cost-effective. While it does require frequent dosing for effectiveness it has been shown to be clinically beneficial in healing mucus membranes. A number of studies dating from the 1970s to present have demonstrated its usefulness in treating peptic ulcer, aphthous ulcers, as well as radiotherapy induced mucositis.
One of the earlier studies reported on the 2-week use of mouthwash containing DGL in the treatment of aphthous ulcers. In this study, DGL provided pain relief and accelerated the healing time of the ulcers (Das 1989). In a more recent study, a randomized, double-blinded clinical trial, subjects with recurrent aphthous ulcers were assigned to receive either a patch with glycyrrhiza root extract, a placebo patch, or no treatment at the onset of a lesion. Treatment with topical glycyrrhiza resulted in improvements in ulcer size (p <0.05) and pain (p <0.01), compared to both the placebo and no-treatment groups (Martin 2008).
Other, older clinical trials have compared DGL to carbenoxolone, cimetidine, and ranitidine (Mills 2000, Morgan 1982) and found it to be equally effective in healing gastric and duodenal ulcers.
With respect to cancer related mucositis, a couple recent studies demonstrated significant benefit. One clinical trial pertaining to mucositis induced by cancer treatment involved a total of 75 patients who received radiotherapy to the head and neck and were divided into 4 groups: Group A applied licorice powder and honey locally and consumed 10mL of a licorice preparation twice daily; Group B applied licorice powder and honey locally; Group C applied only honey locally; and Group D was the control group which received standard medical treatment for mucositis (Das 2011). Each group received treatment for 7 weeks. Of the four groups, Group A had the greatest reduction in radiation-induced mucositis (p< 0.001) compared to the control group. While this study had many inherent flaws in that the treatment agents were not standardized, and blinding of assessors for the evaluation of mucositis was not used, it is one of only two studies to date published in the literature showing promise of DGL’s efficacy in treating radiation-induced mucositis.
The second study was a randomized, double blind trial examining the topical use of mucoadhesive patch containing licorice extract (Ghalayani 2014). A total of 60 patients with radiotherapy-induced mucositis were randomized to treatment with a patch containing triamcinolone acetonide or a patch containing licorice. Over consecutive weeks, both groups experienced significant improvements (p<0.05) in the symptoms listed as part of the WHO Mucositis Score (Table 1). There was little change seen in pain ratings however.
DGL is contraindicated in hormone-sensitive breast, uterine, and ovarian cancer due to its phytoestrogenic effects and may interfere with medications and chemotherapy that rely on cytochrome P450 2B6, 2C9, and 3A4 metabolism (Stolpman 1999).
GLUTAMINE
Glutamine is the most abundant free amino acid in the human blood stream and is conditionally essential to cells (Chen 2012). It plays a regulatory role in metabolism (oxidative fuel, gluconeogenic precursor, lipogenic precursor), cell integrity (apoptosis and cell proliferation), protein synthesis, and degradation, among other processes (Curi 2005).
While many practitioners find great benefit using glutamine as a treatment for mucositis induced by chemotherapy and radiation, existing research shows mixed findings. A 2011 Cochrane review by Worthington et al. evaluated the prevention of oral mucositis and showed no statistically significant benefit of using oral glutamine. The review did find weak but statistically significant evidence for intravenous glutamine in preventing severe mucositis however (Worthington 2011).
Smaller trials suggest a benefit for using glutamine during radiation (Savarese 2003) and recommend contact with mucous membranes via a swish and swallow method of administration (Noe 2009, Savarese 2003). A small trial reviewed by Worthington et al. found similar protective effects with intravenous glutamine, 0.4 g/kg weight/day given on chemotherapy days, among patients undergoing chemo-radiotherapy for head and neck cancer (Cerchietti 2006). Phase I and II pilot studies on dosage guidelines found that 20 to 30 g daily of glutamine in divided doses was more effective than lower doses (Noe 2009). It is most effective when administered from the start of radiation until 2 weeks after completion.
A systematic review by Gibson et al performed in 2013 analyzed the available literature and defined evidence-based clinical practice guidelines for the use of agents used to treat and prevent mucositis. One of the most important findings in this review was the change in guideline in regards to the use of systemic glutamine. Newer literature demonstrates that glutamine may be effective and without severe toxicity. However, due to conflicting evidence at this time, the guidelines were merely changed from “not recommended” to “no guideline possible.” (Stubbe 2013)
Due to the fact that cancer produces a state of glutamine deficiency (Guarav 2012) that can be further aggravated by the toxic effects of chemotherapy, common recommendations made by naturopathic physicians with special interests in oncology include 15g swish and swallow twice daily for approximately 5 days after chemotherapy agents such as Taxol for example, and 8-10 days post 5-Fluorouracil (5-FU).
Preparation of the following recipe has been shown to help clinically in the prevention and treatment of oral mucositis. Directions are to prepare one glass per day; take frequent sips and swish and spit throughout the day.
- ½ tsp salt
- ½ tsp baking soda
- 1 tablespoon glutamine
- 250mL room temperature water
Currently, there is controversy regarding whether glutamine may serve as a possible fuel for cancer cells, when orally ingested. As a result, it is generally advised that as a precaution, glutamine should be administered as a swish and swallow formula rather than being swallowed. Limitations of the idea that glutamine may fuel cancer cell growth is that it is based predominantly on in vitro studies, whose generalizability to the complex human body is uncertain (Son 2013). Some have argued that since it is the most abundant amino acid in the body, and is synthesized in vivo when not supplied externally, supplemental glutamine is unlikely to have harmful effects on cancer progression, especially when weighed against the benefits of correcting the state of malnutrition produced by cancer, supporting immune function, and preventing mucositis and neuropathy. Data from higher level evidence appears to support this counter-argument: a retrospective study of patients with stage IIIB non-small cell lung cancer (NSCLC) found that glutamine supplementation (10g 3 times daily) given for the prevention of radiation induced esophagitis was not associated with worse survival metrics or tumor control (Topkan 2012). On the other hand there was significant benefits for preventing radiation esophagitis, weight loss, and associated treatment delays. Nonetheless, it may be prudent that when possible, glutamine supplementation be limited to periods of active chemo- and/ or radiation therapy for the time being.
HONEY
Honey is an agent that has long been used to soothe mucus membranes. Impressively, a recent systematic review and meta-analysis showed an 80% relative risk reduction in radiation-induced oral mucositis among honey-treated patients when compared with control group (Song 2012). The meta-analysis included three studies in which 120 patients with head and neck cancers receiving radiation therapy were evaluated for radiation-induced mucositis using the WHO (Table 1) and Radiation Therapy Oncology Group (RTOG) criteria (Table 2).
In these three studies, honey was applied before, directly after, and several hours after radiation therapy, to the inside of the mouth. The control group did not actively receive treatment for mucositis. The risk of developing mucositis in the honey-treatment group was 80% lower than in the control group (relative risk [RR] 0.19, 95% confidence interval [CI] 0.098-0.371) (Song 2012).
The topical application of natural honey is a simple and cost-effective treatment for radiation mucositis that warrants further investigation in large multicentre randomized trials.
Honey Plus Coffee
In addition to use of honey alone, research has investigated the effect of honey when used in conjunction with coffee, a surprising addition. A recent double-blinded randomized controlled trial evaluated a total of 75 eligible adult patients who were assigned to one of three treatment groups. Each patient was given a syrup-like solution. The first group was given 20 ampoules of betamethasone, each containing 8mg betamethasone. The second group was given 300g of honey only. The third group was given 300g of honey plus 20g of instant coffee. The participants were told to sip 10mL (three teaspoons) of the prescribed product and then swallow it every three hours for one week. The severity of the lesions was clinically evaluated before the treatment as well as one week after the intervention. Results showed that all three treatment regimens reduced the severity of the mucositis lesions, however the greatest reduction in lesion severity was achieved in the honey plus coffee group, followed by the honey only group.
The idea to combine coffee plus honey was extrapolated from previous studies performed by the same research team in which they assessed the effect of honey plus coffee on the treatment of persistent post-infectious cough (Raeessi 2014 B, 2013, 2011). In these studies, researchers noted the rapid healing effect of this treatment modality on the lesions in the hypopharynx mucosal membranes, and decided to design a new trial to evaluate the effect of this regimen on oral mucositis induced by cancer chemotherapy (Raeessi 2014 B). The biological basis for this additive effect is unclear, but may be due to possible antioxidant and anti-inflammatory effects (Raeessi 2014 B).
LOW LEVEL LASER
Finally, a systematic review and meta-analysis by Oberoi et al. found that prophylactic Low Level Laser Therapy (LLLT) was able to reduce severe mucositis and pain in patients with cancer undergoing hematopoietic stem cell transplantation and associated chemo/ radiation. The review included 18 RCTs with 1144 subjects. Results showed that LLLT reduced the overall risk of severe mucositis (RR 0.37, 95%CI 0.20-0.67, p =0.001). When compared to placebo (no therapy), LLLT also reduced severe mucositis at the time of anticipated maximal mucositis (RR 0.34, 95% CI 0.20-0.59), overall mean grade of mucositis (standardized mean difference -1.49, 95% CI -2.02 to -0.95), duration of severe mucositis (weighted mean difference -5.32, 95% CI -9.45 to -1.19), and incidence of severe pain (RR 0.26, 95% CI 0.18 to 0.37) (Oberoi 2014).
Increasing supportive evidence for low-level laser therapy has allowed for new guidelines in the prevention of oral mucositis in adult patients receiving hematopoietic stem cell transplantation with high-dose chemotherapy and with or without total body irradiation. Treatment recommendations included using a wavelength of 650nm, power of 40mW, and each square centimetre treated with the required time to a tissue energy dose of 2 J/cm(2) (2s/point)) (Migliorati 2013).
HPV Status
An important clinical management consideration when aiding patients in preparation for radiotherapy is HPV (Human Papillomavirus) status. A new study evaluated HPV positive patients with oropharyngeal cancer and found that consideration of additional specific risk factors is required to optimize care (Vatca 2014). This retrospective analysis of 72 patients found that there was a 6.86-fold increase in the risk of having severe, grade 3-4 mucositis in HPV-positive patients. This effect was observed after adjusting for patient smoking status, nodal stage, radiotherapy technique, and radiotherapy maximum dose. Additionally, HPV status had significant effects on the objective weight loss during treatment and at three months following treatment. Non-smokers had a significant 2.70-fold increase in the risk of developing severe mucositis (Vatca 2014). This study highlights the need to take extra precaution and employ aggressive prophylactic measures in these patient populations.
Conclusion
Naturopathic doctors are well equipped with a variety of natural interventions to help prevent and manage mucositis in patients with cancer undergoing chemo and/ or radiation therapy. These include the use of chamomile, licorice, DGL, glutamine, honey, and low level laser therapy. As is often the case, it is unlikely there will be one therapy that is suitable for treating all patients with oral mucositis. Using a multi-agent and sequenced approach tailored to each individual patient, while taking into consideration specific risk factors such as local radiation to the head or neck, chemotherapy agents known to cause high grades of mucositis, HPV-status, may be the most effective treatment approach at this time. Patients in these high risk categories should be treated more aggressively. Controversy around use of glutamine currently dictates that its use should be limited to patients undergoing active treatment. Further investigation of these safe, simple measures is needed.
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