Reference
Elad S, Meidan I, Sellam G, et al. Topical curcumin for the prevention of oral mucositis in pediatric patients: case series. Altern Ther Health Med. 2013;19(3):21-24.
Design
A case series. Presence/severity of oral mucositis was assessed on days 0, 7, 10, 14, and 21 of a cytotoxic (chemotherapy) course. The study was initially slated to be placebo controlled; however, adverse events (nausea and vomiting), affected the compliance of the first 3 subjects, all in the placebo arm. The research team therefore considered it unethical to continue the use of the placebo, so they converted their study into a case series.
Participants
All subjects were pediatric or young-adult patients ranging in age from 13 to 25, who had a diagnosis of cancer and were presently receiving a doxorubicin-containing chemotherapy. Seven patients participated initially, but data were only collected on 4 subjects because 3 subjects demonstrated low compliance (failing to use the medication within the first week).
Study Medication and Dosage
All patients received standard, preventative oral care—chlorhexidine 0.2% mouthwash for 30 seconds twice per day with 10 drops of Curcumall. Curcumall is a tincture of curcumin C3 95%, turmeric, and ginger, dissolved in glycerin and 0.4% alcohol base produced by Tumron Health Products, Jerusalem, Israel. Participants received an equivalent of 330 mg of curcumin. All subjects received a doxorubicin chemotherapy that was a dose of at least 60 mg/ml2 per course.
Outcome Measures
Oral mucositis was assessed with use of the World Health Organization (WHO) scale, the Oral Mucositis Assessment Scale (OMAS), and a Visual Analog pain scale (VAS; patient reporting scale of 0–10) on days 0, 7, 10, 14, and 21 of cytotoxic therapy course. Adverse events were tracked.
Key Findings
As stated, 7 participants were in the original intervention group, but only 4 complied with study parameters. Of those subjects who rinsed twice daily for 30 seconds with the curcumin mouthwash, no adverse events were observed. All participants did develop some oral mucositis (OM) as recorded and defined by at least one of the OM scales (WHO, OMAS and/or VAS). The degree of OM was described as mild, according to those values reported by both examiners and participants. The WHO and OMAS scales reflected the worst scores; 2 out of 4 (WHO) and 5 out of 45 (OMAS). Notably, there was an outlier who reported an OMAS score of 11 due to a herpetic reactivation. Duration of neutropenia ranged from 3 to 8 days, with an average of 4. Opioid use ranged from 0 to 4 days with an average of 1.5 days. And finally, hospitalization ranged for all subjects between 0 and 12 days with a median of 7. No parenteral nutrition was required.
Practice Implications
Oral mucositis can significantly compromise a patient’s quality of life. It occurs against a background of cytotoxic therapy that involves the atrophy, inflammation, and slowed renewal of mucosal epithelium. The pathological process is often compounded by lymphocytopenia, neutropenia, bacterial invasion/infection, and oral trauma. Some of the most stomatotoxic agents include the antimetabolites 5-fluorouracil, methotrexate, and cytarabine. OM typically begins 5 to 10 days into a course of treatment and continues for an average of 7 to 14 days. Resolution seems to coincide with recovery of white blood cell and neutrophil counts. The most common symptoms include oral pain; erythema; difficulty opening the mouth, eating, drinking, and speaking; and difficulty with mouth care regimens.1 When at its worse, parenteral nutrition is required.
In a retrospective analysis of nearly 600 patients receiving chemotherapy, oral and gastrointestinal (GI) mucositis developed during 37% of 1,236 cycles of chemotherapy. In addition, oral mucositis was significantly correlated with infection. Those patients who developed oral mucositis, compared to those who did not, had higher rates of infection and antibiotic use (68% vs 36%), more weight loss (61% vs 54%), increased use of antiviral therapy (45% vs 10%) and antifungal drugs (34% vs 6%), more frequent chemotherapy dose reductions (25% vs 11%), and delayed cycles (11% vs 9%).2
Even a small reduction in the frequency of severity of OM will have a significant impact on a patient’s treatment.
Studies to date on chemotherapy-induced oral mucositis offer limited data and no single, effective intervention. In fact, the Multinational Association for Supportive Care in Cancer (MASCC), a panel that provides clinical practice guidelines for the management of chemotherapy-induced OM, recommends against the use of most natural substances, with the exception of zinc, in the treatment of OM. The MASCC clinical practice guidelines are dependent on the cytotoxic therapy employed and type of cancer. For example, the panel recommends that 30 minutes of oral cryotherapy be used in patients receiving 5-fluorouracil chemotherapy. Recombinant human keratinocyte growth factor-1 is recommended as a preventative for those receiving high-dose chemotherapy and total body irradiation followed by autologous stem cell transplantations. Morphine and opiate pain medications remain a mainstay to manage OM associated pain.3 The panel has not named a single agent to control or prevent OM for use with all types of chemotherapy and all types of cancer. However, MASCC does suggest “oral care protocols” be used to prevent oral mucositis in all age groups and across all cancer treatment modalities. These “oral care protocols” are not defined and likely vary from patient and physicians alike.
A systematic review, published in February 2013, analyzed interventions for the prevention of oral mucositis in children receiving cancer therapy. Twenty-seven articles were included in the review. The interventions consisted of oral care protocols, chlorhexidine mouthwash, laser therapy, granulocyte stimulating factor (GM-SCF), iseganan mouthwash, and benzydamine mouthwash, oral/enteral glutamine, oral propantheline with cryotherapy, oral cryotherapy, oral sucralate suspension, prostaglandin E2 tablets, and chewing gum. Of those studies reviewed, the authors suggest only the use of oral care protocols and avoiding all other interventions due to low or conflicting evidence.4
A second systematic review, published in November 2013, analyzed the use of natural agents for the management of OM in cancer patients. A total of 49 papers and 15 interventions were analyzed. Study outcomes revealed a preference for zinc supplements. Again, there was insufficient evidence regarding the use of other natural therapies due to inadequate research. No recommendations were made to use natural agents in the treatment of OM. A recommendation was made against the use of intravenous glutamine for the prevention of mucositis.5 No recommendation was made for or against its use orally.
While this current study provides some promise that use of a curcumin mouthwash may have benefit, the reality is that it is non-statistical, non-blinded, and non-placebo controlled. The small number of participants makes any reported outcome questionable. In addition, the cytotoxic therapy used in this study (doxorubicin) is not commonly associated with precipitating significant OM.6 What this paper does do is to hint to us that an herb already valued in the clinical oncology arena, might have utility in treating this common problem.
A February 2014 study may further elucidate this potential use of curcumin for OM. Researchers compared synthetic versus natural curcumin in an in vitro oral mucositis model. This study evaluated the composition of curcumin and its potential relation to primary outcome measures. Synthetic curcumin (sCUR) was compared to natural purified curcumin (nCUR). nCUR was purified from curcuma longa (containing >65–70% diferuloylmethane curcumin) and greater than 90% curcuminoids. The sCUR was reported to be greater than 99% pure. Both sCUR and nCUR were evaluated for the parameters commonly measured in assessing agents for treating OM, including ease of use as a topical agent, bactericidal activity, ability to inhibit bacterial adherence and invasion to epithelial cells, and power to inhibit epithelial cytokine/chemokine release.
No great differences were found between sCUR and nCUR, though sCUR was more soluble in DMSO than nCUR. It also had less odor and taste. There was no difference in bactericidal activity. Both reduced bacterial adherence to epithelial cells at concentrations of 200 μm and higher. Both forms suppressed the release of all cytokines (IL-8, GM-CSF, IL-6, MCP-1, VEGF, and TNFa), with the exception of IL-10 and FGF-2.7 Although this recent paper was in vitro the data reported provide encouragement that topical curcumin may show benefit in more rigorous future clinical trials.
Use of synthetic curcumin is rare; the curcumin products commonly utilized are by and large all naturally derived curcumin products. From this comparison, outcomes are similar for both. The sCUR may have a slight advantage in having no odor or taste, but it is unlikely that the patient population that seeks out naturopathic physicians will choose anything labeled synthetic over something that is natural. Yet to a child lack of taste may outweigh the philosophic preferences of the parents.
The greater solubility of the synthetic forms of curcumin may provide advantage as well if we are to dispense it in liquid solution. Effectiveness of curcumin may depend on finding an appropriate delivery system. N-succinyl chitosan is 1 delivery system offering promise. This substance has already been studied for its buccal penetration and to deliver herbal agents. It consists of microemulsified eugenol, honey and sodium hyaluronate. (Of course honey itself has been studied and found effective in the management of radiation and chemotherapy induced OM.8,9) Its pH of 6.4 is lower than most oral delivery solutions. A 2013 in vivo study evaluated the use of N-succinyl chitosan vs chitosan oral gel and chlorhexidine in a 5-fluorouracil induced OM rat model. Rats given N-succinyl chitosan had significantly improved outcomes measured by greater survival, weight gain, increased tissue regeneration, and decreased inflammation.10 The addition of curcumin to N-succinyl chitosan may provide greater efficacy in the management of OM, and a formula to study in future clinical trials.
So, what practice implications does this study mean for our management of chemotherapy induced OM? While we may fall back on the common response that more studies are needed, some patients will consider using oral topical curcumin in some form. Finding effective delivery agents and a form of curcumin without objectionable odor or taste may be important as well. A formula that penetrates the mucosa such as N-succinyl chitosan–based ones may prove more effective than the simple tincture used in these case reports.
Final note
While it is rare for NMJ to review research weak in study design, we chose to do so in this situation due to the strong need to find an effective treatment for OM. The use of topical curcumin, as this study hints, might offer benefit to this end. This is both intriguing and worth pursuing.
