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Table of Contents   
ORIGINAL RESEARCH  
Year : 2020  |  Volume : 31  |  Issue : 5  |  Page : 718-727
Effectiveness of curcumin mouthwash on radiation-induced oral mucositis among head and neck cancer patients: A triple-blind, pilot randomised controlled trial


1 Department of Public Health Dentistry, S.C.B Dental College, Cuttack, Odisha, India
2 Department of Radiation Oncology, Acharya Harihara Regional Cancer Centre, Cuttack, Odisha, India
3 Department of Oral Medicine & Radiology, S.C.B Dental College, Cuttack, Odisha, India

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Date of Submission05-Nov-2018
Date of Decision04-Jan-2020
Date of Acceptance30-Jun-2020
Date of Web Publication08-Jan-2021
 

   Abstract 


Introduction: Radiation-induced oral mucositis (RIOM) is considered the most severe non-haematological complication affecting almost every head and neck cancer patient during the course of radiotherapy (RT). Curcumin, a herbal agent present in Indian spice 'Turmeric' has anti-inflammatory, immunomodulation and wound healing properties. The objective of this pilot randomised controlled clinical trial was to compare the effectiveness and safety of 0.1% curcumin (freshly prepared using nanoparticles) and 0.15% benzydamine mouthwash on RIOM among 74 head and neck cancer patients scheduled to receive RT. Materials and Methods: Assessment of RIOM was carried out using WHO criteria once in a week for 6 weeks. Both modified intention to treat (MIT) and per protocol (PP) analysis were carried out to test the null hypothesis of equal effectiveness on prevention and severity of RIOM. Results: As far as the onset of RIOM is concerned, MIT analysis showed that the instantaneous risk of getting the onset of RIOM was 50% lower (hazard ratio 0.5) in curcumin. Onset of RIOM was also significantly delayed (mean = 19.56, median = 21) in the test group by 2 weeks. But in 'PP' analysis, no significant difference was observed between two preparations and almost all patients experienced the onset. Both the mouthwashes were equally effective in preventing the occurrence of severe form of RIOM in PP analysis after dichotomisation of severity score (≥3 and ≤2). Conclusion: Though both the mouthwashes were not able to completely prevent the onset of RIOM and reduce the severity of RIOM, use of 0.1% curcumin mouthwash was able to significantly delay the onset of RIOM (Clinical trial registration no. CTRI/2018/04/013362).

Keywords: Benzydamine, curcumin, intention to treat analysis, oral mucositis, radiotherapy

How to cite this article:
Shah S, Rath H, Sharma G, Senapati SN, Mishra E. Effectiveness of curcumin mouthwash on radiation-induced oral mucositis among head and neck cancer patients: A triple-blind, pilot randomised controlled trial. Indian J Dent Res 2020;31:718-27

How to cite this URL:
Shah S, Rath H, Sharma G, Senapati SN, Mishra E. Effectiveness of curcumin mouthwash on radiation-induced oral mucositis among head and neck cancer patients: A triple-blind, pilot randomised controlled trial. Indian J Dent Res [serial online] 2020 [cited 2021 Jan 28];31:718-27. Available from: https://www.ijdr.in/text.asp?2020/31/5/718/306462



   Introduction Top


Oral cancer ranks among the top three of all cancers, accounting for over thirty percent of cancers reported in India with an incidence rate of 12.6 per 1,00,000 population.[1] Traditionally, the clinical management of head and neck cancer commonly involves surgery followed by non-invasive procedures, i.e., radiotherapy (RT) and chemotherapy. Usually, radiation in advanced head and neck cancers is given in an adjuvant setting, i.e., after surgery. The reason for higher response of RT in oral cavity is because of its structural origin (endoderm, endoderm and mesoderm) which explains its increased sensitivity towards radiation. Radiation is a pack of energy, i.e., X-rays, gamma rays and electrons; when it is applied to any affected part of cancer tissue, it has the potential to kill cancer cells as well as the surrounding normal tissues but in course of time, normal tissues survive despite the internal damage occurring in their DNA, RNA and enzyme cell system.[2]

In therapeutic radiation of head and neck region, a condition known as radiation-induced oral mucositis (RIOM) is a common occurrence which can significantly produce clinical manifestations. The term 'mucositis' emerged in the year 1980 to describe the ulcerative lesions of mucosa in patients who are under RT and chemotherapy. Owing to its ambiguity with the 'stomatitis', ICD-10 (2007) has adopted and defined the term 'mucositis'. The general manifestation of mucositis includes pain, ulceration, erythema, soreness, dryness and white patches. In addition to the above sign and symptoms, oral mucositis presents with xerostomia, dysphagia, dysarthria, odynophagia and opportunistic infections.[3],[4] The severity of mucositis depends upon type, dose and duration of the radiation and even cumulative RT doses as low as 1000–2000 cGy (centigrays) administered at a rate of 200 cGy/day can induce the onset of RIOM.[5],[6]

Currently, oral mucositis is considered to be the most severe non-haematological complication affecting almost every head and neck cancer patients during the course of RT. It holds a prominent role in the success of cancer treatment as it can severely affect patient compliance and motivation level and sometimes leads to discontinuation of chemotherapy and RT because of uncontrolled signs and symptoms of pain.[3],[7]

Benzydamine mouthwash among non-herbal agents shows strong evidence in support of its effectiveness as mouthwash in preventing RIOM in head and neck cancer patients receiving moderate dose RT (up to 50Gy), without concomitant chemotherapy.[7],[8] Benzydamine hydrochloride, a non-steroidal agent with analgesic, anaesthetic, anti-inflammatory and antimicrobial properties, has been found to be efficacious for both stomatitis and RIOM. It acts by suppressing selected pro-inflammatory cytokine production and particularly effective inhibitor of TNF-α production, which may explain its anti-inflammatory effects.[5],[9] But owing to its high cost and intolerance to burning symptoms, there is still a need for well-designed clinical trials with sufficient numbers of participants to find an effective, economical and standard way to prevent RIOM.[10]

The quest for the use of new herbal agents, curcumin has been paid much attention in recent time for its use in preventing and treating RIOM. Curcumin (I) is among the four curcuminoids present in an Indian spice—'Turmeric' or 'Golden Spice'. Turmeric is a perennial herb of the ginger family. The most useful part of this plant is its roots or rhizome for culinary and medicinal purposes. Curcuminoids other than curcumin present in turmeric are demethoxycurcumin (curcumin II), bisdemethoxycurcumin (curcumin III) and the recently identified cyclocurcumin. It is observed scientifically that curcumin has anti-inflammatory, chemotherapeutic, antiangiogenic, antioxidant, chemopreventive, immunomodulation and wound healing properties. It is an orange-yellow crystalline powder practically insoluble in water and ether but soluble in ethanol, dimethylsulfoxide and acetone.[11]

Various laboratory and clinical trials have been conducted to test the effect of curcumin in reducing incidence and severity of RIOM.[12–14] The results from these studies have provided encouraging evidence regarding the beneficial effect of curcumin in preventing RIOM. But a strong data in support of this novel substance is still lacking.

The objective of this pilot study was to compare the effectiveness and safety of 0.1% curcumin and 0.15% benzydamine mouthwash on RIOM in head and neck cancer patients scheduled to receive RT. The primary outcome involved three different dimensions: compare the risk of onset, the effect on progression and risk of getting a more severe form of RIOM. Secondary outcome was the safety aspect of these mouthwashes.


   Materials and Methodology Top


The present pilot study was randomised, parallel arm, triple-blinded controlled clinical trial carried out from May 2016 to October 2016 in Acharya Harihara Regional cancer centre (AHRCC), Cuttack, Odisha.

Data regarding demographic details and oral cancer-related information were collected using a structured proforma including assessment of RIOM by WHO criteria.[15] Dental mouth mirror, kidney tray, cassette tray and torchlight were used for data collection and assessment of oral mucositis.

The benzydamine (0.15%) mouthwash used for the study was a commercially available (Brand name-COOLORA™, ICPA health products limited, Ankleshwar, India). It contains benzydamine hydrochloride BP 0.15% w/v as active component, aqueous base QS, brilliant blue and tartrazine yellow for colour.

Curcumin (0.1%) mouthwash was freshly made using nanoparticle curcumin powder, sodium benzoate (preservative) and clove oil (flavouring agent) provided by School of Biotechnology, KIIT University, Bhubaneswar, Odisha. Scientific details of the product used were as per the requirement of CONSORT (Extension requirements for conducting clinical trials on herbal intervention).[16]

For the preparation of curcumin mouthwash, the following procedure was followed: Glass apparatus and fresh opaque food-grade plastic bottles (250 mL) were first autoclaved which was then allowed to cool in radiation chamber. Flask was filled with 1 L of filtered drinking water and to this, curcumin powder (1 g) and sodium benzoate (1.5 g) were added followed by vigorous shaking for 10 min. The solution was allowed to mix for 30 min and then clove oil (1 mL) was added to it to prevent lipophilic reaction between curcumin molecule and clove oil, forming aggregates. The solution was then transferred to sterilised bottles after measuring 210 mL (10 mL*3 times/day for 7 days) with the help of graduated cylindrical. Bottles were then coded with the random numbers under the sterile condition and finally sealed with an inner safety cap and outer screw cap. Labelling and grouping were done by another dental personnel involved in record keeping to maintain the triple-blinded study design. Each patient was provided with new bottles at each of the seven visits (baseline and 6 follow-ups) after freshly preparing the curcumin mouthwash.

Ethical approval for the study was obtained from the institutional ethical committee of S.C.B Medical College and Hospital, Cuttack, Odisha and registered at Clinical Trial Registry- India (Clinical Trial Registration No. CTRI/2018/04/013362). Training and calibration of the Principal Investigator (PI) were carried out prior to the commencement of the proper study and the intra-rater reliability was found to be good after evaluation by an expert (kappa = 0.85).

Inclusion criteria:

  1. Patients having histopathologically confirmed squamous cell carcinoma of head and neck region scheduled for 6–7 weeks of RT with 60–70Gy radiation dose (200cGy/fraction for 5 days/week) irrespective of age and gender.
  2. Patients with Karnofsky performance status score ≥70% (to assess the ability of the patients to follow instructions).


Exclusion criteria:

  1. Physically handicapped/terminally ill patients which can affect the use of mouthwash.
  2. Patients using any other mouthwash.


At baseline, patients were screened for eligibility by SS, prior to commencement of RT at AHRCC. Eligible patients willing to sign the informed consent were recruited for the study. Data was recorded on a structured proforma and baseline oral mucosal examination was performed using a plane mouth mirror and torchlight. Patients were then allocated randomly to any of the two study groups to receive the mouthwashes after baseline examination. Randomisation procedure was carried out using a computer-generated random number sequence[17] and study participants (N = 74) were randomly divided equally into two groups, benzydamine group (positive control group) and curcumin group (test group).

The study was triple blinded as the participants, the PI and the statistician analysing the data were unaware of the treatment given to the study and test group until the completion of the trial. Identical bottles and labels in terms of size, texture, colour and shape were used for packaging of both the mouthwashes. Instructions, contact number of PI and allocated group code were mentioned on the label. Allocation of mouthwashes to patients was done as per computer-generated random sequence number.

Patients were advised to use 10 mL of mouthwash thrice daily for 7 days without mixing with water; to avoid eating or drinking for 30 min after mouth rinse; to bring the bottle in next visit (after 7 days); not to skip the dosage; to avoid the use of any other oral gel or mouthwash. All participants were instructed to shake the bottle before use.

Every patient was contacted over phone call one day before their scheduled date as a reminder for a check-up and mouthwash collection. After the baseline examination, at every subsequent visit, the remaining amount of mouthwash in the bottle was measured for calculation of patient compliance and a new bottle with the assigned mouthwash was provided to patients. Oral mucositis was scored until the end of 6 weeks. A follow-up sheet was maintained for patients in order to track their radiation schedule and call them for follow-up accordingly. Preparation and packaging of mouthwash were carried out in Dept. of Biotechnology and provided in opaque bottles with codes and instructions for use. Examinations of patients at baseline and follow-up were carried out by SS. Allocation concealment was done by GS using sequentially numbered opaque sealed envelope.

Statistical analysis

The raw data was entered into Microsoft excel worksheet and statistical analysis was done using Statistical Package for Social Sciences (SPSS) version 16. Statistical test was applied as per 'per protocol (PP)' (patients with complete follow-ups) and 'modified intention to treat (MIT)' (patients who at least had one follow-up after baseline as originally assigned group) method. Level of significance was set to P < 0.05 for all statistical inferences.

Normality of demographic and other confounding variables was confirmed by Shapiro-Wilk test. Normally distributed data (age) was analysed using independent t-test. Chi-Square and Fischer's exact test was used for comparing categorical data.

'Onset of RIOM' was defined as obtaining a score ≥1 as per the specified criteria.

According to 'PP' analysis, the effect on the risk of getting onset and severity of RIOM was calculated using Chi-square. To analyse the effect of mouthwashes on progression, Friedman's test was applied (ordinal data) followed by Wilcoxon signed-rank test (Bonferroni corrected) for intra-group (Post hoc) analysis and Mann-Whitney test for inter-group comparison. For assessment of the severity of RIOM, the scores were dichotomised into: '≤2-tolerable mucositis' and '≥3-intolerable mucositis'.[18]

According to 'MIT' model, a time-to-event analysis was performed using Kaplan-Meier (K-M) test for assessment of the instantaneous risk of having the onset of RIOM after taking the censored data into consideration. For this analysis 'the event' was the onset of RIOM and was coded as '1'. Patients were censored if they were lost to follow up or withdrew from the study or the event did not occur within the study period and was coded as '0'. Log-rank test was applied to assess the statistical significance between the survival probabilities of the groups.

Cox proportional hazard regression model was used to estimate the adjusted hazards ratio. Seven covariates (age, gender, socioeconomic status, site and grade of tumour, absence or presence of surgery and chemotherapy) were included for final cox model. Covariates were first analysed individually with the treatment groups to find their effect on level of significance (Log-rank test) and were considered as confounder if there was a change in P value. Coding for variables in SPSS software was as follows: gender (0-female, 1-male), socioeconomic status (1-lower, 2-upper lower, 3-lower middle, 4-upper middle and 5-upper), site of tumour (1-buccal mucosa, 2-tongue, 3-pyriform fossa, 4-mandibular alveolus, 5-others), grade of tumour (1-G1, 2-G2, 3-G3), Karnofsky performance status score (2-70%, 3-80%, 4-90%), surgery (0-no, 1-yes), chemotherapy (0-No, 1-Yes) and compliance (0 <80%, 1 ≥80%). Assumptions for proportional hazard for the final model were evaluated by using log-minus-log plot.


   Results Top


Age range of the complete sample was 26–96 years with a mean age of patients being 54.34 ± 13.78 years. Around 70% patients were male. There was no difference between both the groups for any of the sociodemographic factors [Table 1].
Table 1: Distribution of baseline demographic and other variables

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1. Distribution of RIOM scores

1A. According to 'MODIFIED INTENTION TO TREAT', group wise distribution of RIOM scores:

From the total sample size of 74 patients, 35 patients in benzydamine group and 33 in curcumin group completed at least one follow-up after baseline assessment.

With increasing time of follow-up, number of patients with higher scores increased. Most of the patient had onset of RIOM by 3 weeks. Even after completion of total follow-up, none of the patient reported the most severe score (4). The last row shows the number and percentage of missing data with each follow-up. It can be observed from the data that with increasing number of follow-up visits, number of missing data is increasing [Table 2].
Table 2: Distribution of study participants in Benzydamine and Curcumin group at various visits (in days) as per WHO scoring criteria according to modified intention to treat model

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1B. According to 'PER PROTOCOL', group wise distribution of RIOM scores:

Only 17 patients (nine in benzydamine group and eight in curcumin group) completed full follow-up. In benzydamine group, none presented with score 4. In curcumin group, none scored 3 and 4 [Table 3].
Table 3: Distribution of study participants in Benzydamine and Curcumin group at various visits (in days) as per WHO scoring criteria according to per protocol analysis

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2. Effect of both mouthwashes on the onset, progression and severity of RIOM

The null hypotheses were:

  1. No difference between the effects of both the mouthwashes on the risk of getting the onset of RIOM (Score ≥1).
  2. No difference between effects of mouthwashes on the progression of RIOM.
  3. No difference between the effects of both the mouthwashes on the risk of getting the most severe score of RIOM.


Both 'PP analysis' and 'MIT' analysis to test the hypothesis were performed as the number of patients who were lost during follow-up went on increasing with the increased number of follow-up visits.

2A. Testing hypothesis according to 'PER PROTOCOL' analysis

a) To test the first hypothesis to compare the effect of both the mouthwashes on risk of getting onset of RIOM (Onset of RIOM = Score ≥ 1)

All the nine (100%) patients in benzydamine group and six (75%) patients in the curcumin group experienced RIOM but the difference was not statistically significant, rejecting the null hypothesis that there is no difference in risk of getting RIOM between the two mouthwashes [Table 4].
Table 4: Cross tabulation for risk of onset as per WHO criteria according to per-protocol model

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b) Testing the second hypothesis that there is no difference between the effect of mouthwashes on the progression of RIOM

i) Intra-group comparison of RIOM followed by posthoc test for both the mouthwashes. Comparison of intra-group oral mucositis score was done using Friedman's test which showed a statistically significant difference (P = 0.001) between the follow-ups for 6 weeks at 1-week interval [Table 5] indicating with time, the score increases in both the groups. Post hoc comparison showed no significant difference among various visits in both groups [Table 6] and [Table 7].
Table 5: Comparison of oral mucositis scores as per WHO criteria at various visits (in days) in Benzydamine and Curcumin group as per protocol analysis

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Table 6: Post hoc analysis of oral mucositis score as per WHO criteria among various visits (in days) in Benzydamine group as per-protocol analysis

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Table 7: Post hoc analysis of oral mucositis score as per WHO criteria among various visits (in days) in Curcumin group as per per-protocol analysis

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ii) Inter-group comparison of scores at different time interval indicated no statistical difference between the groups [Table 8], rejecting the null hypothesis that there is no difference in the effect of both the mouthwashes as far as the progression of RIOM is concerned.
Table 8: Intergroup comparison of oral mucositis score as per WHO criteria at various visits between study groups

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c) Testing the third null hypothesis comparing the effect on severity of RIOM

Group wise distribution of the most severe score detected for the whole follow-up period. Almost no patient reported with a score of more than or equal to 3 and the difference is not statistically significant, rejecting the null hypothesis as far as the severity of RIOM is concerned [Table 9].
Table 9: Group wise distribution of the most severe score detected for the whole follow-up period using WHO scale

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2B. Testing hypothesis according to 'MODIFIED INTENTION TO TREAT' analysis

This analysis was done including all the patients as randomised into the assigned group and who came for at least one follow-up. Hence, out of 74 patients, 68 were included in the analysis.

a) The first hypothesis: No difference in risk of the onset of RIOM between the two mouthwashes

'Time-to-event' analysis was performed to find the effect of benzydamine and curcumin mouthwashes on the onset RIOM. In this study, the event of interest was 'the onset of RIOM' (RIOM score ≥1). Patients were censored either due to lost to follow-up or withdrawal from the study or the event did not occur within the study period. In benzydamine group, thirty-two (91.4%) patients experienced the event (onset) and three (8.6%) patients were censored. In curcumin group, twenty-three (69.7%) patients experienced event (onset) and ten (30.3%) patients were censored [Table 10]. Kaplan Meier test was applied to compare the survival probabilities of both groups for a period of 6 weeks [Table 11], [Figure 1].
Table 10: Distribution of events (onset) and censoring in the study groups according to WHO criteria

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Table 11: Comparison of median onset score of study groups according to WHO criteria

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Figure 1: Comparison of probabilities of not experiencing onset of RIOM between study groups

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The result of the analysis is two graphs plotted one over other representing two study groups. The vertical axis of the graph shows the cumulative probability of survival, i.e., the proportion of patients who did not experience the event (onset of RIOM) at a given time and the horizontal axis (X-axis) represents the time of 6 weeks at weekly intervals. Any point on the survival curve represents the proportion or percentage of survival (absence of onset of RIOM). Each vertical fall on the graph represents the occurrence of an event (onset of RIOM) and forms a curve for a large sample size but due to small sample size of this study, staircase appearance was observed in Kaplan Meier survival probability curve.

At every event, the probability decreases and remains constant until the occurrence of the next event. The vertical distance between the horizontal points illustrates the change in cumulative probability as the curve advances. The censoring events are denoted by a '+' sign on the curve. The curve descended all the way to zero, implies that almost no one is escaped from RIOM, but has not touched zero implying that very few patients did not experience RIOM until the study period was over. Here, two curves for both the groups were plotted together.

The difference between the onset of the event between both the groups was tested by Log-rank test and was statistically significant (P = 0.001). Hence, the probability or risk of getting onset in benzydamine might be more than curcumin at each time interval as curcumin curve is constantly above benzydamine.

Median survival is defined as the time after which 50% of people are still event free from the onset of RIOM and 50% had experienced the onset of RIOM. The median estimate of benzydamine group is 7.00 days and curcumin group is 21.00 days (P = 0.001) [Table 11].

After getting a significant result in Kaplan-Meier analysis, Cox proportional regression analysis was performed to find out the adjusted hazard ratio. The assumption of proportionality of hazard was tested using Log-minus-Log plot. The adjusted hazard ratio was 0.50 and it was statistically significant (P = 0.039). This means an instantaneous risk of getting onset of RIOM in curcumin group was 50% less than benzydamine even after adjusting for other confounding variables such as age, gender, etc., [Table 12].
Table 12: Hazards ratio for all the covariates on effectiveness of RIOM (intervention group, age, sex, socioeconomic status, site and grade of tumour, surgery, chemotherapy and Karnofsky performance status score)

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Hence, the null hypothesis was rejected after performing time-to-event analysis as use of curcumin mouthwash not only reduced the risk of the onset of RIOM by 50%, but also delayed the onset by 2 weeks.

b) The testing of null hypothesis related to progression and severity of RIOM was not possible according to the MIT analysis owing to missing data (exceeding > 10%).

In the present study, one patient in each study groups reported burning sensation as side effect after 3 weeks of mouthwash usage.


   Discussion Top


RIOM is a self-limiting and dose-dependent oral condition; it usually starts at 2–3 weeks after the start of RT and peaks until 4–5 weeks and then slowly resolves with time. The condition can be very painful and can significantly affect nutritional intake, mouth care and quality of life.[19] Various topical agents have been studied in the therapeutic prevention of RIOM. The literature gives evidence of trials conducted with various agents including benzydamine mouthwash[5],[9],[20],[21] which has been proven to be most effective and is the most recommended treatment protocol.[7]

Curcumin has shown better results in preventing RIOM because of its analgesic, antipyretics, immunomodulator, antineoplastic, antifungal and antibacterial properties.[11] Very few studies have been reported citing benefits of curcumin in treating RIOM, of which four studies were conducted in India,[18],[22],[23] one in Israel[24] and another in Iran.[25]

Curcumin has the known property of being insoluble in water, ether and soluble in ethanol. Use of ethanol for preparing curcumin mouthwash was not considered in this study because of its dehydrating effect on oral mucosa, aggravating existing xerostomia associated with RT.[26] Alternatively, nanoparticles of curcumin powder were considered in this study to enable its use as a mouthwash with aqueous base (0.1%). Use of nanoparticles of curcumin powder accounts for its miscibility in water and less patient compliance required for its home-based use. Other studies have used curcumin in various forms having concentration of 0.004% with 1:5 dilution,[12] 10% gel,[22] 0.5% turmeric gel,[25] 3% turmeric mouthwash[23] and 5% turmeric solution.[18] To our knowledge, this is the first study to use a nanocurcumin mouthwash with 0.1% curcumin preparation. From all the six curcumin based trials, two studies[12],[22] had chlorhexidine as a control group, one had povidone-iodine,[18] one had placebo[25] and one had saline mouthwash.[23] In our study, we chose benzydamine rather than any active placebo to avoid the risk of developing RIOM and associated oral complications in control group.[18]

The present study was conducted over a period of 6–7 weeks. This study recruited patients at the start of RT and followed them until the end of RT to evaluate the preventive effect of mouthwash usage on onset, progression and attainment of maximum severity score of RIOM. In the past, studies have been documented assessing RIOM for a period of 6 weeks,[18] 21 days,[24],[25] 20 days,[12] 14 days[22] and 5 days.[23] As oral mucositis is a self-limiting and dose-dependent oral condition, it usually starts at 2–3 weeks after the start of RT and peaks until 4–5 weeks and in the present study, patients were followed for 6 weeks.[19]

To clinically assess RIOM, various criteria have been reported: WHO,[12],[22],[24] RTOG[18] and OMAS[12],[22],[24] of which WHO criteria being the most widely used one. Though a better measure of RIOM is by histopathological assessment, it is not recommended because of ethical issues as it involves repetitive biopsies at each follow-up.

No significant difference between the study groups for all the baseline variables indicated that the randomisation method was proper. Data was analysed by both 'MIT' and 'PP' model as the loss to follow-up were found to be increasing with each week of evaluation, making it impossible to calculate the crude risk of onset and severity of RIOM for the entire sample at the end of 6 weeks as for calculation of crude risk, a constant denominator is required.

As far as the onset of RIOM is concerned in 'PP' analysis, no significant difference was observed between two preparations and almost all of the patient in both the groups experienced onset, similar to the finding obtained from literature.[18],[25] In MIT analysis, the calculation of crude risk of onset and its timings using MIT analysis was difficult as percentage of missing data was more than 10%,[27] as a result multiple imputations were not feasible. Hence, the time-to-event analysis was performed for differential effect on the onset of RIOM. In Indian scenario, the compliance of cancer patients for RT is very poor.[28] This explains a high proportion of loss to follow-up encountered in either study groups. The significant difference between groups and the risk of the onset of RIOM was seen on analysis. The K-M curve and the cox proportion regression showed that the instantaneous risk of getting the onset was 50% higher in benzydamine group than curcumin even after adjusting for confounders (age, gender, socioeconomic status, site and grade of tumour, surgery and chemotherapy). Again the onset of RIOM is delayed by 14 days (at least for 50% of patients) in curcumin group and the difference was significant (P = 0.001).

Based on the outcome of the time-to-event analysis, with a large sample size, the null hypothesis was rejected (P = 0.039). Curcumin mouthwash not only reduced the instantaneous risk of the onset of RIOM by 50% compared to benzydamine but also significantly delayed the onset (mean = 19.56, median = 21) by 2 weeks. No previous study has reported instantaneous risk of the onset of RIOM with use of curcumin. A similar finding was reported by an Indian study although the mean or median delay in onset was not reported.[18] As far as censoring is concerned, three patients were censored in benzydamine group as they were lost to follow-up after 1 week. Out of ten patients censored in curcumin group, eight were lost to follow-up and two patients did not experience the onset until the full follow-up period was over which might have influenced the results of the present study to a certain extent. Based on the outcome of the time-to-event analysis, the null hypothesis of no differences in the effect of mouthwashes on the risk and duration of onset of RIOM was rejected.

On the effect of both the intervention on the progression of RIOM, it is evident from the literature that RIOM scores usually increased with time due to the cumulative dosage of radiation increasing in both the groups. In PP analysis though it was detected that the median RIOM score increased with time, because of very small sample size, no significant change between any two follow-ups in both the groups was seen in post hoc analysis, which is almost similar to the study conducted evaluating the therapeutic effectiveness of curcumin.[22] This is in contrast with the findings of a study conducted in 2014[18] and 2015[12] which concluded that curcumin reduces the levels of RIOM significantly at all-time points.

Both the mouthwashes were equally effective in preventing the occurrence of a severe form of RIOM in PP analysis dichotomisation of severity score (≥3 and ≤2). Hence, though both the mouthwashes are not able to completely prevent RIOM, they are able to reduce the severity with equal effectiveness. In the present study, at the final follow-up (42nd day), none in curcumin group experienced severe (≥3 score) score of RIOM similar to an Iranian study[25] and Israel study.[24] In an Indian study,[18] 35.9% patients using curcumin developed intolerable form of mucositis (>3 score in RTOG) although it was significantly lesser compared to povidone-iodine group (85%). They also reported that the timing of intolerable form of RIOM is delayed in curcumin group, although the exact timing of delay was not reported. It was not possible to perform such analysis in our study because of higher loss to follow-up.

In the present study, one patient in each study groups reported burning sensation as side effect after 3 weeks of mouthwash usage. This might be because of the onset of RIOM rather than being the side effect of mouthwash use. Hence, both the preparations were well tolerated by the patients similar to a case series reported among pediatric patients.[24] In another Iranian study, two patients reported a feeling of nausea after application of curcumin gel which completely resolved after 2 weeks of application. Overall the literature gave evidence of curcumin to be not at all toxic to animal or human even after a high dose of systemic intake.[25]

The strength of the study was its triple-blinded randomised controlled design, comparison with the most recommended mouthwash (benzydamine), nanoparticle preparation which is more soluble in water and thus less dependent on patient compliance. The limitations were significantly small sample size, sampling from one institute, large loss to follow-up, difference in the number of censored subjects might have influenced the result of time-to-event analysis (as more number of patients were censored early in the study, the reliability of the survival curve is questionable) and inability to test the hypothesis regarding the progression and severity of RIOM using MIT because of a very high proportion of missing data.

It is recommended to conduct proper clinical trials with larger sample size covering all the sectors (private and government) involved in cancer treatment. This can minimise loss to follow-up to maintain the power of the study and improve the generalizability of the results. Studies with higher concentration and varying dosage of curcumin should be conducted to explore the best possible concentration having maximum effectiveness in preventing RIOM.

To conclude, though both the mouthwashes were not able to completely prevent the onset of RIOM, use of 0.1% curcumin mouthwash was able to significantly delay the onset of RIOM. As far as progression and severity of RIOM are concerned, both mouthwashes reduced the signs and prevent the occurrence of a severe form of RIOM. Also, both the mouthwashes were equally safe and well-tolerated by patients. Hence, the herbal medication, curcumin is equally effective and safe as the standard medication benzydamine. It has the additional advantage of delaying the onset of RIOM as assessed by the most commonly used scale of RIOM.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Correspondence Address:
Dr. Gaurav Sharma
Assistant Professor, Department of Public Health Dentistry, SCB Dental College, Cuttack - 753 007, Odisha
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdr.IJDR_822_18

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