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ORIGINAL ARTICLE
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Safety and efficacy of Oro-T oral rinse in oral mucositis during cancer radiotherapy and/or chemotherapy: Cumulative analysis of two studies


1 Department of Radiotherapy, M S Ramaiah Medical College and Hospital, Bengaluru, Karnataka, India
2 Head Medical Services and Clinical Development, The Himalaya Drug Company, Bengaluru, Karnataka, India
3 Chief Scientific officer, The Himalaya Drug Company, Bengaluru, Karnataka, India
4 Principal Scientist-Medical Services and Clinical Development, The Himalaya Drug Company, Bengaluru, Karnataka, India

Date of Submission05-Dec-2017
Date of Decision07-Mar-2018
Date of Acceptance28-Jul-2018
Date of Web Publication24-Jul-2021

Correspondence Address:
Kirthi Koushik,
Associate professor, Department of Radiotherapy, M S Ramaiah Medical College and Hospital, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_988_17

 > Abstract 


Introduction: Oral mucositis is inflammation of the mucosa of the mouth which ranges from redness to severe ulceration. It results from the local effects of radiation to the oral mucosa.
Objectives: The study is cumulative analysis of two studies (one comparative and the other open labeled) evaluated in individuals with oral mucositis during cancer radiotherapy and/or chemotherapy for the safety and efficacy of Oro-T mouthwash in a comparative design with normal saline.
Methodology: Both the studies were similar with respect to clinical and laboratory parameters for analysis. The participants were advised to use 10 ml of Oro-T for 1 min 4 times daily for 6 weeks starting from day 1 of standard care. Patients were followed up, and the results were assessed from baseline on visit days: At entry and at the end of every week for 6 weeks. Clinical assessment of oral condition was done objectively (by the investigator) and also subjectively. Clinical symptoms such as sore throat, number of ulcer, burning sensation, pain, difficulty in chewing, difficulty in drinking, and mucositis grading along with Patient Reported Outcome Measures Scale were evaluated at each interval. Data was available for 40 subjects in Oro-T and 15 subjects in NS groups respectively.
Results and Conclusion: The significant positive outcome was reported both subjectively and objectively in Oro-T group as compared to NS group with the delay in the onset of symptoms and less severe manifestation of oral mucositis with an improvement in quality of life. No adverse effects were reported that prompted discontinuation of study medication. Overall compliance to study medication was good.

Keywords: Oral mucositis, Oro-T, Patient-Reported Outcome Measures Scale, radiotherapy



How to cite this URL:
Koushik K, Janaki M G, Kumawat R, Paramesh R, Palaniyamma D. Safety and efficacy of Oro-T oral rinse in oral mucositis during cancer radiotherapy and/or chemotherapy: Cumulative analysis of two studies. J Can Res Ther [Epub ahead of print] [cited 2021 Dec 6]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=322275




 > Introduction Top


Oral mucositis refers to erythematous and ulcerative lesions of the oral mucosa observed in patients with cancer being treated with chemotherapy and/or with radiation therapy to fields involving the oral cavity.[1] Lesions of oral mucositis are often very painful and compromise nutrition and oral hygiene as well as increase risk for local and systemic infection. Thus, mucositis is a highly significant and sometimes dose-limiting complication of cancer therapy.[2],[3]

Oral mucositis can be very painful and can significantly affect nutritional intake, mouth care, and quality of life.[2],[4] Infections associated with the oral mucositis lesions can cause life-threatening systemic sepsis during periods of profound immunosuppression.[5] Moderate-to-severe oral mucositis has been correlated with systemic infection and transplant-related mortality.[6] In patients with hematologic malignancies receiving allogenic hematopoietic cell transplantation, increased severity of oral mucositis was found to be significantly associated with an increased number of days requiring total parenteral nutrition and parenteral narcotic therapy, increased number of days with fever, incidence of significant infection, increased time in hospital, and increased total inpatient charges.[7]

The majority of patients receiving radiation therapy for head-and-neck cancer are unable to continue eating by mouth due to mucositis pain and often receive nutrition through a gastrostomy tube or intravenous line. It has been demonstrated that patients with oral mucositis are significantly more likely to have severe pain and a weight loss of ≥5%.[8] In one study, approximately 16% of patients receiving radiation therapy for head-and-neck cancer were hospitalized due to mucositis.[9] Further, 11% of the patients receiving radiation therapy for head-and-neck cancer had unplanned breaks in radiation therapy due to severe mucositis.[9] Thus, oral mucositis is a major dose-limiting toxicity of radiation therapy to the head-and-neck region.

Recent studies have indicated that the fundamental mechanisms involved in the pathogenesis of mucositis are much more complex than direct damage to epithelium alone.[3] Mechanisms for radiation-induced and chemotherapy-induced mucositis are believed to be similar.

The degree and extent of oral mucositis that develops in any particular patient and site appear to depend on factors such as age, gender, underlying systemic disease, and race as well as tissue-specific factors (e.g., epithelial types, local microbial environment, and function). The effects of patient age and gender on the development of oral mucositis are not clear.

In radiation-induced oral mucositis, lesions are limited to the tissues in the field of radiation, with nonkeratinized tissues affected more often. The clinical severity is directly proportional to the dose of radiation administered. Most patients who have received more than 5000 cGy to the oral mucosa will develop severe ulcerative oral mucositis.[10]

Management of oral mucositis has been largely palliative to date, although targeted therapeutic interventions are now being developed.[11] Based on a comprehensive systematic review of the literature, the Mucositis Study Group of the Multinational Association for Supportive Care in Cancer (MASCC) and the International Society of Oral Oncology (ISOO) have developed clinical practice guidelines for the management of mucositis.[12] These guidelines are referenced below as applicable. Management of oral mucositis is divided into the following sections: nutritional support, pain control, oral decontamination, palliation of dry mouth, management of oral bleeding, and therapeutic interventions for oral mucositis.

The present investigational polyherbal formulation has turmeric, triphala, and honey as principal ingredients. All these three ingredients are known to possess anti-inflammatory, antioxidant properties and thus help in ulcer healing.

Objectives of the study

The objective of this study is to evaluate the clinical efficacy and safety of Oro-T in Oral mucositis in patients during cancer radiotherapy.

Primary endpoints were clinical and symptomatic recovery from oral mucositis post-cancer radio and/or chemotherapy. Secondary endpoints were safety profile evaluation of Oro-T and compliance to the therapy.

Subject selection criteria

Participants aged 18 years and more, of either the sex with head-and-neck cancer, confirmed histopathological diagnosis; preferably oropharyngeal, scheduled to receive radiotherapy with or without chemotherapy as standard care and those with a history of oral mucositis during cancer chemotherapy or radiotherapy were included in this study. Only the participants willing to give a written informed consent and follow the schedule of the study as per the protocol were included in the study.

Participants who had participated in a similar clinical investigation in the past 4 weeks, severe uncontrolled systemic disorders, diabetes, hypertension, or genetic and endocrinal disorders were excluded from the study. Participants who had used a similar product in the past 4 weeks or using any medication for mucositis, participants who refused to sign informed consent and pregnant and lactating women were also excluded from the study.


 > Methodology Top


The study protocol, CRF's, investigators brochure, and other study specific documents were submitted and approved in the Institutional Ethics committee. Participants who fulfilled the inclusion criteria were selected and included in the study after they willingly signed the informed consent form. All the participants were instructed regarding the study procedure and the weekly follow-up visits and information regarding the contact person during an emergency. All the patients were explained regarding the investigations that will be carried out during the study.

A total of 40 participants were included in the study to evaluate the safety and efficacy in Oro-T Oral Rinse. The participants were advised to use 10 ml of Undiluted Oro-T for 1 min 4 times daily for 6 weeks starting from day 1 of radiotherapy. Each 100 ml of medication contains Curcuma longa ext. (10.5 mg-Eq. to 5 g powder), Triphala; ayurveda polyherbal combination (400 mg) and Honey (10 g) as active ingredients. Data on 40 participants from this study were compared with data from 40 cases in NS group as control from the earlier study for analysis in the adaptive design for statistical analysis.

Patients were followed up, and the results were assessed from baseline on visit days: At entry, end of 1st week, end of 2nd week, end of 3rd week, end of 4th week, end of 5th week and end of 6th week.

At follow-up visit, participants were asked about the frequency of usage of the Oro-T and overall compliance to the product. Clinical assessment of oral condition was done objectively (by the investigator) and also subjectively. A thorough examination was done after completion of 6 week that is at the end of the study. At the check-up clinical response to the treatment, any adverse events and subject compliance were assessed.

All the participants were questioned for any untoward effects of the product such as erythema, edema, pain, pruritus, and urticaria and burning sensation. These untoward effects were rated on a scale ranging from 0 (none) to 3 (severe). All the scores were expressed in 0 (none), mild-1, moderate-2, and severe-3.

Patient self-reported mouth and throat soreness and the resulting limitations on daily functional activities were obtained from the Patient-Reported Outcome Measure Scale (PROMS) questionnaire [Appendix 1].[13] Safety evaluation was done which included hematological and biochemical investigations.



All adverse events, either reported or observed by participants, were recorded with information about severity, date of onset, duration, and action taken regarding the study drug for causality assessment. Participants were allowed to voluntarily withdraw from the study if they so desired without assigning reasons.

Statistical analysis

Results were analyzed statistically for comparison between the groups using Mann–Whitney test to find out the statistical significance. Safety parameters were analyzed using paired t-test. PROMS questionnaire was analyzed using Mann–Whitney test. Analysis was performed using GraphPad Prism software Version 6.0, San Diego, California, USA.


 > Results Top


Demographic data of the study patients are given in [Table 1]. Safety parameters on hematological and biochemical parameters were assessed within the groups. All the safety parameters were found to be within the normal limits at pre- and post-treatment tests [Table 2]. This is suggestive of the safety profile of the study medication.
Table 1: Demographic data of patients on entry into the study

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Table 2: Hematological and biochemical parameters

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Significant improvement in clinical symptoms of oral mucositis was noted in participants of Oro-T group as compared to NS group. The evaluation of the effect of Oro-T in comparison to NS group conducted between the groups is shown in [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]. [Figure 7], [Figure 8], [Figure 9] represent delay in incidence of tolerable and intolerable mucositis in Oro-T as compared to NS group.
Figure 1: Sore mouth. a: P <0.0009, b: P <0.0001 and c: P <0.0001 as compared to saline-treated group

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Figure 2: Number of ulcer. a: P <0.0043, b: P <0.0011, c: P <0.0001, d: P <0.0001 and e: P <0.0009 as compared to saline-treated group

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Figure 3: Burning sensation Oro-T group compared to Saline group

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Figure 4: Pain. a: P <0.0399 as compared to saline-treated group

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Figure 5: Difficulty in chewing. a: P <0.0147, b: P <0.0001 and c: P <0.0198 as compared to saline-treated group

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Figure 6: Mucositis grading. a: P <0.014, b: P <0.0426 and c: P <0.025 as compared to saline-treated group

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Figure 7: Tolerable mucositis (in %) as compared to saline-treated group

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Figure 8: Intolerable mucositis (in %) as compared to saline-treated group

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Figure 9: Difficulty in drinking. a: P <0.0147, b: P <0.0006, c: P <0.0027, d: P <0.0092 and e: P <0.0092 as compared to saline-treated group

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Clinical signs and symptoms were assessed at weekly intervals using PROMS questionnaire as a validated tool. The results are detailed in [Table 3]. Statistically significant improvement in symptom score was observed in seven out of ten symptoms as compared to NS group. Significance was observed in four symptoms at week 1, 6 symptoms at week 2, 5 symptoms at week 3, 7 symptoms at week 4, and 3 symptoms at week 5, respectively. A significant reduction was observed for mouth pain, difficulty in speaking, and restriction of speech by week 1 onward. For rest of the symptoms, there was an initial rise in the symptom score and gradual improvement in subsequent weeks. However, the changes were significant as compared to NS group.
Table 3: Patient-Reported Outcome Measure Scale questionnaire

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Looking into the natural history of radiotherapy and associated adverse effects, it was clearly observed that there was a delay as well as decrease in severity in oral mucositis and a trend in improvement was seen in Oro-T group as compared to NS group with respect to restriction of speech because of mouth sores, difficulty eating hard and soft foods, restriction of eating, difficulty drinking, restriction of drinking, difficulty swallowing, and change in taste.

Overall impression on study medication by both investigator and patient is tabulated in [Table 4]. More than 80% of patients felt slight improvement with Oro-T and the rest felt no change in symptoms. Nearly 95% patients had slight improvement, and 5% had no change according to investigator. In NS group, 92.31% (by patient) and 84.62% (by investigator) had worsening of symptoms.
Table 4: Overall impression

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 > Discussion Top


The currently available therapies consisting of dental care, use of anti-inflammatory agents, application of topical antiseptics, and antimicrobial agents are essentially palliative, and there is no widely accepted prophylactic or effective treatment for intolerable mucositis.[14]

Measures to palliate the oral cavity dryness are the use of water, baking soda solution as gargle, and sugarless chewing gums to stimulate salivation. These measures carry no therapeutic benefit in treating the oral mucositis. Some of the therapeutic interventions are available in view of MASCC/ISOO guidelines; use of cryotherapy, growth factors, Anti-inflammatory agents, and antioxidants and low-level radiation therapy. Cryotherapy is hypothesized to have little role in chemotherapy and no role in radiotherapy-induced oral mucositis. Anti-inflammatory agents may help in radiations up to 50 Gy (cumulative) and use of antioxidants topically has little evidence of benefits. Some growth factors that help improve epithelial cell proliferation are found to be useful in preventing oral mucositis.[12]

However, uses of alternative remedies either topical or systemic have been gradually gaining acceptance on both research and clinical fronts. Experimental studies on curcumin-based preparations have shown good evidence of benefit of herbal formulations in preventing or reducing the severity of oral mucositis.[15] Patil et al.[16] evaluated the efficacy and safety of curcumin mouthwash in reducing the severity of signs and symptoms of radiochemotherapy-induced oral mucositis in cancer patients. Curcumin mouthwash was well tolerated and effective in controlling the signs and symptoms of induced oral mucositis.

Saldanha and Almeida[17] adopted two group pre- and post-test time series design to determine the effectiveness of turmeric and saline mouthwash on mucositis. The authors concluded that both mouthwashes were individually effective but on comparison turmeric mouthwash was better than saline.

Preliminary study on Oro-T oral rinse compared to normal saline (NS) in alleviating symptoms of oral mucositis over a period of 6 weeks, in a comparative study demonstrated a positive suggestive trend with Oro-T as compared to NS. There was delay in the onset of Oral Mucositis, reduced severity, faster recovery from symptoms of oral mucositis such as sore mouth, burning sensation, pain, difficulty in chewing, difficulty in drinking, and difficulty in opening the mouth. Hence, another study in 40 cases was conducted to evaluate the safety and efficacy of turmeric oral rinse in oral mucositis in patients during cancer radiotherapy. In this study, the efficacy of Oro-T in oral mucositis was investigated. There was significant symptomatic relief from symptoms of oral mucositis in Oro-T as compared to NS group. The positive outcome observed in study patients might be due to the synergistic mechanism of action of the ingredients of Oro-T. Additionally, one more clinical study of Turmeric oral rinse was carried out to establish the efficacy and safety. A total of 66 completed cases from two studies were taken for cumulative analysis (51 cases and 15 cases). Effect of Turmeric Oral Rinseas compared to Normal Saline in alleviating symptoms of oral mucositis over a period of 6 weeks was evalauted in this cumulative analysis. All the subjects were asked to rinse their mouth with 10ml of Turmeric Oral Rinse or with 10ml of Normal Saline for 1minute 4 times daily.Turmeric Oral Rinse demonstrated a positive trend in the management of the symptoms associated with Turmeric Oral Rinse as compared to Normal Saline. Cumulative analysis of two clinical studies showed that Turmeric Oral Rinse is effective in the management of Oral Mucositis as compared to Normal Saline. There was a significant reduction in the symptoms of Oral Mucositis like, ulcer, burning sensation, pain, difficulty in chewing, difficulty in drinking. There was also an improvement seen in the PROMs quality of life questionnaire.

Curcumin, a chief component of Curcuma longa, may be responsible for the majority of turmeric's therapeutic effects. Turmeric has also been widely used for its anti-oxidant, analgesic, and anti-inflammatory properties. In addition to the inhibitory effects on the production of nitric oxide and the ability to scavenge DNA damaging superoxide radicals, curcumin also affects both the Phase I and Phase II enzymes of the hepatic cytochrome p450 enzyme system involved in the oxidation and detoxification of toxic substances. Curcuminoids, such as curcumin (diferuloyl methane), demethoxycurcumin, and bisdemethoxycurcmin, also possess anti-inflammatory, anticarcinogenic, antimutagenic, and immunomodulatory effects. Curcumin also modulates pro-inflammatory cytokines, apoptotic proteins, nuclear factor-κB, cyclooxygenase-2, 5-LOX, STAT3, C-reactive protein, and prostaglandin E2.

Triphala is polyherbal Ayurvedic preparation which contains Terminalia chebula, Terminalia belerica, and Embilica officinalis are used in cancer as anti-cancer, chemoprotective, and radio protective agent. Anti-inflammatory effect of Triphala shows significant inhibition in levels of lysosomal enzymes, LPO, and inflammatory mediator tumor necrosis factor-Alpha. Honey has effects on the proliferation of B and T lymphocytes.[18],[19],[20],[21]

`

The present study indicated good clinical efficacy of Oro-T to help relieve the symptoms associated with Oral mucositis. Oro-T has shown to be effective in relieving the symptoms associated with oral mucositis as compared to NS group. There were no clinically significant short-and long-term adverse events, either reported or observed, during the entire study period. Hence, it may be concluded that Oro-T is safe and effective in relieving the symptoms associated with oral mucositis.

Acknowledgment

The authors would like to acknowledge Dr Padmanabha Rugvedi MD (Ayu), The Himalaya Drug Company.

Financial support and sponsorship

This study was financially Sponsored by the Himalaya Drug Company, Bengaluru.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Lalla RV, Sonis ST, Peterson DE. Management of oral mucositis in patients who have cancer. Dent Clin North Am 2008;52:61-77, viii.  Back to cited text no. 1
    
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Rapoport AP, Miller Watelet LF, Linder T, Eberly S, Raubertas RF, Lipp J, et al. Analysis of factors that correlate with mucositis in recipients of autologous and allogeneic stem-cell transplants. J Clin Oncol 1999;17:2446-53.  Back to cited text no. 5
    
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Epstein JB, Gorsky M, Guglietta A, Le N, Sonis ST. The correlation between epidermal growth factor levels in saliva and the severity of oral mucositis during oropharyngeal radiation therapy. Cancer 2000;89:2258-65.  Back to cited text no. 10
    
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Lalla RV, Peterson DE. Treatment of mucositis, including new medications. Cancer J 2006;12:348-54.  Back to cited text no. 11
    
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Keefe DM, Schubert MM, Elting LS, Sonis ST, Epstein JB, Raber-Durlacher JE, et al. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer 2007;109:820-31.  Back to cited text no. 12
    
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Kushner JA, Lawrence HP, Shoval I, Kiss TL, Devins GM, Lee L, et al. Development and validation of a patient reported oral mucositis symptom (PROMS) scale, J Can Dent Assoc 2008;74-1.  Back to cited text no. 13
    
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Rodríguez-Caballero A, Torres-Lagares D, Robles-García M, Pachón-Ibáñez J, González-Padilla D, Gutiérrez-Pérez JL, et al. Cancer treatment-induced oral mucositis: A critical review. Int J Oral Maxillofac Surg 2012;41:225-38.  Back to cited text no. 14
    
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Farid RM. A focus on curcumin local application in oral diseases management: Mini review. IOSR J Pharm 2016;6:30-40.  Back to cited text no. 15
    
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Patil K, Guledgud MV, Kulkarni PK, Keshari D, Tayal S. Use of curcumin mouthrinse in radio-chemotherapy induced oral mucositis patients: A pilot study. J Clin Diagn Res 2015;9:ZC59-62.  Back to cited text no. 16
    
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Saldanha SP, Almeida VD. A comparative study to assess the effectiveness of turmeric mouth wash versus saline mouth wash on treatment induced oral mucositis (Tiom) in a selected hospital at Mangalore. J Clin Res Bioeth 2014;5:1.  Back to cited text no. 17
    
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Calabrese V, Bates TE, Mancuso C, Cornelius C, Ventimiglia B, Cambria MT, et al. Curcumin and the cellular stress response in free radical-related diseases. Mol Nutr Food Res 2008;52:1062-73.  Back to cited text no. 20
    
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Gupta SC, Patchva S, Aggarwal BB. Therapeutic roles of curcumin: Lessons learned from clinical trials. AAPS J 2013;15:195-218.  Back to cited text no. 21
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

 
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