Evaluating Chinese Medicine Oral Rinse for Irradiated Oral Mucositis in Head & Neck Cancer Patients

Study Overview
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Brief Summary
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Approximately 60% and 90% of patients with head and neck (H&N) cancers receiving standard radiotherapy (RT) and chemoradiotherapy (chemo-RT) will develop oral mucositis respectively. Oral mucositis (OM) is one of the dose-limiting adverse events which can also lead to emotional and nutritional problems. Clinically, it is usually observed by the end of first week of RT (after 10 Gy) and reaches peak damage in 14-21 days or by the end of treatment. Healing then takes approximately 2 to 3 weeks after completion of RT. For the Chinese Medicine (CM) interventions, many studies have been reviewed on the efficacy of mouthwash or internal herbal decoction to OM. Although some positive results were observed, most of them were performed by applying different assessment tools and lack of quality of life (QOL) or self-reported symptoms assessment. In addition, the intervention time and follow-up period were usually insufficient (stopped at the end of RT), therefore they could not review the long-term efficacy of CM according to normal progression of OM and the safety of using CM. Therefore, we hope this pilot study can evaluate the efficacy and safety of CM in a strict protocol.

Detailed Description
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Approximately 60% and 90% of patients with head and neck (H&N) cancers receiving standard radiotherapy (RT) and chemoradiotherapy (chemo-RT) will develop oral mucositis respectively. Oral mucositis (OM) is one of the dose-limiting adverse events which can also lead to emotional and nutritional problems. Clinically, it is usually observed by the end of first week of RT (after 10 Gy) and reaches peak damage in 14-21 days or by the end of treatment. Healing then takes approximately 2 to 3 weeks after completion of RT. The risk of OM is especially high in NPC patients who receive concomitant chemotherapy, receive a total dose over 5,000 Gy, treat with altered fractionation radiation schedules, have bad oral hygiene status, do not use antibiotic at early stage mucositis, have smoking history, drink alcohol, have problems in nutritional status like anorexia, malnutrition, lack of vitamins, restriction of food due to specific dietary requirements, have haematological disease or non-ideal hematological status, have advanced localization of tumors and stage, receive immunotherapy, have pre-existing dry mouth (Xerostomia), have episodes of OM during prior treatment cycles and low BMI, etc. According to some weighed guidelines such as The Multinational Association of Supportive Care in Cancer and International Society for Oral Oncology (MASCC/ISOO) guidelines for the management of OM, recent systematic reviews and researches, there are mainly several sections for intervention: (1) Basic oral care, (2) Anti-inflammatory agents, (3) Photobiomodulation, (4) Cryotherapy, (5) Antimicrobials, coating agents, anesthetics, and analgesics, (6) Growth factors and cytokines, and (7) Natural and miscellaneous. We can summarize several suggestions for the prevention of OM in H&N cancer adults receiving RT from the above protocols: multiagent combination oral care protocols (increasing the awareness of good oral hygiene), professional dental care (a desirable option before or during cancer therapy for local and systemic infections from odontogenic sources), benzydamine mouthwash (as the anti-inflammaotary agents for moderate dose of RT (<50 Gy)) and intraoral photobiomodulation therapy using low-level laser therapy. Over the years, the number of interventions studied for OM and their quality of study design have been dramatically increasing. However, since there are still some advantages and disadvantages for some suggested agents, some clinical settings have not yet been recommended with appropriate intervention. Natural and miscellaneous agents are also reviewed in the past years while honey is suggested for prevention of OM in patients with H&N cancer who receive treatment with either RT or chemo-RT. However, if honey is applied repeatedly on a daily basis for a longer period, we have to be cautions with its deleterious effects. A strict oral hygiene protocol has to be followed to prevent dental caries. For the Chinese Medicine (CM) interventions, many studies have been reviewed on the efficacy of mouthwash or internal herbal decoction to OM. Although some positive results were observed, most of them were performed by applying different assessment tools and lack of quality of life (QOL) or self-reported symptoms assessment. In addition, the intervention time and follow-up period were usually insufficient (stopped at the end of RT), therefore they could not review the long-term efficacy of CM according to normal progression of OM and the safety of using CM. Therefore, we hope this pilot study can evaluate the efficacy and safety of CM in a strict protocol.

Official Title
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Evaluating Efficacy and Safety of Chinese Medicine Oral Rinse in Treating and Preventing Irradiated Oral Mucositis in Head-and-Neck Cancer Patients - a Pilot Trial

Conditions
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Head and Neck Neoplasms, Oral Mucositis (Ulcerative) Due to Radiation, Chinese Medicine Oral Rinse

Intervention / Treatment
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* Drug: Chinese Medicine Oral Rinse Formula-I (CMORF-I)
* Other: Standard Care
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who are aged ≥18, with known diagnosis of non-metastatic hypopharyngeal cancer, laryngeal cancer, lip and oral cavity cancer, nasopharyngeal cancer, oropharyngeal cancer, paranasal sinus and nasal cavity cancer, and salivary gland cancer. are the first time to receive RT to the primary tumor in the area of the head or face, neck, or oral cavity. start RT recently within 14 days. are assessed by CMPs for the condition of oral mucositis according to modified World Health Organization (WHO) Mucositis Grades with Grade ≦1. have Karnofsky Performance Status (KPS) ≥ 60 (patients require occasional assistance, but is able to care for most personal needs will be 60 or above). are able to read or understand and sign the consent form. Exclusion Criteria: Patients who receive concurrent chemo-radiation. have known medication on bacterial or fungal infections of oropharynx at recruitment. have other known diseases such as serious and uncontrolled Diabetes mellitus (with symptom of delayed wound healing over the past half year) or hyperthyroidism (with symptom of serious oral dryness over the past half year), known connective vascular disorders or known Human Immunodeficiency Virus (HIV) infections etc. have known history of allergy to CMORF-I ingredients or Glucose-6-Phosphate Dehydrogenase (G6PD) patients. are known pregnant or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A randomized controlled pilot study will be employed, participants will receive either CM Oral Rinse granules (CMORF-I) or placebo while they will receive standard care too. Since the duration of RT and recruitment time may vary, the intervention period starts from baseline (14 days within RT starts) to 2 weeks after the end of RT, while the post-intervention period will be 10 weeks starting from 2 weeks after the end of RT with 3 post-intervention follow-up visits (4 weeks, 8 weeks and 12 weeks after the end of RT).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intervention Group: Chinese Medicine Oral Rinse and Standard Care<br>Prescription and oral rinsing with Chinese Medicine Oral Rinse Formula-I (CMORF-I) which mainly consists of the Nong's concentrated CM granules of Wu Wei Xiao Du Yin and other ingredients. Standard care will be following the indications provided by patient's western medical doctor. Patients should not take any other TCM and non-prescribed medication and nutritional supplements during the intervention period. | Drug: Chinese Medicine Oral Rinse Formula-I (CMORF-I)<br>* Prescription of Chinese Medicine Oral Rinse Formula-I (CMORF-I) Instruction to rinse: The above amount of concentrated CM granules will be divided and packed in 4 bags per day. Dissolve 1 bag of concentrated CM granules with 150ml 80'C boiled hot water, and wait for 20 mins to cool down. Clean the mouth thoughtfully by rinsing with 150ml of distilled water for 2 minutes. Rinse the mouth thoughtfully with one-third of the dissolved and cooled CM oral rinse, gargle, expel after 3 minutes, do not swallow and repeat twice. To ensure better contact of the CM oral rinse in all parts and folds of the oral cavity, our research assistant and CMP will guide the patients to fully agitate the mouth, use the tongue to stir repeatedly among the teeth, cheeks and palate surface, and to raise the tip of the tongue for a moment and tilt the head back. 4 times a day (half an hour after every meal, half an hour before sleep), from baseline to 2 weeks after RT.<br>* Other names: CMORF-I;Other: Standard Care<br>* • Standard care including normal saline or medical mouthwash, optional analgesics and antibiotics will be offered by hospital.<br>|
| Placebo Comparator: Control Group: Placebo and Standard Care<br>Placebo: The placebo consists of an inert substance, made of starch filler, flavor and colorings. It is also manufactured under GMP standard. To ensure blinding, the CMORF-I formula and placebo will be indistinguishable in appearance, smell and favour. Standard care will be following the indications provided by patient's western medical doctor. Patients should not take any other TCM and non-prescribed medication and nutritional supplements during the intervention period. | Other: Standard Care<br>* • Standard care including normal saline or medical mouthwash, optional analgesics and antibiotics will be offered by hospital.<br>Other: Placebo<br>* Placebo granules, instruction is the same as CMORF-I.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of the proportion of the most severe modified WHO Mucositis Grades | Comparison of the proportion of the most severe modified WHO Mucositis Grades among intervention and control groups during RT. Grades of the OM will be assessed by a Registered Chinese medicine practitioner (CMP) at baseline and day 7 (±1d) of every week during the RT, the most severe grades during the treatment will be regarded for data analysis. Modified WHO Mucositis Grading Scale: Grade 0 (none) - normal; Grade 1 (mild) - soreness/erythema; Grade 2 (moderate) - erythema, ulcer/pseudo-membranes, can eat solids (erythema with ulcers less than 1 cm); Grade 3 (severe) - ulcer/pseudo-membrane, (erythema with ulcers more than 1cm) requires liquid diet only; Grade 4 (life-threatening) - ulcer with hemorrhage and necrosis, alimentation not possible; cancer treatment that results in or contribute to death is reported separately. | From baseline to week 12 after the end of RT during post intervention period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 10cm visual analogue scale (VAS) of oral pain | It is a measurement of oral pain. Scores are recorded by making a handwritten mark on a 10-cm line that represents a continuum between no pain on the left and worst pain on the right. | Day 3 and day 7 (±1d) of every week during intervention period, end of week 4, week 8 and week 12 after the end of RT during post intervention period. | 
| Oral Mucositis Daily Questionnaire (OMDQ) (validated Chinese version with modification) | It is a measurement of self-reported quality of life. It contains 10 items, for most questions in the OMDQ, a higher score indicated a worsening in symptom severity or more interference with functional activity. For the question pertaining to overall health, a higher score indicates better overall health status. | Day 3 and day 7 (±1d) of every week during intervention period, once a week during post intervention period, end of week 4, week 8 and week 12 after the end of RT during post intervention period. | 
| European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (Head and Neck) (EORTC QLQ-C30) (Hong Kong Cantonese version) | It is a specific measurement of self-reported quality of life for Head and Neck cancer patients. It consists of 30 questions that indicate the extent to which you have experienced these symptoms or problems during the past week. Scoring from 1 Not at all to 4 Very much. | Day 7 (±1d) of every week during intervention period, end of week 4, week 8 and week 12 after the end of RT during post intervention period. | 
| European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (Head and Neck) (EORTC QLQ-H&N35) (Hong Kong Cantonese version) | It is a specific measurement of self-reported quality of life for Head and Neck cancer patients. It consists of 35 questions that indicate the extent to which you have experienced these symptoms or problems during the past week. Scoring from 1 Not at all to 4 Very much. | Day 7 (±1d) of every week during intervention period, end of week 4, week 8 and week 12 after the end of RT during post intervention period. | 
| Body mass index (BMI) | It is a measurement of the amount of body fat based on height and weight that applies to adult men and women. It can assess and monitor the risk of OM to a certain extent. | From baseline to week 12 after the end of RT during post intervention period | 
| Number of analgesic and antibiotics use daily | It can assess and monitor the conditions of OM. | From baseline to week 12 after the end of RT during post intervention period |