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Serine

Concurrent chemoradiotherapy (CCRT) and intravenous drip of ulinastatin, the details are as follows:

1. Intensity modulated radiation therapy combined with concurrent chemotherapy of cisplatin 100mg/m2 on day 1 and day 22 of RT;
2. Ulinastatin through intravenous drip at a dose of one hundred thousand units added to 100 ml of 0.9% normal saline, 3 times every radiation day, until the end of radiotherapy.

Concurrent chemoradiotherapy (CCRT) alone:

Intensity modulated radiation therapy combined with concurrent chemotherapy of cisplatin 100mg/m2 on day 1 and day 22 of RT.

Patients in both arms received concurrent cisplatin chemotherapy:

100 mg/m² cisplatin given intravenously every 3 weeks on days 1, 22 concurrently with radiotherapy.

Patients in both arms received Intensity Modulated Radiation Therapy:

All target volumes were outlined slice by slice on the axial contrast-enhanced CT with MR fusion images in the treatment planning system. The target volumes were defined in accordance with the International Commission on Radiation Units and Measurements Reports 50 and 62. The prescribed dose was 68-72 Gy to PTVnx (Planning target volume of the primary tumor), 64-68 Gy to GTVnd (Gross tumor volume of the cervical lymph node), 60- 64Gy to PTVnd and PTV1 (Planning target volume 1), and 54-58 Gy to PTV2 (Planning target volume 2) in 30-32 fractions. The details of dose limits for organs at risk were based on the study 0225 from The Radiation Therapy Oncology Group (RTOG 0225).

Intensity Modulated Radiation Therapy

Patients in the experimental group were received ulinastatin:

Ulinastatin (UTI): ulinastatin was intravenous drip at a dose of one hundred thousand units added to 100 ml of 0.9% normal saline every time, 3 times every radiation day, and until the end of radiotherapy.

Ulinastatin

zhao chong

This is a phase 3, open-label, multicenter, randomized controlled phase III clinical trial. The purpose of this study is to evaluate the efficacy of ulinastatin, a kind of protease inhibitor, in the treatment of radiation-induced acute oral mucositis in localregionally advanced nasopharyngeal carcinoma(NPC) patients treated with concurrent chemoradiotherapy(CCRT). To Explore a new and efficient way to reduce the incidence and severity of radiation-induced acute oral mucositis.

Radiation-induced acute oral mucositis (RTOM) in Nasopharyngeal Carcinoma (NPC) patients treat with concurrent chemoradiotherapy (CCRT) is common. Currently, there is no effective treatment for RTOM. Ulinastatin, is a kind of natural anti-inflammatory substance. And this substance is insufficient when the body's inflammatory response is strongly. There are a series of studies have confirmed the efficacy and safety of ulinastatin in the treatment of body's inflammatory response. From the observation of our previous clinical practice, we found that ulinastatin can relieve the severity of RTOM. The present study is undertaken to evaluate the efficacy of ulinastatin in the treatment of RTOM in localregionally advanced NPC patients treated with CCRT.

Efficacy of Ulinastatin for Reducing Radiation-Induced Oral Mucositis in Nasopharyngeal Carcinoma Patients

A Phase 3, Open Label, Multicenter, Randomized Controlled Clinical Trial to Evaluate the Efficacy of Ulinastatin in the Reduction of Acute Oral Mucositis Caused by Concurrent Chemoradiotherapy(CCRT) for Patients With Localregionally Advanced Nasopharyngeal Carcinoma (NPC).

The primary outcome measures planned in the protocol were the incidence of actue oral mucositis grade greater than or equal to 3 using the Common Terminology Criteria for Adverse Events of Version 4.03 (CTCAE 4.03) in the experimental group and control group. CTCAE 4.03 grade 3 = severe pain; interfering with oral; CTCAE 4.03 grade 4 = Life-threatening consequences; urgent intervention indicated; CTCAE 4.03 grade 5 = death. Mucositis will be assessed weely during concurrent chemoradiotherapy (CCRT) for 7 weeks, and assessed once at 1 month after CCRT and 3 months after CCRT, respectively. The whole observation time may up to 19 weeks.

Weeks to onset is the duration from the start of radiotherapy to the week of first severe oral mucositis occurred. Severe oral mucositis was defined as a Grade 3 or above of Common Terminology Criteria For Adverse Events of Version 4.03 (CTCAE 4.03). CTCAE 4.03 grade 3 = severe pain; interfering with oral; CTCAE 4.03 grade 4 = Life-threatening consequences; urgent intervention indicated; CTCAE 4.03 grade 5 = death. Mucositis will be assessed weekly during concurrent chemoradiotherapy (CCRT) for 7 weeks, and assessed once at 1 month after CCRT and 3 months after CCRT, respectively. Time to onset of severe mucositis will be recorded. The whole observation time may up to 19 weeks.

The Oral Assessment Guide (OAG) score is calculated based on the following categories: ability of swallow; the appearance of lips; the appearance of tongue; the appearance of oral mucous membranes; the appearance of gingivae; the appearance of teeth; and the change of voice. There are three grades in every category. The details about Oral Assessment Guide is available in: http://www.rch.org.au/rchcpg/hospital_clinical_guideline_index/Mouth_Care_of_the_paediatric_oncology_patient/. The OAG score will be assessed weekly during concurrent chemoradiotherapy (CCRT) for 7 weeks, and assessed once at 1 month after CCRT and 3 months after CCRT, respectively. The whole observation time may up to 19 weeks.

The Oral Mucositis Score of World Health Organization (WHO) was classified based on the changes of patients' oral mucosa and ability to eat, and are classified to 4 grades. WHO scale for oral mucositis (available in: Peterson DE, Boersdoets CB, Bensadoun RJ, et al. Management of oral and gastrointestinal mucosal injury: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Annals of Oncology 2015; 26(supply5). https://doi.org/10.1093/annonc/mdv202): Grade 0 = no oral mucositis; Grade 1 = erythema and soreness; Grade 2 = ulcers, able to eat solids; Grade 3 = ulcers, requires liquid diet (due to mucositis); Grade 4 = ulcers, alimentation not possible (due to mucositis). The WHO score will be assessed weekly during concurrent chemoradiotherapy (CCRT) for 7 weeks, and assessed once at 1 month after CCRT and 3 months after CCRT, respectively. The whole observation time may up to 19 weeks.

Participants with a duration of 5 days or more without an administration of radiotherapy or who discontinue radiotherapy prior to completion of planned radiotherapy were considered to have an unplanned break in radiotherapy. The rate of unplanned break was calculated for both arms.

The quality of life for all participants was evaluated according to The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) (available in: Grønvold M. EORTC QLQ-C30 Scoring Manual 2014.). The EORTC QLQ-C30 shoule be completed weekly during concurrent chemoradiotherapy (CCRT) for 7 weeks, and assessed once at 1 month after CCRT and 3 months after CCRT, respectively. The whole observation time may up to 19 weeks.

The functional status for all participants was assessed according to Karnofsky Performance Status Scale (KPS Scale) (available in: Friendlander AH, Ettinger RL. Karnofsky performance status scale\[J\]. Special Care in Dentistry, 2009, 29(4):147.). The KPS Scale was range from 0 to 100, and were averagely divided into eleven grades begin with 0. The KPS Scale will be recoreded weekly during concurrent chemoradiotherapy (CCRT) for 7 weeks, and assessed once at 1 month after CCRT and 3 months after CCRT, respectively. The whole observation time may up to 19 weeks.

The pain caused by oral mucositis for all participants was assessed according to Numeric Rating Scale (NRS scale), by which a respondent selects a whole number (0-10 integers) that best reflects the intensity of their pain. And an 11-point scale where 0 indicates no pain and 10 indicates the worst imaginable pain. The scale for each patient was recorded. The NRS scale will be assessed weekly during concurrent chemoradiotherapy (CCRT) for 7 weeks, and assessed once at 1 month after CCRT and 3 months after CCRT, respectively. The whole observation time may up to 19 weeks.

Efficacy was estimated according to Response Evaluation Criteria in Solid Tumor version 1.1 (RECIST 1.1) (available in: Watanabe H, Okada M, Kaji Y, et al. New response evaluation criteria in solid tumours-revised RECIST guideline (version 1.1. European Journal of Cancer, 2009, 45(2):228-247.). The efficacy was divided into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). And CR was defined as disappearance of all target lesions, PR was defined as at least a 30% reduction in the sum of the longest diameter of target lesions. Overall response rate (ORR) is the sum rate of patients with CR and PR for the total number of evaluable patients.

The adverse events related to ulinastatin based on medicine specification of ulinastatin was observed and recorded down according to Common toxicity criteria, version 2.0. (available in: Version CTC, Version CTC, Date P, et al. Common toxicity criteria (ctc) 1999.).

Affiliated Cancer Hospital & Institute of Guangzhou Medical University

First People's Hospital of Foshan

People's Hospital of Zhongshan

Fifth Affiliated Hospital, Sun Yat-Sen University

Sun Yat-sen University

Clinical Professor

Wounds and Injuries

Infections

Gingivitis

Gingivitis, Necrotizing Ulcerative

Communicable Diseases

Fusobacterium Infections

Bacterial Infections

Gram-Negative Bacterial Infections

Mycoses

Bacterial Infections and Mycoses

Gingival Diseases

Periodontal Diseases

Analgesics

The MuReva Phototherapy System consists of Light Control Unit and two Mouthpiece Cable Assemblies. Subjects will begin device treatment photobiomodulation sessions on the first day of radiotherapy (RT) treatment. They will receive once-daily investigative device photobiomodulation treatments prior to radiation therapy (RT) with their assigned Mouthpiece for 5 days per week for the duration of their CRT treatment. Each device treatment session will last up to 5 minutes, not including up to 5 additional minutes for treatment breaks. All subjects will visit the study site once during the Screening period (Days -28 to 1) and an anticipated 30 to 40 times during the treatment period. Each patient will be assigned their own Mouthpiece Cable Assembly set.

The MuReva Phototherapy System (or sham control) is a Light Control Unit and a set of Mouthpiece Cable Assemblies. The sham control Mouthpiece Cable Assemblies will appear identical to the active Mouthpiece Cable Assembly, and will be used in the same manner as the active cohort. However, the sham control device will be configured where the mouthpiece will not emit any light at any time during the study. The same Light Control Unit will be used with sham and active Mouthpiece Cable Assemblies. Each patient will be assigned their own Mouthpiece Cable Assembly set.

Provide photobiomodulation therapy to subjects prior to each radiation therapy session.

Photobiomodulation

Standard oral care, oral hygiene and oral pain protocols

Routine Oral Care and Analgesia

Nancy B Lipko, MD MBA

The overall purpose of this clinical study is to evaluate safety and efficacy of the MuReva Phototherapy System with a light delivery mouthpiece to reduce the severity of oral mucositis (OM) in adult patients with squamous cell carcinoma of the oral cavity, oropharynx, tonsils and base of tongue receiving radiation therapy with or without concurrent chemotherapy.

Study Design: A prospective, multi-center, randomized, double-blind, placebo controlled, adaptive sample size, two-treatment parallel, pivotal clinical study.

Protocol-eligible subjects will be randomized in a 1:1 allocation to receive either the active MuReva Phototherapy System or a sham control. Both the subjects and clinician evaluating the patients will be blinded to the treatment assignments. The sham device will be placed in the patient's mouth and operated in the same manner as the active device, but not deliver any therapy.

Subjects will begin device treatment sessions on the first day of radiation treatment (RT) and will continue to receive once daily treatments prior to RT with their assigned device for 5 days per week for the duration of their RT treatment (approximately 6 to 8 weeks, for a total of 30 to 40 device sessions depending on the standard of care regimen for the type of cancer). Each device treatment session will last approximately 10 minutes in total. Light therapy parameters for the MuReva Phototherapy System will be as follows for all subjects receiving active light therapy: 660nm, 2-12 J/cm2 nominal fluence. Subjects who stay on RT treatment past 6 weeks will continue to receive treatment with their assigned devices up through 8 total weeks of treatment (for a maximum total of 40 phototherapy sessions). In addition, all subjects, regardless of randomization, will be kept on standard oral care, oral hygiene and oral pain protocols.

All subjects will visit the study site once during the Screening period (Days -28 to 1) and an anticipated 30 to 40 times during the treatment period (i.e., 5 days during each of the 6-8 RT treatment weeks). Weekly, subjects will be evaluated for oral mucositis and for device safety. The weekly assessments will continue through the final RT session. A post-therapy assessment will be done approximately 2 weeks after completion of RT. At the conclusion of this assessment each subject's participation in the study will be complete.

A prospective, multi-center, randomized, double-blind, placebo controlled, adaptive sample size, two-treatment parallel, pivotal clinical study.

The sponsor, clinical research organization (CRO), subjects, research staff and Investigators performing the weekly OM evaluations for the study will be blinded to the treatment assignments. Subjects will be mandated to use light-blocking eyewear.

Only the research staff delivering treatment will be unblinded. No other personnel or visitors will be allowed in the treatment room during active/sham treatment.

The Investigators will not administer the daily treatment and will not visit or observe the patient during device use in order to remain blinded. The Investigators will also remain blinded to the patients' responses to the weekly Self-Assessments.

Photobiomodulation to Demonstrate Safety and Reduce the Incidence of Oral Mucositis in Adult Head & Neck Cancer Patients

Photobiomodulation Therapy Using the MuReva Phototherapy System to Demonstrate Safety and Reduce the Incidence of Oral Mucositis in Adult Patients With Head and Neck Cancer Receiving Radiation Therapy With or Without Concurrent Chemotherapy

A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify individual subjects. At most, the Web site will include a summary of the results after the study is completed. You can search this Web site at any time.

If the results of this study are published, individual subject identity will remain confidential.

Data, salivary fluid specimens and photographs collected in this research might be de-identified (name and any identifying information will be removed) and used for future research or distributed to another investigator for future research.

The primary effectiveness endpoint of the study is the severity of oral mucositis as assessed by the Oral Mucositis Index (OMI) score, on a scale of 0-60.

The proportion of patients who have severe oral mucositis (Grade 3 or 4) at week 6 of treatment according to the World Health Organization (WHO) Oral Toxicity Scale.

Oral Mucositis Weekly Questionnaire-Head and Neck Cancer

MuReva Phototherapy Inc.

Anti-Bacterial Agents

Antibiotics, Antitubercular

* 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.

* 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.

* Prescription of Chinese Medicine Oral Rinse Formula-I (CMORF-I)
* Instruction to rinse:

  1. The above amount of concentrated CM granules will be divided and packed in 4 bags per day.
  2. Dissolve 1 bag of concentrated CM granules with 150ml 80'C boiled hot water, and wait for 20 mins to cool down.
  3. Clean the mouth thoughtfully by rinsing with 150ml of distilled water for 2 minutes.
  4. 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.
  5. 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.
  6. 4 times a day (half an hour after every meal, half an hour before sleep), from baseline to 2 weeks after RT.

Chinese Medicine Oral Rinse Formula-I (CMORF-I)

• Standard care including normal saline or medical mouthwash, optional analgesics and antibiotics will be offered by hospital.

Standard Care

Placebo granules, instruction is the same as CMORF-I.

Placebo

KWOK YIN AU, Doctor of Medicine

KWOK YIN AU, PhD

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.

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.

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).

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

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

* 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.

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.

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.

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".

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".

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.

It can assess and monitor the conditions of OM.

Chinese University of Hong Kong

Dr. AU Kwok Yin

Other Dietary Supplements

Acidophilus

Lactobacillus Reuteri lozenges (NOW Foods, Sweden) contained no less than 2×10\^7 CFU viable cells of Lactobacillus Reuteri as the active ingredient.

Lactobacillus Reuteri Tablets

Starch preparations that look and taste like Lactobacillus Reuteri

Placebo-containing tablets

One of the inclusion criteria for the study was that patients with squamous carcinoma of the head and neck (including nasopharyngeal carcinoma) needed to receive either radiotherapy alone or simultaneous radiotherapy and chemotherapy, with radiotherapy using intensity-modulated radiotherapy techniques.

Radiotherapy

Xingchen Peng

Xingchen Peng, PhD

Radiation therapy is a common treatment modality in the management of head and neck malignancies. However, head and neck tumors often have some adverse reactions when receiving radiation therapy, such as dry mouth, change of taste, oral mucositis, etc. Among them, the incidence of oral mucositis is more than 90%, and the incidence of oral mucositis of degree 3 or more than degree 3 is more than 50%. Severe oral mucositis seriously affects the quality of survival of patients. Lactobacillus Reuteri is a natural flora of the human body that can be found in the gastrointestinal tract, skin, etc. Among them, Lactobacillus Reuteri DSM 17938 and ATCC PTA 5289 can be isolated from healthy mammals as well as poultry, and are common Lactobacillus strains marketed for the production of oral probiotics, which are commonly used in infant formulas, among others. In oral inflammatory diseases, it has been reported in the literature that Lactobacillus Reuteri DSM 17938 and ATCC PTA 5289 can reduce gingival and periodontal inflammation, mainly through the mechanisms of modulating the host inflammatory response and displacing pathogenic bacteria. In terms of safety, oral Lactobacillus Reuteri has good stability, very low pathogenic potential, and is not toxic to humans. Therefore, this study is a placebo-controlled, multi-center, open, randomized controlled clinical study to evaluate the efficacy of Lactobacillus Reuteri for the prevention of radioactive oral mucosal reactions in intensity-modulated radiotherapy for head and neck tumors, including nasopharyngeal carcinoma.

Radiotherapy (RT) is an important treatment for head and neck malignant tumors and can be used alone or in combination with chemotherapy as radical or adjuvant therapy. Despite improvements in RT equipment and techniques, there are still a variety of acute oral complications, including oral mucositis (OM), xerostomia, taste dysfunction, and oral infection. OM is one of the most common acute radiation-related toxicity in head and neck malignant tumor patients receiving RT, and approximately 50\~70% of patients experience severe oral mucositis (SOM). The painful inflammation and ulceration associated with OM not only profoundly affect patients' ability to eat, swallow, and speak but also decrease patients' tolerance to anti-cancer treatment, seriously impairing patients' quality of life (QoL) and causing interruptions and cancellations of cancer treatment. Standard treatment for OM focuses on pain control, rehydration, and good oral hygiene. For patients with hematopoietic stem cell transplantation, palifermin (keratinocyte growth factor-1) is recommended. Although some clinical strategies for OM such as non-steroidal anti-inflammatory drugs, mucosal protective agents, growth factors and cytokines, antibacterial, and pain relief drugs have been recommended by the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO), the therapeutic benefit is limited6. Thus, it is crucial to develop effective drugs or treatment strategies to decrease radiation-induced mucosal toxicity.

The resident microbiota plays an important role in the pathogenesis and development of radiation-induced OM. Microbiota can release pathogen-associated molecular patterns (PAMPs) that bind to pathogen recognition receptors (PRR) and activate the initial innate immune response, a known pathogenic pathway. Recent studies have suggested that dysbiosis of oral microbial contributes to the occurrence and severity of radiation-induced OM and manipulation of the patient microbial community may be key to preventing and treating effectively OM. Probiotics are defined as live microorganisms which when administered in adequate amounts can improve the microecological balance and confer a health benefit on the host. Conventional probiotics typically belong to the genera Lactobacillus or Bifidobacterium and Lactobacillus brevis CD2 is the most widely studied probiotic for preventing cancer therapy-induced OM, but its effectiveness is still debated.

Lactobacillus Reuteri is the body's natural flora and can be found in the gastrointestinal tract, skin, breast milk, etc. And they do not trigger infections in healthy individuals15. Among them, Lactobacillus Reuteri DSM 17938 and ATCC PTA 5289 can be isolated from healthy mammals as well as poultry, and are common Lactobacillus strains used in the market for making oral probiotics16. Lactobacillus Reuteri DSM 17938 has been reported to alleviate chronic inflammatory conditions such as infantile colic and irritable bowel-syndrome17.In oral inflammatory diseases, Lactobacillus Reuteri DSM 17938 and ATCC PTA 5289 have been found to reduce gingival and periodontal inflammation, which is mainly achieved through mechanisms such as modulation of the host inflammatory response and displacement of pathogenic bacteria. The development of oral mucositis caused by radiotherapy or chemoradiotherapy is associated with DNA damage and high production of various inflammatory factors such as interleukin-1(IL-1), interleukin-6 (IL-6) and tumor necrosis factor-a(TNF-a). Recently, the results of the study by Nitasha et al. showed that Lactobacillus Reuteri DSM 17938 and ATCC PTA 5289 can reduce oxidative stress and Inflammation in a preclinical rodent model. All of the above imply Lactobacillus reuteri's potential use in the prevention of OM.

The purpose of this placebo-controlled randomized trial was to investigate the prevention effects of Lactobacillus Reuteri versus placebo in patients with head and neck malignant tumors receiving RT.

Lactobacillus Reuteri Alleviates Oral Mucositis in Patients Undergoing Radiotherapy for Malignant Head and Neck Tumors

Lactobacillus Reuteri Alleviates Oral Mucositis in Patients Undergoing Radiotherapy for Malignant Head and Neck Tumors: A Randomized Controlled Trial

Oral mucositis is assessed by trained physicians according to World Health Organization (WHO) oral toxicity Scale.The WHO Oral Toxicity Scale categorizes oral mucositis into grades 0-4, with the higher the grade the more severe the patient's oral mucositis. Grade 0 means that the oral mucosa is normal and the patient has no symptoms or signs; grade 1 means that the mucosa is erythematous with or without pain and does not interfere with eating; grade 2 means that the mucosa is erythematous and ulcerated, but still able to eat solid food; grade 3 means that the mucosa is severely ulcerated with extensive erythema and unable to eat solid food; and grade 4 means that the ulcers of the mucosa are fused together into a sheet, and their severity is so severe that it is not possible to eat.

Time from the first day of radiotherapy to the first determination of SOM. Patients without observed SOM were assigned onset days of 6 or 6.5 weeks

The first determination of SOM to the first instance of non-severe OM (WHO grade \<3), without a subsequent instance of SOM. Patients without observed SOM were assigned a duration of 0 days

Electrogustometer test and taste strips test.

Xerostomia is subjectively assessed on the Summated Xerostomia Inventory (SXI). The SXI is categorized according to score as 0 no dry mouth (5), 1 mild dry mouth (6-8), 2 moderate dry mouth (9-12), and 3 severe (13-15). Objectively the researchers measured the salivary flow rate to rate dry mouth, i.e., a 2% citric acid solution was applied to the side of the tongue every 30 seconds for 5 minutes, the secreted saliva was flowed into a sterile tube and the salivary flow rate (ml/min) was calculated, normal stimulated salivary flow rate was between 1.5 - 2.0 mL/min and low stimulated salivary flow rate was \< 0.5 \~ 0.7 mL/min.

FACT- H\&N quality of life questionnaire 4.0 is a scale used to assess quality of life in patients with head and neck tumors. It includes all aspects of quality of life, such as physical, emotional, functional, and social. With this scale, physicians can gain a more comprehensive understanding of a patient's quality of life status, which can lead to better treatment planning and support. The FACT-HN 4.0 scale has a total score range of 0-180, which includes four dimensions such as physical health, social/family, emotional, and functional/symptomatic. Each dimension has a different range of scores.The lowest score is 0, which indicates the worst quality of survival, and the highest score is 180, which indicates the best quality of survival. As the score increases, it indicates a better quality of survival; conversely, as the score decreases, it indicates a decreased quality of survival.

Common Terminology Criteria for Adverse Events (CTCAE) 5.0 version

Patients report the degree to the impact of MTS on oral activities (including swallowing, drinking, eating, talking, sleeping) (Likert scale 1 to 5) via the oral mucositis weekly questionnaire （OMWQ）. Higher score indicates more severe symptoms

Patients report mouth and throat soreness (MTS) scores (Likert scale 1 to 5) via the oral mucositis weekly questionnaire （OMWQ）. Higher score indicates more severe symptoms

West China Hospital

PhD, Professor

Anti-Inflammatory Agents

Respiratory System Agents

Acetylcysteine

N-monoacetylcystine

Antioxidants

Benzydamine

Antiviral Agents

Expectorants

Protective Agents

Antidotes

Cysteine

A potent antioxidant and anti-inflammatory drug (A precursor of the endogenous antioxidant glutathione)

N-Acetyl-Cysteine with Institutional standard care

Institutional standard care

Mohamed Shams, Professor

Rasha Abd-Ellatif, Professor

A prospective, randomized, controlled, parallel clinical trial will be conducted at Clinical Oncology and Nuclear Medicine Center at Mansoura University Hospital to assess the efficacy of N-acetylcysteine in the prevention of radiotherapy induced oral mucositis in Head and Neck cancer patients.

Efficacy of N-acetylcysteine in Preventing Radiotherapy-Induced Oral Mucositis in Head and Neck Cancer Patients.

Clinical Study Evaluating the Efficacy and Safety of N-acetylcysteine in Preventing Radiotherapy-Induced Oral Mucositis in Head and Neck Cancer Patients.

Difference between the two arms regarding incidence of grade ≥ 2 according to World Health Organization scale for Oral Mucositis.

Difference between the two arms regarding time to develop oral mucositis with grade ≥ 2 according to WHO scale for oral mucositis.

World Health Organization scale for oral mucositis

* Grade 0: no oral mucositis
* Grade 1: erythema and soreness
* Grade 2: ulcers, able to eat solids
* Grade 3: ulcers, requires liquid diet
* Grade 4: ulcers, alimentation not possible (due to mucositis).

Difference between the two arms regarding duration of oral mucositis with grade ≥ 2 according to WHO scale for oral mucositis.

The pain VAS is a unidimensional measure of pain intensity, used to record patients' pain progression. The most simple VAS is a straight horizontal line of fixed length usually 100 mm. The ends are defined as the extreme limits of the parameter to be measured (pain) orientated from the left (worst) to the right (best).

we will allocate this scale in comparing pain severity between the two arms.

TUBE DEPENDENT (levels 1-3)

1. No oral intake
2. Tube dependent with minimal/inconsistent oral intake 3 Tube supplements with consistent oral intake

TOTAL ORAL INTAKE (levels 4-7) 4. Total oral intake of a single consistency 5. Total oral intake of multiple consistencies requiring special preparation 6. Total oral intake with no special preparation, but must avoid specific foods or liquid items 7. Total oral intake with no restrictions

A questionnaire filled by head and neck cancer patient to assess the quality of life.

H\&N1 I am able to eat the foods that I like H\&N2 My mouth is dry H\&N3 I have trouble breathing H\&N4 My voice has its usual quality and strength H\&N5 I am able to eat as much food as I want H\&N6 I am unhappy with how my face and neck look H\&N7 I can swallow naturally and easily H\&N8 I smoke cigarettes or other tobacco products H\&N9 I drink alcohol (e.g. beer, wine, etc.) H\&N10 I am able to communicate with others H\&N11 I can eat solid foods H\&N12 I have pain in my mouth, throat or neck

Scoring:Not at all (0) A little bit (1) Somewhat (2) Quite a bit (3) Very much(4)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Efficacy of Ulinastatin for Reducing Radiation-Induced Oral Mucositis in Nasopharyngeal Carcinoma Patients	NCT03387774	Oral Mucositis ...	Cisplatin Intensity Modul... Ulinastatin	18 Years - 65 Years	Sun Yat-sen University
Photobiomodulation to Demonstrate Safety and Reduce the Incidence of Oral Mucositis in Adult Head & Neck Cancer Patients	NCT03972527	Oral Mucositis ... Oral Mucositis ... Oral Mucositis ... Head and Neck C...	Photobiomodulat... Routine Oral Ca...	22 Years -	MuReva Phototherapy Inc.
Evaluating Chinese Medicine Oral Rinse for Irradiated Oral Mucositis in Head & Neck Cancer Patients	NCT05664906	Head and Neck N... Oral Mucositis ... Chinese Medicin...	Chinese Medicin... Standard Care Placebo	18 Years -	Chinese University of Hong Kong
Lactobacillus Reuteri Alleviates Oral Mucositis in Patients Undergoing Radiotherapy for Malignant Head and Neck Tumors	NCT06285591	Oral Mucositis ...	Lactobacillus R... Placebo-contain... Radiotherapy	18 Years - 80 Years	West China Hospital
Photobiomodulation to Demonstrate Safety and Reduce the Incidence of Oral Mucositis in Adult Head & Neck Cancer Patients	NCT03972527	Oral Mucositis ... Oral Mucositis ... Oral Mucositis ... Head and Neck C...	Photobiomodulat... Routine Oral Ca...	22 Years -	MuReva Phototherapy Inc.
Efficacy of N-acetylcysteine in Preventing Radiotherapy-Induced Oral Mucositis in Head and Neck Cancer Patients.	NCT06354712	Oral Mucositis ...	N-Acetyl-Cystei... Institutional s...	18 Years - 80 Years	Mansoura University

Spots Global Cancer Trial Database for oral mucositis (ulcerative) due to radiation