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

Oral Mucositis (Ulcerative) Due to Radiation Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06285591
• Other study ID #: 2023-1801
• Status: Recruiting
• Phase: N/A
• Start date: November 10, 2023
• Est. completion date: March 31, 2025

Study information

• Verified date: February 2024
• Source: West China Hospital
• Contact: Xingchen Peng
• Phone: +86 18980606753
• Email: pxx2014[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 130
• Est. completion date: March 31, 2025
• Est. primary completion date: March 31, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Patients pathologically diagnosed with non-metastatic head and neck malignant tumors;

2. Aged 18-80 years;

3. Eastern Cooperative Oncology Group performance status of =2;

4. Planning to receive definitive RT or postoperative adjuvant RT;

5. Normal liver, kidney and bone marrow function;

6. Sign informed consent.

Exclusion Criteria:

1. Known hypersensitivity or more severe allergies to Lactobacillus Reuteri components;

2. Those with poor compliance;

3. Pregnancy or breastfeeding;

4. History of head and neck radiotherapy;

5. Taking antifungal or viral medications one week prior to the start of radiation therapy.

6. Other patients (with any other serious other medical condition) who, in the opinion of the investigator, are not suitable for participation in this study.

Related Conditions & MeSH terms

• Head and Neck Neoplasms
• Mucositis
• Oral Mucositis (Ulcerative) Due to Radiation
• Stomatitis

Intervention

Dietary Supplement:
• Lactobacillus Reuteri Tablets
Lactobacillus Reuteri lozenges (NOW Foods, Sweden) contained no less than 2×10^7 CFU viable cells of Lactobacillus Reuteri as the active ingredient.
• Placebo-containing tablets
Starch preparations that look and taste like Lactobacillus Reuteri

Radiation:
• Radiotherapy
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.

Locations

Country	Name	City	State
China	West China Hospital, Sichuan University	Chengdu	Sichuan

Sponsors (1)

Lead Sponsor	Collaborator
West China Hospital

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The incidence of Severe Oral mucositis (WHO grade =3)	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.	From the start of radiotherapy to 8 weeks after completion of radiotherapy
Primary	The time to onset of Severe Oral mucositis (WHO grade =3)	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	From the start of radiotherapy to 8 weeks after completion of radiotherapy
Primary	The duration of Severe Oral mucositis (WHO grade =3)	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	From the start of radiotherapy to 8 weeks after completion of radiotherapy
Secondary	Taste function	Electrogustometer test and taste strips test.	1 week before radiotherapy ; at the middle of radiotherapy (3 weeks after the start of radiotherapy) ; at the end of radiotherapy (the last radiation dose received, usually 6 or 6.5 weeks); and 1, 3, 6, 9 and 12 months after the end of radiotherapy
Secondary	Xerostomia summated xerostomia inventory (SXI)	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.	1 week before radiotherapy ; at the middle of radiotherapy (3 weeks after the start of radiotherapy) ; at the end of radiotherapy (the last radiation dose received, usually 6 or 6.5 weeks); and 1, 3, 6, 9 and 12 months after the end of radiotherapy
Secondary	Functional assessment of cancer therapy-head and neck (FACT- H&N) quality of life questionnaire	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.	1 week before radiotherapy; at the end of radiotherapy(the last radiation dose received, usually 6 or 6.5 weeks); ; and 1, 3, 6, 9 and 12 months after the end of radiotherapy
Secondary	Adverse events	Common Terminology Criteria for Adverse Events (CTCAE) 5.0 version	From the first day of radiotherapy to the day of the last radiation dose received, usually 6 or 6.5 weeks
Secondary	Oral activities scores	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	The time period is the period from the start of radiotherapy to the completion of radiotherapy. The evaluation period is approximately 6 weeks and 6 1/2 weeks
Secondary	Mouth and throat soreness (MTS) scores	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	The time period is the period from the start of radiotherapy to the completion of radiotherapy.The evaluation period is approximately 6 weeks and 6 1/2 weeks