Hangeshashinto (TJ-14)

To study the safety and efficacy of TJ-14 in preventing or treating chemotherapy-induced mucositis versus a placebo in patients with gastric cancer

Patients who identified a Common Terminology Criteria for Adverse Events (CTCAE version 4) grade 1 or greater mucositis were randomized on a one-to-one ratio and stratified according to age, chemotherapy regimen, institution, and previous treatment for oral mucositis. Participants received either TJ-14 or a placebo beginning with their next cycle of chemotherapy. The placebo was prepared to mimic the intervention. TJ-14 and the placebo were given three times per day. Patients were instructed to dissolve 2.5 g (total daily dose 7.5 g) of either TJ-14 or the placebo in 50 mL of regular drinking water and to rinse the oral cavity for 10 seconds. Treatment began on the first day of the protocol treatment, continued till the final day, and was administered as much as possible for one course of treatment. No other mouthwash prophylactic interventions for oral mucositis were allowed during the trial period. Assessments took place during the screening cycle from the beginning of the protocol treatment or the appearance of mucositis until all symptoms disappeared.

• N = 91
• AVERAGE AGE = 68 years
• MALES: 62.2% (TJ-14); 60.9% (placebo), FEMALES: 37.8% (TJ-14); 39.1% (placebo)
• KEY DISEASE CHARACTERISTICS: Patients with gastric cancer who developed an oral mucositis score > 1 on the CTCAE scale during the screening cycle of chemotherapy.
• OTHER KEY SAMPLE CHARACTERISTICS: None

• SITE: Multi-institutional facilities           
• SETTING TYPE: Cancer center
• LOCATION: Japan

• PHASE OF CARE: Active treatment
• APPLICATIONS: Elder care, palliative care 

Randomized, double-blinded, controlled, phase II trial

• The National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0
• Time to resolution of mucositis was defined by the authors as the time from the initiation of the protocol treatment or the first day of mucositis to the day when the patient was symptom-free.
• Patients self-reported the ability to eat solid foods.
• Physical examinations, laboratory evaluations, and the reporting of adverse events were used to evaluate safety.

In this study, 40% of patients in the intervention group and 41.3% of patients in the placebo group experienced ≥ grade 2 oral mucositis, and there was no difference between the groups (p = .588). In addition, there was no difference between the two groups concerning the duration of oral mucositis (p = .937).

This study did not demonstrate any beneficial effects of TJ-14 in reducing the incidence of chemotherapy-induced oral mucositis.

• Small sample (< 100)
• Other limitations/explanation: It is possible that dose reductions in chemotherapy affected the duration of the treatment instead of the standard treatment, which postpones chemotherapy because of mucositis.

No prophylactic or treatment-related benefits of TH-14 were evident in this study regardless of the grade of chemotherapy-induced oral mucositis. Nurses should consider other interventions for the prevention and treatment of oral mucositis.

To investigate the effect of hangeshashinto to relieve chemotherapy-induced oral mucositis

Patients were to gargle three times daily with 2.5 g hangeshashinto (TJ-14) in 50 ml of water and rinse the oral cavity for about five seconds. Patients were instructed not to swallow it and not eat or drink anything for 30 minutes. Patients who received the intervention were compared to patients who did not. Measurements were done at baseline and at eight weeks.

• N = 57, only 12 received the intervention  
• MEAN AGE = 59.5 years
• AGE RANGE = 40–75 years
• MALES: 93%, FEMALES: 7%
• CURRENT TREATMENT: Combination radiation and chemotherapy
• KEY DISEASE CHARACTERISTICS: Oropharyngeal and hypopharyngeal cancers; total radiation dose of 70 Gy and cisplatin
• OTHER KEY SAMPLE CHARACTERISTICS: The majority of patients had stage IV disease.

• SITE: Single site   
• SETTING TYPE: Inpatient    
• LOCATION: Japan

• PHASE OF CARE: Active antitumor treatment

• Nonrandomized two-group prospective study

• Common Terminology Criteria for Adverse Events (CTCAE)
• Bioimpedance for body composition
• Measurement of food intake

No significant differences in maximum grade of mucositis or daily morphine dose existed. Oral intake and body weight were improved in those who took the hangeshashinto, but no comparative information on this measure from the control group was provided. The radiation completion rate was higher in the treated group (p = 0.045). Twenty-five percent of patients would not continue to use the gargle because of the bitter taste, nausea, vomiting, and refusal to wait 30 minutes before eating.

The findings do not show a benefit of hangeshashinto gargle on mucositis severity or associated pain.

• Small sample (< 100)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Measurement/methods not well described
• Measurement validity/reliability questionable
• Subject withdrawals ≥ 10%  
• Very few patients actually received the intervention. Little comparative information is provided. The timing of measurement was not clearly reported.

This study did not show the effectiveness of hangeshashinto to prevent or reduce the severity of oral mucositis in patients with head and neck cancer receiving combined radiation and chemotherapy. Multiple report limitations are noted.

To determine if hangeshashinto (TJ-14) is an effective treatment for oral mucositis

Patients with oral lesions 7–10 days after chemotherapy were given a 50 ml oral rinse with 2.5 g of TJ-14 and tap water three times per day for 7 days. Patients held the solution in their mouth for 10 seconds and spit it out. TJ-14 also was applied to the lesions with a cotton pellet as soon as the lesion appeared. Patients could not eat or drink 30 minutes before or after treatment. No other mucosal treatments were used during the study. Two blinded physicians graded mucositis.

• N = 14  
• MEAN AGE: 62 years
• AGE RANGE: 34–80 years
• MALES: 43%, FEMALES: 57%
• KEY DISEASE CHARACTERISTICS: Colorectal cancer

• SITE: Single site   
• SETTING TYPE: Outpatient   
• LOCATION: Japan

• PHASE OF CARE: Active antitumor treatment

• Non-randomized trial

• Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 mucositis scale

In this study, 92.8% of patients had improvements in oral mucositis. There was a significant reduction in CTCAE grades of mucositis for all participants from 2.4 ± 0.8 to 1.1 ± 0.8 (p = 0.0012). No adverse events or side effects from NJ-14 were reported.

NJ-14 was effective at improving oral mucositis and did not have any reported side effects in this small sample. However, caution must be used in interpreting this data due to the limitations of the study.

• Small sample (< 30)
• Risk of bias (no control group)
• Risk of bias (no random assignment)
• Risk of bias (no appropriate attentional control condition)

NJ-14 is a promising intervention to treat chemotherapy-induced oral mucositis; however, more research is needed from large RCTs.

To determine if TJ-1 (hangeshanshinto), a Japanese traditional herbal medicine, prevents and controls chemotherapy-induced oral mucositis

Patients who developed greater than World Health Organization (WHO) grade 1 oral mucositis during the first screening cycle of chemotherapy were eligible for a central 1:1 randomization to the study or control group. Three times each day, patients dissolved 2.5 g of TJ-14 or a placebo in 50 ml of water and rinsed the oral cavity. Patients were trained in the clinic. Treatment started on the first day of chemotherapy and continued for 14 days. Assessments using the WHO oral mucositis scale were done three times per week on nonconsecutive days during the screening cycle and treatment cycles 1 and 2. Assessments continued for three weeks or until mucositis returned to grade 0. Safety and adverse events were assessed.

• N = 90  
• MEDIAN AGE = 67 years (range = 49–84 years) 
• MALES: 55.5%, FEMALES: 44.5%
• KEY DISEASE CHARACTERISTICS: Chemotherapy-induced oral mucositis in patients with colorectal cancer 
• OTHER KEY SAMPLE CHARACTERISTICS: Fluorinated pyrimidine-based chemotherapy

• SITE: Multi-site    
• SETTING TYPE: Outpatient    
• LOCATION: Japan

• PHASE OF CARE: Active antitumor treatment

Multi-institutional, double-blinded, placebo-controlled, randomized, phase 2 trial

• World Health Organization (WHO) mucositis grading

There was no significant difference in the incidence and severity of oral mucositis between the groups. The duration of grade ≥ 2 mucositis was 5.5 days in the treatment group and 10.5 days in the placebo group.

This study did not meet its primary endpoint. TJ-14 demonstrated a potential treatment effect on mucositis ≥ grade 2 .

• Small sample (< 100)

TJ-14 is a Japanese traditional herbal medicine consisting of a mixture of seven herbs. Additional study is needed to fully evaluate its effectiveness.

To investigate the efficacy of a traditional Japanese medicine, hangeshashinto (TJ-14), in the prevention of chemoradiation-induced oral mucositis

Records were reviewed retrospectively. All patients underwent fractioned radiation with or without concurrent chemotherapy. Researchers compared data from 40 patients who were treated with TJ-14 to those of 40 patients who underwent radiotherapy or concurrent chemoradiotherapy treatment during the study period and did not receive TJ-14 (the control group). Those who received TJ-14 rinsed and gargled with 2.5 g of the intervention drug dissolved in 100 mL of oral rinse solution. Patients rinsed and gargled with the solution three times per day for 30 seconds after meals and during and after chemoradiation treatment and then swallowed or expectorated the solution. No food or drink was allowed for 30 minutes after treatment. Both groups brushed and gargled with six drops of 4% sodium gualenate hydrate and tap water as well as lidocaine gargle, NSAIDs, and opioids as needed.

• N = 80  
• AVERAGE AGE = 68 years
• MALES: 95%, FEMALES: 5% 
• KEY SAMPLE CHARACTERISTICS: Patients who underwent whole-neck radiation of > 60 Gy with or without chemotherapy

• SITE: Single-site
• SETTING TYPE: Outpatient  
• LOCATION: Japan

• PHASE OF CARE: Active treatment

Retrospective chart review comparing those who used the study medication and those who did not.

• National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 for oral mucositis

A mulivariate analysis indicated that the use of TJ-14 (p = .019), a patient's gender (p = .024), and a patient's primary tumor location (p = .028) were significant factors associated with the severity of oral mucositis. TJ-14 was associated with a significantly improved rate of completion of chemoradiation with cisplatin (p = .002). However, the study purpose was to prove the effectiveness in preventing oral mucositis. No primary endpoint was ever mentioned.

Additional studies to determine effectiveness are needed. Future studies should be more specific as to the type of chemotherapy used and how by whom oral assessments are completed. The authors of this study were trying to measure too many variables within one small study. Study purpose was too general.

• Small sample (< 100)
• Baseline sample/group differences of import
• Risk of bias (no random assignment)
• Key sample group differences that could influence results 
• Measurement/methods not well described 
• Measurement validity/reliability questionable 
• Findings not generalizable
• Other limitations/explanation: No way to validate whether the oral assessments were reliable, valid, or reproducible. The measurement method was questionable. The written report was confusing and contained too many study variables.

This retrospective record review provides a platform on which well-designed, randomized, controlled studies can be based to evaluate the effectiveness of TJ-14 for the prevention of oral mucositis. Well-designed studies are needed to prove the effectiveness of this medication.