Herbal Medicine

• STUDY PURPOSE: To examine the evidence of Chinese herbal treatment in oral mucositis
• TYPE OF STUDY: Systematic review

• DATABASES USED: PubMed, MEDLINE via OVID, Embase via OVID, Cochrane Database, and CNKI
• KEYWORDS: Chemotherapy, chemotherapy-induced, oral ulcer, mouth ulcer, oral mucositis, stomatitis, Chinese herbal medicine, medicinal herbs, Chinese herbs, traditional Chinese medicine, antioxidant, anti-inflammatory
• INCLUSION CRITERIA: All induced oral mucositis treated by Chinese herbal medicine that offered an English or Chinese medicine were included.  
• EXCLUSION CRITERIA: Articles investigating radiochemotherapy-induced oral mucositis were excluded.

• TOTAL REFERENCES RETRIEVED: 686
• EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Only articles that included oral mucositis treated by Chinese herbal medicine were included. Therefore, 632 articles were excluded, leaving 54 articles of which only 18 met the inclusion criteria.

• FINAL NUMBER STUDIES INCLUDED = 18
• TOTAL PATIENTS INCLUDED IN REVIEW: 1, 476
• KEY SAMPLE CHARACTERISTICS: Patients with oral mucositis, based on the World Health Organization Oral Toxicity Scale, who were treated with either a single herb or a combination of herbs involving more than one component

PHASE OF CARE: Active treatment

All reviewed studies reported positive effects of Chinese herbal treatment for chemotherapy-induced oral mucositis.

Additional well-designed RCT studies are needed, especially to look at the mechanism of action for each herbal remedy. Due to poor design in terms of treatment and control groups, it was almost impossible to evaluate which parts of the treatment concepts are responsible for the measured effects in the reviewed trials.

Some studies used more than one herbal treatment with different routes of administration; therefore, it was difficult to determine which agent may have been more effective in treating oral mucositis. In general, most trials had a poor design.

No recommendations for use in clinical practice were made; recommendations were made for further studies. These studies could use placebo capsules or placebo liquids. It also was recommended that future studies decrease the complexity of the treatments in order to determine what treatments were effective.

Primary: To evaluate the use of Zataria multiflora (ZM) extract mouthwash to reduce the incidence and severity of oral mucositis (OM) in adult patients with head and neck cancer undergoing radiation therapy alone or combined radiation and chemotherapy. 

Secondary: The impact of ZM extract mouthwash on the amount of opioid used, the use of anti-inflammatory drug use, antibiotic use, and body weight over the course of therapy

• Double blinded, randomized
• Intervention group: Used a mouthwash containing ZM extract
• Control group: Used a placebo mouthwash with no ZM extract
• Both groups: Oral examination prior to initiation of therapy and then weekly until completion of the last radiation dose. Participants encouraged to use the mouthwash three times daily (after breakfast and lunch and at bedtime) in addition to one half hour prior to each radiation session. Maintained for seven weeks after therapy (data collected only until the end of therapy). Participants instructed to not rinse mouth with water up to one hour after gargling with mouthwash. Participants were also instructed not to smoke or eat hot, spicy, or very cold foods. Oral analgesics and anti-inflammatory medications were given as needed and per standard of care.

• N: 63 patients randomized, 25 in treatment group (16% attrition) and 27 in placebo group (20% attrition)   
• AGE: 57.48 years (SD = 17.98) in treatment group, 64.62 years (SD = 12.75) in placebo group
• MALES: 71%  
• FEMALES: 29%
• CURRENT TREATMENT: Radiation, combination radiation and chemotherapy
• KEY DISEASE CHARACTERISTICS: Head and neck cancer (radiation [at least 6000 cGy] planned for the entire oropharynx, nasopharynx, and/or greater than one-third of the oral cavity, a KPS > 70, with or without chemotherapy)
• OTHER KEY SAMPLE CHARACTERISTICS: No prior history of head and neck radiation, no current poor oral hygiene, no active infections of the mouth, no liver or kidney disease, no diabetes, no autoimmune disease or disease that might alter healing

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: Iran

• PHASE OF CARE: Active anti-tumor treatment
• APPLICATIONS: Elder care

Double blinded, randomized, placebo controlled study

• World Health Organization (WHO) mucositis scale
• Oral Mucositis Assessment Scale (OMAS)
• Visual analogue score (VAS) for pain
• Required opioid analgesia (weekly)
• Required anti-inflammatory drugs (weekly)
• Required antibiotics (weekly)
• Weekly body weights

Primary outcomes: 

• The presence and intensity of OM the groups was significantly different using the OMAS for all six weeks of assessment (p < 0.05 [range = 0.002-0.016]) and for weeks 3, 4, and 6 using the WHO OM scale (p < 0.05 [range = 0.009-0.045]) favoring the ZM group. There was a decrease in the incidence of grades 3-4 OM in the ZM group in comparison to the placebo group (24% versus 55.5%).

Secondary outcomes: 

• Pain: The ZM group demonstrated a lower pain score in weeks 2-6
• Weight loss: Less in the ZM group (p = 0.000)
• Required analgesia: Less in the ZM group (p = 0.010)
• Antibiotic use: Less in the ZM group (p = 0.037)

The use of ZM mouthwash positively impacted the incidence and severity of OM in patients with head and neck cancer undergoing head and neck radiation with or without concurrent chemotherapy. In addition, the ZM mouthwash contributed to less use of opioid analgesia, less antibiotic use, and decreased weight loss.

• Small sample (< 100)
• Subject withdrawals ≥ 10%  
• Other limitations/explanation: It is hard to discern how analgesic and anti-inflammatory use was ascertained.

ZM may offer an option for decreasing OM in patients undergoing radiation with or without concurrent chemotherapy in the head and neck cancer population.

To evaluate/compare three treatments for oral mucositis: (1) Plantago major extract mouthwash, (2) chlorhexidine 0.12%, and (3) aqueous solution of 5% sodium bicarbonate for  the treatment of oral mucositis in patients with solid tumors. Evaluation points included healing time, pain, oral intake, and quality of life.

Randomized controlled trial (phase 3)

• Group A: Control group, received standard of care which included sodium bicarbonate 5% aqueous solution with an additional dose of sodium bicarbonate 5% aqueous solution. 
• Group B: Experimental group, received sodium bicarbonate 5% aqueous solution plus Plantago major extract
• Group C: Experimental group, received sodium bicarbonate 5% aqueous solution plus chlorhexidine 0.12%

The treatment was 14 days for all groups. All groups received education regarding the management of mucositis, a set of instructions, a diary to record signs and symptoms of mucositis, and instruction for proper storing of the mouthwashes. All participants were instructed to rinse with 8 ml of solution for two minutes every six hours. They were instructed to leave 15 minutes between the two mouthwashes.

• N = 50 (evaluable)   
• AGE: Mean age = 59.5 years (SD = 14.3)
• MALES: 48%  
• FEMALES: 52%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Tumor types: breast (30.6%), colorectal (32.7%), lung (14.3%), gastric (8.2%) and other (14.2%)
• OTHER KEY SAMPLE CHARACTERISTICS: Patients had a mean of 3.6 (SD = 3.2) chemotherapy cycles prior to oral mucositis outbreak. Patients received many different chemotherapy drugs. No participants developed neutropenia.

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

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

Randomized controlled trial; investigators, participants, care providers, and statistician were all blinded.

• WHO mucositis scale
• Visual analogue scale (VAS) for pain intensity
• Intake capacity was captured by asking the participants if they could tolerated liquids only or liquids and solids. 
• European Organizsation for Research and Treatment of Cancer Quality of Life Core 30 Questionnaire (EORTC QLQ-C30)
• CBC (evaluation of neutropenia)
• Patient diary

• Healing time: No statistical difference between groups. The group that used the double 5% sodium bicarbonate solution did have a shorter time to heal by two days, which may be clinically significant. 
• Pain intensity: No significant difference
• Oral intake capacity: No significant difference
• Quality of life: No significant difference

In this small group, there is no advantage in using a chlorhexidine or Plantago major extract mouthwash in comparison to a double sodium bicarbonate solution. The latter is likely less expensive and more readily available

• Small sample (< 100)
• Findings not generalizable
• Subject withdrawals ≥ 10%
• Other limitations/explanation: Not generalizable to those patients who become neutropenic or patients with non-solid tumors. Potentially some bias as there was self-reporting of oral intake versus an objective measure. Attrition rate 16% (failure to follow through with monitoring, interruption of the intervention)

This study does not support the use of Plantago major or chlorhexidine mouthwashes over double doses of sodium bicarbonate 5% aqueous solution.

To demonstrate the benefits and tolerance of a multicomponent herbal oral agent for mucositis in patients with head and neck cancer receiving radiation or combination therapy

Orasol plus solution (a mixture of lapacho, hyaluronic acid, green tea, calendula, erisiom, propolis, marigold, plantain, and mauve) was administered to patients from the first day of radiotherapy until the end of therapy. It was given at a dose of 10 ml three times daily. The authors indicated that it can be swallowed, but did not state how patients were instructed to use it.

• N = 40
• AGE = 70% were older than 60 years
• MALES: 68%, FEMALES: 32%
• KEY DISEASE CHARACTERISTICS: Patients had head and neck cancer. The primary site of cancer was the oral cavity in 30% of patients and the hypopharynx in 30%. In addition, 72.5% were getting radiation only, and the rest were getting radiation and chemotherapy
• OTHER KEY SAMPLE CHARACTERISTICS: Thirty-five percent were current smokers.

• SITE: Single site  
• SETTING TYPE: Not specified  
• LOCATION: Italy

• PHASE OF CARE: Active antitumor treatment

• Phase II prospective trial

• Common Terminology Criteria for Adverse Effects (CTCAE) version 4

Of the patients, 47.5% developed grade 1, 27.5% developed grade 2, and 10% developed grade 3 mucositis. Median Gy doses to the oral mucosa were lowest in those with grade 1 mucositis. Six patients did not develop mucositis. None of these patients was receiving radiation and chemotherapy. The prevalence of grade 2 or greater mucositis was higher among smokers (p < 0.02). One patient developed itching and one developed glossitis. Twenty-five percent needed an increase in dosage or additional analgesic therapy.

The herbal nutritional supplement tested here may have some benefit for the prevention of severe mucositis in patients with head and neck cancer during therapy. Additional research is needed to establish any benefit.

• Small sample (< 100)
• Baseline sample/group differences of import
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• No information is given regarding patient adherence to use. The sample was too small for subgroup analysis for those getting combination chemoradiation therapy.

Very few interventions have been shown to be effective for the prevention and treatment of oral mucositis in patients receiving cancer treatment. The substance tested here appeared safe, and findings suggest that it may be beneficial; however, numerous study design limitations exist. Further research with this agent is needed to determine efficacy.

To evaluate the efficacy and safety of Kangfuxin solution, a pure Chinese herbal medicine, on mucositis induced by chemo/radiotherapy in patients with nasopharyngeal carcinoma

The treatment patients gargled three times a day after each meal. Patients were monitored from the first day of chemotherapy or radiotherapy until the emergence of grade 3 oral mucositis or when the patients finished the entire course of radiotherapy using the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Oral mucositis and pain were measured according to guidelines.

• N = 215   
• AGE = 46.3 years (SD = 11)  
• MALES: 62 (28.8%), FEMALES: 153 (71.2%) 
• CURRENT TREATMENT: Combination radiation and chemotherapy
• KEY DISEASE CHARACTERISTICS: Nasopharyngeal carcinoma

• SITE: Multi-site   
• SETTING TYPE: Inpatient    
• LOCATION: China

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care

Randomized, parallel-group clinical trial

• CTCAE, version 3.0 
• Verbal rating scale (VRS) 
• Karnofsky Performance Scale

Kangfuxin solution reduced the incidence of all levels of mucositis, especially high-grade mucositis, to improve patients' tolerance to radiation, ensuring the continuity of radiotherapy. So, it demonstrated its superiority to compound borax gargle on mucositis induced by chemo/radiotherapy.

• Small sample (< 100)
• Risk of bias (no blinding)
• Control intervention not standard

Kangfuxin solution effectively prevented chemo/radiotherapy-induced oral mucositis, reduced the incidence of upper gastrointestinal inflammation, and decreased the severity of oral pain compared with compound borax gargle. It improves the quality of life in patients. Additional research to confirm the effects is warranted.

To test the effectiveness of four natural compounds (propolis, aloe vera, calendula, and chamomile) in the prevention of acute mucositis during chemoradiotherapy for head and neck cancer.

The patients were randomized to receive a mixture of the natural ingredients or placebo. All patients received dental and nutritional evaluations and were allowed to use standard supportive care such as baking soda mouth rinses, NSAIDs, opioids, and IV hydration. The placebo had the same volume, color, flavor, and density as the experimental solution. The pharmacist who dispensed the study drugs managed the randomization list. Patients were instructed to rinse with 7 ml four times per day (before each meal and RT) during weekdays and before each meal (three times per day) on weekends. Weekly interviews were conducted along with a physical examination, including visual inspection of the oral cavity and the oropharynx, by a nurse and a radiation oncologist. Body weight, objective mucositis, pain control, and dysphagia were assessed during these visits.

• N = 104   
• AGE: median = 57 years
• MALES (%): 86.45  
• FEMALES (%): 13.55
• CURRENT TREATMENT: Combination radiation and chemotherapy
• KEY DISEASE CHARACTERISTICS: Head and neck
• OTHER KEY SAMPLE CHARACTERISTICS: Squamous cell carcinoma of the oral cavity, pharynx, or larynx. Squamous cell carcinoma in the neck of unknown primary. Previously untreated with chemotherapy or radiation therapy for head and neck cancer, good oral intake with no feeding tubes (NG or PEG) at study entry, and ECOG 0-1.

• SITE: Single site   
• SETTING TYPE: Not specified    
• LOCATION: Regina Elena National Cancer Institute, Rome, Italy

PHASE OF CARE: Active anti-tumor treatment

Phase III double-blind randomized placebo controlled; 1:1 experimental versus control

CTCAE, version 3.0, was used for grading mucositis. The Verbal Descriptor Scale was used for assessing pain. Locoregional control and OS were computed with the Kaplan-Meier method from the last day of treatment and comparison was done with the log-rank test (These were included in the secondary endpoints of the study).

No difference was noted between arms.

The prophylactic use of the natural agent combination, propolis, aloe vera, calendula, and chamomile, did not show a benefit versus placebo in the prevention of oral mucositis for patients with head and neck cancer receiving chemoradiotherapy.

This was a well-conducted single-site clinical trial.

Use of natural ingredients for supportive care in oncology is usually preferable to more expensive, hard to access pharmacologic interventions. However, if the evidence does not support their use, even natural ingredients should not be used due to potential increase costs and untoward effects. Nurses play an important role in patient and HCP education about evidence-based interventions.

To see the preventive effect of a sage tea–thyme–peppermint hydrosol oral rinse used in combination with oral care

This study aimed at discovering the preventive effect of sage tea–thyme–peppermint hydrosol oral rinse four times a day in addition to oral care (saline rinse and teeth brushing) in patients receiving chemotherapy regimens using 5-fluorouracil (5-FU). The study collected data through a patient questionnaire, the World Health Organization (WHO) Oral Toxicity Scale, oral cavity photos, and compliance checklists. The study completed assessments at 5 and 14 days after the completion of chemotherapy.

• N = 60, 30 in control group and 30 in intervention   
• MEAN AGE = intervention group: 52.6 years (SD = 8.2 years), control group: 48.7 years (SD = 10 years)
• MALES: 40%, FEMALES: 60%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Colon cancer (majority), solid tumor 
• OTHER KEY SAMPLE CHARACTERISTICS: Denture use varied in the control and intervention groups.

• SITE: Multi-site   
• SETTING TYPE: Outpatient    
• LOCATION: Ankara, Turkey

PHASE OF CARE: Active antitumor treatment

Patients receiving bolus or infusion of 5-FU chemotherapy were randomly assigned to the intervention or control group.

Measurement tools used included a patient questionnaire, the WHO Oral Toxicity Scale, oral cavity photos, and compliance checklists (self-reported by the patients).

Using kappa analysis, the kappa coefficient on day 5 was 0.98 and on day 14 was 0.85 in the intervention group. Oral mucositis in the invention group occurred in 30% of patients compared to 60% of patients in the intervention group. Grade 1 mucositis was statistically lower in the intervention group (10%) versus the control group (53.3%) on day 5 (p < 0.001). Grade 2 mucositis occurred more in the intervention group (20%) versus the control group (6.7%); on day 5, there was no statistical significance. On day 14, 93% of patients in the intervention group did not have mucositis and 96% in the control group did not have mucositis. No grade 3 or 4 mucositis occurred during this study.

Oral mucositis occurred in only 30% of the intervention group compared to 60% of the control group. The sage tea–thyme–peppermint hydrosol rinses are cost-effective, well tolerated, safe, and noninvasive. This intervention may be effective, but more randomized, controlled clinical trials of different types of treatment, as well as larger sample sizes, are needed.

• Small sample (< 100)
• Risk of bias (no blinding)
• Lack of follow-up
• Some patient-reported data

This intervention is a low-cost, effective, and well tolerated intervention. One downside is that this hydrosol needs refrigerated, and the solution needs to be analyzed in the pharmacy for consistency. Nurses need to educate patients and reinforce the importance of oral hygiene and adherence to the schedule of oral rinsing with this solution four times a day. This intervention may be effective but needs more research and data to show its effectiveness.

To estimate the efficacy of traditional Chinese medicine (Chining decoction, CHIN) for radiation-induced oral mucositis in patients with head and neck cancer.

70 consecutive patients were randomly assigned to receive CHIN (treatment group) or recombinant human epidermal growth factor (rhEGF) spray (control group) at a 1:1 ratio in the period between May 2014 to December 2015. CHIN was administered to treatment group from the first day of radiotherapy until the completion of radiotherapy. Simultaneously, the rhEGF spray was administered to control group on the oral mucosa of the irradiated area. The clinical benefit was determined by gradation of mucositis (Common Terminology Criteria for Adverse Events, version 4.0), oral pain, and xerostomia (visual analysis scale) for each week during radiotherapy. Body mass index was evaluated before and after radiotherapy.

• N = 70   
• AGE: 17-76
• MALES: 76%  
• FEMALES: 24%
• CURRENT TREATMENT: Radiation
• KEY DISEASE CHARACTERISTICS: Head and neck cancer
• OTHER KEY SAMPLE CHARACTERISTICS: No history of oral ulcer and salivary gland diseases, No history of anti-tumor therapies.

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

PHASE OF CARE: Active anti-tumor treatment

Prospective control randomized trial

• The National Cancer Institute Common Toxicity Criteria Oral Mucositis Scale.
• Oral pain and xerostomia were assessed by the patients with the visual analysis scale (VAS).
• Body mass index (BMI) was used to assess the nutritional status of patients before and after treatment.

• Patients in the treatment group had prominent remission of oral pain and grade of mucositis on each observing point compared with those in control group (p < 0.01).
• Xerostomia was decreased notably in treatment group compared with control group (p < 0.01).
• The degrees of OM in the treatment group were 1.57 (SD = 0.51) versus 2.49 (SD = 0.7) in the control group (p < 0.01).

CHIN presented an obvious advantage in preventing radiation-induced oral mucositis compared with rhEGF spray.

• Small sample (< 100)
• Risk of bias (no control group)

To evaluate if Shaunghaubaihe tablets can prevent oral mucositis for patients with locally advanced nasopharyngeal carcinoma undergoing chemoradiotherapy.

Multi-site, randomized, double blind study of Shuanghuabaihe tablets versus placebo (four tablets, three times a day) started at the initiation of chemoradiotherapy and lasting seven weeks. Patients could stop taking the tablets if grade 3 mucositis developed.

• N = 240   
• AGE: 18-70 years old 
• MALES: 70% (intervention) and 63.03% (placebo)  
• FEMALES: 30% (intervention) and 36.97% (placebo)
• CURRENT TREATMENT: Combination radiation and chemotherapy
• KEY DISEASE CHARACTERISTICS: Nasopharyngeal carcinoma

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: China

PHASE OF CARE: Active anti-tumor treatment

RCT. Patients age 18-70 years with locally advanced nasopharygeal carcinoma randomly assigned to receive Shaunghaubaihe tablets or a placebo, starting at the initiation of chemoradiation.

The incidence of different stages of mucositis was compared using Fisher’s exact test and the 95% confidence intervals. The Kaplan-Meier method was used to estimate the median time of the occurrence of OM (latency). To compare latency, the Cox proportional hazard model was used for hazard ratio (HR) and 95% CI values. One-way ANOVA and Fisher’s exact were used to compare toxicities and secondary efficacy endpoints. All data was analyzed using SAS, version 9.2, software.

Shaunghaubaihe tablets significantly reduced the incidence, latency, and severity of oral mucositis in patients with nasopharyngeal cancer.

Two patients from placebo and eight from treatment arm did not complete the entire course of radiation therapy. This is an initial study and further clinical study is needed to evaluate and verify therapeutic effects.

Therapeutic agents that prevent oral mucositis are needed because systemic oral care alone is insufficient.