Herbal Medicine for Oral Mucositis Induced by Chemoradiation Therapy: A Systematic Review and Meta-analysis
Article information
Abstract
Background:
This systematic review evaluated the therapeutic and preventive effects of herbal medicines on chemoradiation-induced oral mucositis (OM).
Methods:
Randomized controlled trials sourced from nine electronic databases that evaluated the effectiveness of herbal medicine for OM caused by chemoradiation therapy were included. Risk-of-bias assessment and meta-analysis were conducted for selected studies.
Results:
This review included 63 studies involving 5,052 patients. In the meta-analysis, herbal medicine treatment significantly decreased the incidence of OM compared with the control group (n=1670; random-effects OR: 0.28, 95% CI 0.21-0.37, p<0.00001; heterogeneity I²=15%) and significantly improved the total effective rate compared with the control group (n=2874; random-effects OR: 5.10, 95% CI 3.73 -6.97, p<0.00001; heterogeneity I²=33%). Furthermore, despite high heterogeneity among studies, the herbal treatment group showed significant effects on the degree, duration, and area of OM.
Conclusion:
Herbal medicines may reduce the incidence of oral mucositis and improve the total effective rate in individuals undergoing cancer treatment. Therefore, herbal medicines may be used to prevent and manage OM during cancer therapy. However, conclusive interpretation is limited by the quality of evidence and heterogeneity among included studies. Further well-designed studies are required.
I. Introduction
Oral mucositis (OM) is a common complication that is difficult to prevent in patients undergoing systemic chemotherapy or radiation therapy to the head and neck region1. Depending on the dose and cytotoxicity of the medicine, approximately 20% to 40% of solid tumor patients receiving chemotherapy are affected by oral mucositis2. Almost all patients receiving radiation therapy for head and neck cancer develop oral mucositis3.
Oral mucositis not only causes severe pain in many patients, resulting in poor quality of life, but it is also a clinically important disease as a high-risk factor for sepsis in cancer patients with neutropenia. In some patients, oral mucositis either prevents them from receiving an appropriate dose of chemotherapy or forces them to cancel or delay their planned treatment. In addition, the reduction in oral nutritional intake as a result of pain leads to a higher demand for intravenous feeding, seriously impacting patients by increasing the risk of systemic infection, prolonging hospitalization, and adding to the costs of treatment4.
In the past, mucositis was thought to result only from damage to basal epithelial cells caused by chemotherapy or radiation. The pathogenesis is now understood to be much more complex, involving the generation of damaging reactive oxygen species, activation of transcription factors such as nuclear factor-κB, inflammatory pathways such as the cyclooxygenase pathway, and the upregulation of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin(IL)-1β5.
In terms of treatment, previously, the focus was on pain control after oral mucositis had occurred. Several treatment methods including debridement, disinfection, topical or systemic analgesics, and control of bleeding have been introduced to treat oral mucositis. Many agents, such as allopurinol, chlorhexidine, diphenhydramine, aluminum hydroxide, and palifermin, have been used to prevent or alleviate oral mucositis6. However, it is currently unclear which treatment is effective against oral mucositis that has already occurred in patients who have received standard chemotherapy7. Since oral mucositis is caused by the cytotoxicity of anticancer treatment, there has been significant interest in the use of natural compounds perceived to have fewer side effects than synthetic medicines8.
As the interest in natural compounds increases, the number of patients seeking herbal medicine to prevent or treat oral mucositis induced by chemoradiation therapy is rising. A previous study shows that herbal medicine has anti-inflammatory and analgesic efficacy and is effective for oral mucositis9. Herbal medicine contains antioxidants that reduce the production of reactive oxygen species, thereby reducing mucositis10.
As studies on the effects of herbal medicines on chemoradiation-induced oral mucositis have progressed, several systematic reviews have also been reported. However, most systematic reviews include only studies that have been published in the English language. This study aimed to conduct a literature review focused on East Asia, where the use of herbal medicine complexes is prevalent, in order to evaluate the therapeutic and preventive effects of herbal medicine on chemoradiation-induced oral mucositis through research without any language restrictions.
II. Methods
1. Study Registration
This systematic review with meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines 2020 state. The protocol for this study was registered with PROSPERO prior to conducting the review. (University of York, Centre for Reviews and Dissemination, York, UK. Registration number: CRD42024566397)
2. Search Strategy
A comprehensive literature search was performed on nine electronic databases from inception to November 2025, using search terms including “Oral mucositis,” “Stomatitis,” “Cancer,” “Chemotherapy,” “Radiotherapy,” and “Herbal medicine.” Detailed search strategies are prescribed in Appendix 1. A list of databases is presented in Table 1.
Databases Used in Systematic Literature Search
3. Criteria for inclusion and exclusion
1) Types of studies
Only randomized controlled trials (RCTs) in humans were included in this study. Other designs such as experimental studies, case reports, or retrospective studies were excluded. No restrictions were placed on language and time to minimize publication bias.
2) Types of patients
The included studies involved patients with oral mucositis induced by chemotherapy or radiotherapy, without restrictions on sex, race, nationality, age, or type of cancer. Studies involving oral mucositis unrelated to chemotherapy or radiotherapy were excluded.
3) Types of interventions
All types of herbal medicine (e.g., decoctions, granules, powders, oral liquids, tablets, and pills) were included. The routes of administration for the herbal medicine were limited to oral intake or gargling. Studies confirming the composition of herbal medicine were included, even in cases where the components could be identified because they were produced by pharmaceutical companies. Studies in which the composition of herbal medicine could not be verified were excluded. Studies in which supplementary interventions, such as lidocaine, Amphotericin B, or laser, were performed in conjunction with herbal medicine, were excluded. However, cases in which additional interventions were identical to those of the control group were also included.
4) Types of control groups
The control groups included placebo or conventional treatment for oral mucositis. Conventional treatments included routine oral care, mouthwashes, or pharmacological agents commonly used for the prevention or management of oral mucositis. Studies in which the control group received the same co-interventions as the intervention group, except for the herbal medicine, were included. Studies comparing different types of herbal medicine without a non-herbal control group were excluded.
5) Types of outcome measurements
The primary outcomes were the incidence of oral mucositis and the total effective rate (TER). In the case of the total effective rate, the standards for each study were slightly different. In the majority of studies, the severity of oral mucositis was evaluated by the World Health Organization (WHO) scale and the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). Furthermore, this study assessed various outcomes, including the degree of oral mucositis pain, and duration of oral mucositis.
As a secondary outcome, adverse events (AEs) that were reported in the studies were analyzed.
4. Study Selection and Data Extraction
Two researchers independently conducted searches within the database to identify studies that met the inclusion criteria. After elimination of duplicates, the initial screening process was based on the titles and abstracts of all articles retrieved from each database search. Following the initial screening, the full text of articles was reviewed. The initial data extraction was first conducted by one researcher, followed by a review of the extracted data by another researcher. Any disagreement between the two researchers was resolved by discussion.
5. Risk of Bias Assessment
Two researchers assessed the risk of bias to confirm the validity of the included RCTs. Version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2) was used to evaluate the risk of bias. Two researchers performed a risk of bias assessment using the above program, and any disagreement between the two researchers was resolved by discussion. They evaluated five domains for each study - randomization process, deviations from the intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result - scoring each domain as high risk, some concerns, or low risk.
6. Data analysis
A meta-analysis was performed using Review Manager version 5.4 when there were more than five studies reporting the same outcome measure. Since the design of the included studies was inconsistent, the random-effect model was used for data analysis. Odds ratios (ORs) with two-sided 95% confidence intervals (CIs) were calculated for dichotomous outcomes. Mean differences (MDs) with 95% CIs were calculated for continuous outcomes. When the same outcome was evaluated using different measurements, the intervention impact was expressed using the standardized mean difference (SMD) with 95% CIs.
A chi-square test and Higgins I2 statistics were used to assess the statistical heterogeneity among the included studies. The heterogeneity was considered statistically significant when the Higgins I2 reached 50% or higher. If heterogeneity was identified in the results of the meta-analysis, further analyses were performed via subgroup analyses. If there were more than ten studies included in the meta-analysis, publication bias was assessed using a funnel plot.
The evidence level for each outcome was evaluated by GRADEpro, a software for the Grading of Recommendations Assessment, Development, and Evaluation (GRADE).
III. Result
1. Search results and Study Selection
An initial study search was conducted in July 2024, followed by an update on November, 2025.
1) Initial search
A total of 1,713 studies were searched from 9 electronic databases: 249 studies in MEDLINE (via PubMed), 382 studies in EMBASE, 72 studies in Cochrane Library, 10 studies in KCI, 28 studies in RISS, 12 studies in OASIS, 308 studies in CNKI, 276 studies in Wangfang, and 89 studies in CiNii.
Excluding 354 duplicate studies, 1,359 studies were screened. After screening the titles and abstracts, a total of 1,235 studies were excluded for the following reasons: 182 were non-RCT, 101 were not human studies, 362 were not related to cancer or OM, 570 were not related to herbal medicine, 16 had inappropriate interventions, and 4 were from grey literature sources. Of the remaining 124 studies, seven were not published, and nineteen were not retrieved. Consequently, the full texts of 98 studies have been downloaded.
After reviewing the full text of the remaining studies, 38 studies were excluded for various reasons: 16 studies were not RCTs (e.g., retrospective studies), 1 study included inappropriate participants (e.g., tuberculosis), 3 studies were not related to cancer or oral mucositis, 1 study was not related to herbal medicine, 9 studies included inappropriate interventions (e.g., herbal medicine with lidocaine, chlorhexidine, vitamins, or Amphotericin B), 1 study had no information about the composition of herbal medicine, and 7 studies included inappropriate route of administration for herbal medicine (e.g., spray or application).
2) Updated search
A total of 134 studies were searched from 9 electronic databases: 42 studies in MEDLINE (via PubMed), 48 studies in EMBASE, 12 studies in Cochrane Library, one study in KCI, one study in RISS, one study in OASIS, 12 studies in CNKI, 15 studies in Wangfang, and two studies in CiNii.
According to the screening of titles and abstracts, 118 studies were excluded: 30 were non-RCT, 6 were not human studies, 57 were not related to cancer or OM, 24 were not related to herbal medicine, one was including inappropriate intervention.
Additionally, five duplicate studies identified by manual screening and unpublished two studies were excluded. Consequently, the full texts of 9 studies have been downloaded.
After reviewing the full text of studies, 6 studies were excluded for the following reasons: five studies were not related to herbal medicine, and one study included inappropriate route of administration for herbal medicine.
In total, combining the initial and updated searches, 63 studies were finally selected. The study selection process was summarized using the PRISMA flow diagram (Fig. 1).
PRISMA flow diagram of the study selection process.
KCI : Korea Citation Index, RISS : Research Information Service System, OASIS : Oriental Medicine Advanced Searching Integrated System, CNKI : Chinese National Knowledge Infrastructure Database, CiNii : Citation Information by NII, RCT : Randomized Controlled Trial, OM : Oral Mucositis
2. Selected Studies Analysis
A total of 57 studies were published in China, while 6 studies were published in Japan. In terms of publication language, 9 studies were published in English, 53 in Chinese, and 1 in Japanese. All RCTs included in this study were published between 1997 and 2024. A total of 5,052 patients undergoing chemoradiation therapy were included in this study. There were 47 studies on oral mucositis caused by chemotherapy, 7 studies caused by radiation therapy (RT), and 7 studies caused by combined chemoradiation therapy (CCRT). The two studies evaluated the CT and RT groups independently.
Out of all the studies included, 48 investigated herbal medicine monotherapy, while 15 investigated herbal medicine combined therapy with Western medicine. All Western medicine, including antibiotics, lidocaine, chlorhexidine, vitamins, granulocyte colony- stimulating factor (G-CSF), and over-the-counter medicines, was used in the same manner as the control group.
Within the treatment group, the administration route of herbal medicine included 28 studies on oral intake, 26 on gargling, and 9 on intake after gargling. The duration of the treatment periods in the studies varied between three days and seven weeks. Detailed information on the selected studies is presented in Table 2 and Appendix 2.
General Characteristics of the Selected Studies
3. Risk of Bias
All 63 included studies were evaluated for the risk of bias, and the results are visualized in Fig. 2 and summarized in Fig. 3.
Summary of the risk of bias for all included studies.
Risk of bias graph for all included studies.
1) Risk of bias arising from the randomization process
A total of 31 studies described the methods for generating random sequences, such as computer-generated random numbers, random number tables, the envelope method, lot-drawing, and coin flipping. Among these, 8 studies that mentioned concealment of allocation were judged as low risk in domain 1; however, 23 were judged as some concern because there was no information of concealment of allocation. Due to using the allocation method based on the order of admission or patient characteristics, two studies were judged as some concern of bias. The remaining 30 studies, where there was no information on the randomization method, were also judged as some concerns in domain 1.
2) Risk of bias due to deviations from the intended interventions
In 24 studies, the risk of bias was evaluated as low when the blinding method of intervention was mentioned or a placebo was used. The 39 remaining studies, in which the intervention between two groups was so different that the participants or the researchers could recognize this difference (e.g., herbal decoction vs no intervention), were evaluated as some concern.
3) Risk of bias due to missing outcome data
In 55 studies where no participants were eliminated, or where the number of remaining patients is lower than the calculated sample size required for analysis, the risk of bias was evaluated as low. Eight studies were evaluated as high risk, as the number of patients required was not calculated and measurements that were not available for all participants were used.
4) Risk of bias in measurement of the outcome
In most studies, appropriate measurement methods were used according to the outcomes, and the measurements were not significantly affected by blinding. Therefore, there were low risks of bias in domain 4.
5) Risk of bias in selection of the reported result
Except for four studies, most of the studies in domain 5 were evaluated as some concerns due to a lack of a pre-registered protocol.
4. Outcome Measurements
1) Incidence of oral mucositis
A total of 23 studies that evaluated the incidence of oral mucositis or the maximum grade of oral mucositis that occurred were included. The severity of oral mucositis was evaluated using the WHO scale and NCI-CTCAE in most studies, while the Radiation Therapy Oncology Group (RTOG) criteria 2.0 was used in one study.
Among the included studies, 16 studies evaluated the incidence of oral mucositis across all grades (grade Ⅰ to Ⅳ). Five studies reported the overall incidence of oral mucositis without stratification by grade, while two studies reported only the incidence of severe oral mucositis (grade Ⅲ or Ⅳ). Consequently, 21 studies were included in the analysis of OM incidence of grade Ⅰ or higher, and 18 studies were included in the analysis of severe OM incidence (grade Ⅲ or Ⅳ).
In the incidence of grade Ⅰ or higher oral mucositis, data from 841 participants in the treatment group and 829 in the control group were synthesized. As a result, the herbal treatment group had a 0.28-fold lower incidence of oral mucositis after chemoradiation therapy compared to the control group, and this difference was statistically significant (OR 0.28, 95% CI 0.21 to 0.37, p<0.00001). Furthermore, the heterogeneity between studies was low (Heterogeneity: Chi2=23.44, p=0.27; I2=15%)(Fig. 4).
Forest plot for incidence of oral mucositis.
In the incidence of grade Ⅲ or Ⅳ severe oral mucositis, data from 852 participants in the treatment group and 843 in the control group were synthesized. As a result, the herbal treatment group had a 0.16-fold lower incidence of severe oral mucositis than the control group, and this difference was statistically significant (OR 0.16, 95% CI 0.11 to 0.22, p<0.00001). Also, the heterogeneity between studies was low (Heterogeneity: Chi2=12.40, p=0.78, I2=0%) (Fig. 4).
2) Total effective rate
Overall, 38 studies used the total effective rate to describe clinical effectiveness based on the clinical symptoms and signs of oral mucositis. The total effective rate was defined as the proportion of patients classified as having a therapeutic response according to the criteria used in each included study. For the purpose of meta-analysis, TER was analyzed as a dichotomous outcome by combining all response categories defined as effective in the included studies.
Thirty-two studies showed the TER by classifying them into three stages: ‘markedly effective,’ ‘effective,’ and ‘ineffective,’ while 6 studies showed the TER by classifying them into four stages: ‘totally healed,’ ‘markedly effective, ‘effective,’ and ‘ineffective.’
Data from 1,463 participants in the treatment group and 1,411 in the control group were synthesized in 38 studies. As a result, the herbal treatment group had a 5.10-fold higher total effective rate than the control group, and this difference was statistically significant (OR 5.10, 95% CI 3.73 to 6.97, p <0.00001). Additionally, the heterogeneity among studies was found to be low (Heterogeneity: Chi2=55.14, p=0.03, I2=33%) (Fig. 5).
Forest plot for total effective rate of oral mucositis.
3) Degree of oral mucositis pain
A total of 20 studies presented the degree of pain in oral mucositis. Among these, 13 studies evaluated the mean and standard deviation (SD) of the visual analogue scale (VAS) of pain before and after treatment, which were included in the meta-analysis. Substantial heterogeneity was observed among the included studies. Therefore, a subgroup analysis was conducted. Of the 13 studies examined, 8 focused on herbal medicine monotherapy, while the remaining 5 explored herbal medicine combined therapy with Western medicine.
In monotherapy subgroup of herbal medicine, data from 323 participants in the treatment group and 322 in the control group were synthesized in 8 studies. As a result, the pain VAS after intervention in the herbal treatment group showed a reduction of 1.37mm compared to the control group, with a statistically significant difference (MD -1.37, 95% CI -1.65 to -1.09, p <0.00001). There was a high level of heterogeneity among the studies (Heterogeneity: Chi2=201.46, p <0.00001, I2=97%) as shown in Fig. 6.
Forest plot for pain of oral mucositis.
In herbal medicine combined subgroup, data from 166 participants in the treatment group and also 166 in the control group were synthesized from 5 studies. As a result, the pain VAS after intervention in the herbal treatment group showed a reduction of 1.64mm compared to the control group, indicating a statistically significant difference (MD -1.64, 95% CI -2.03 to -1.24, p <0.00001). The heterogeneity among the studies was high (Heterogeneity: Chi2=11.84, p=0.02, I2=66%) (Fig. 6).
The seven studies that were excluded from the meta-analysis are listed below:
(1) In one study, oral pain scores during the course of treatment were recorded according to CTCAE 3.0 criteria and visualized as a graph. The area under the curve of the graph for each of the two groups was calculated and compared.
(2) In a study, pain scores were calculated in quartiles according to the duration of treatment.
(3) In four studies, the VAS of pain was categorized into three levels: mild (VAS 1-3), moderate (VAS 4-6), and severe (VAS 7-9).
(4) In a study, the mean and SD of the change in pain scores before and after treatment were documented.
In each of the seven studies, the herbal medicine group showed a significant decrease in oral mucositis-related pain in comparison to the control group.
4) Duration of oral mucositis
A total of 21 studies presented the duration of oral mucositis. Among these, 17 studies that evaluated the mean and SD of oral mucositis duration during the treatment were included in the meta-analysis.
Data from 534 participants in the treatment group and 547 in the control group were synthesized in 17 studies. As a result, the duration of oral mucositis during treatment in the herbal treatment group was 2.76 days shorter than that of the control group, with a statistically significant difference (SMD -2.76, 95% CI -3.45 to -2.07, p <0.00001). There was a significant level of heterogeneity among the studies (Heterogeneity: Chi2=278.93, p <0.00001, I2=94%) (Fig. 7).
Forest plot for duration of oral mucositis.
Four studies were excluded from the meta-analysis because they reported only means or medians of the duration of OM without accompanying SD. Nevertheless, all four studies consistently showed a significantly shorter duration of oral mucositis in the herbal medicine group compared to the control group.
5. Adverse events
Among the 63 studies included in this review, AEs were reported in 18 studies. Of these, 11 studies reported no clinically significant AEs in either the treatment or control groups.
The remaining seven studies reported AEs and were grouped according to the type of control intervention to facilitate interpretation of whether reported events were related to the intervention.
Two studies compared herbal medicine with OTC gargle interventions. In one study, there was vomiting and mild elevation of liver function only in the treatment group, which resolved after stopping the intervention. In another study, one gastrointestinal AE was reported in the treatment group, along with three gastrointestinal AEs, two cases of liver or kidney dysfunction, and two cases of phlebitis in the control group.
Five studies compared herbal medicine with placebo controls. In these studies, hematologic, gastrointestinal, and dermatologic adverse events were reported in both the treatment and placebo groups. These adverse events were considered unrelated to the study interventions and were instead attributed to the cytotoxicity of the anti-cancer treatments. No severe AEs were reported in any of the placebo-controlled trials.
6. Publication bias
Funnel plot analysis was conducted to explore the potential publication bias for outcomes that were commonly reported in more than 10 studies. The funnel plot for the incidence of OM, TER, and duration of OM is shown in Fig. 8. In the funnel plot for duration of OM (Fig. 8-c), publication bias could not be excluded completely.
Funnel plot for each outcome
(a) Incidence of oral mucositis; (b) Total effective rate; (c) duration of oral mucositis
7. Subgroup analyses
In the incidence of OM and TER, additional analysis was not required due to no significant heterogeneity.
Subgroup analyses were conducted on the pain of OM based on the initial level of pain, whether the herbal treatment was monotherapy or combined therapy, and the type of anti-cancer treatment. The subgroup analysis based on whether the herbal treatment was monotherapy or combined therapy was reported, showing a slight improvement in heterogeneity, although it still remains high.
In duration of OM, subgroup analysis based on whether the herbal treatment was monotherapy or combined therapy is used was done. The subgroup analysis also showed high heterogeneity; therefore, it was not reported.
8. Summary of findings
Table 3 lists the GRADE evidence profile in detail.
The level of evidence for the results in this meta-analysis
1) Since all included studies were RCTs, the levels of evidence were not lowered in the study design area.
2) In the area of risk of bias, if studies with some concerns regarding evaluation results in the RoB 2 tool were included, the level of evidence judged as serious; and if studies with high risk of bias were included, the level of evidence judged as very serious. Therefore, the grade of OM incidence, TER, and duration of OM were judged to be very serious, while the grades of pain was judged as serious.
3) The inconsistency area was evaluated as heterogeneity between studies using the Higgins I2 statistic. The criteria for evaluation are as follows: I2<50% means the levels of inconsistency were not lowered, 50%≤I2<75% means it was lowered by one level, and I2≥75% means it was lowered by two levels. Therefore, the grades of OM incidence and TER were judged as not serious, while the grades of pain, and duration of OM were judged as very serious.
4) In the indirectness area, the grades of objective measurements such as incidence, and duration of oral mucositis were not lowered, while subjective measurements such as TER and pain of oral mucositis were lowered by one level.
5) In the imprecision area, most outcomes with more than 400 participants did not lower the evidence level. However, in the pain of OM, the grade was lowered by one level due to the number of participants being less than 400.
6) In the area of other considerations, all outcomes were evaluated to not be lowered except for the duration of OM. In the duration of OM, the grade was lowered due to strong suspicion of publication bias.
Due to the high risk of bias and heterogeneity, all outcomes were evaluated as low or very low quality.
9. Analysis of herbal medicine prescriptions
Several studies have been modified to align with clinical symptoms, which is the unique property of herbal medicines. For analyses of herbal medicines in this study, the standard prescription compositions were extracted. Appendix 3 presents the composition of the herbal medicines used in each included study.
The Gancao Xiexin decoction (甘草瀉心湯) was mentioned 8 times as frequently used prescription in the studies, followed by Hangeshashinto (半夏瀉心湯) six times and Yingyuan Gancao Decoction (銀花甘草湯) three times. All studies on Gancao Xiexin decoction (甘草瀉心湯) and Yingyuan Gancao Decoction (銀花甘草湯) were exclusively conducted in China and published in Chinese, while studies on Hangeshashinto (半夏瀉心湯) were conducted in Japan, with 5 publications in English and 1 in Japanese.
The ten most frequently used herbs in the studies were as follows: Glycyrrhizae Radix et Rhizoma (甘草) was used 39 times, Coptidis Rhizoma (黃連) 28 times, Scutellariae Radix (黃芩) 22 times, Lonicerae Flos (金銀花) 20 times, Rehmanniae Radix (地黃) 17 times, Pinelliae Tuber (半夏) and Zizyphi Fructus (大棗) 15 times each, Forsythiae Fructus (連翹) and Zingiberis Rhizoma Recens (生薑) 14 times each, and Phellodendri Cortex (黃柏) 12 times.
IV. Discussion
This systematic review and meta-analysis demonstrated that herbal medicine significantly reduced the incidence and severity of chemoradiation-induced oral mucositis, while also improving pain and duration without clinically significant adverse events. These findings should be interpreted within the current understanding that oral mucositis is a complex, multifactorial process involving not only direct epithelial injury but also microvascular damage and inflammatory cascades. In particular, apoptosis of vascular endothelial cells74 and the subsequent upregulation of proinflammatory cytokines such as TNF-α, IL-1, and IL-675 are considered key events in the initiation and amplification of mucosal injury. Considering that the primary outcomes reflect both the onset and progression, these clinical benefits suggest that herbal medicine may modulate these underlying pathogenic pathways. These mechanisms may also be related to oxidative stress induced by chemoradiation, which has been suggested to contribute to the initiation of mucosal injury76.
Among the included studies, Gancao Xiexin decoction (甘草瀉心湯) and Hangeshashinto (半夏瀉心湯) were the most frequently used prescriptions, appearing eight and six times, respectively. Although these prescriptions are distinct, they share several key herbal components, including Coptidis Rhizoma (黃連), Scutellariae Radix (黃芩), and Pinelliae Tuber (半夏). In East Asian medicine, these herbs are commonly classified as having heat-clearing (淸熱) properties, a concept that is often associated with anti-inflammatory and antioxidant effects in contemporary biomedical research.
Previous experimental studies have suggested that Coptidis rhizome (黃連) is involved in immune regulation through modulation of T-cell subtypes and interleukin expression77. In addition, the compositions of Scutellariae Radix (黃芩) and Coptidis rhizome (黃連) have been reported to exert anti-inflammatory and anti-oxidative stress effects78. Pinelliae Tuber (半夏) has also been shown to contain numerous bioactive compounds with diverse pharmacological activities, including anti-inflammatory, antioxidant, and anticancer effects79. Overall, the shared bioactive components among these frequently used prescriptions may help explain the preventive and therapeutic effects observed.
Previous systematic reviews have also examined the efficacy of herbal interventions for chemoradiation-induced oral mucositis, although their scope and methodological approaches differed from the present study. One earlier review, published in 2013, focused on individual Chinese herbal medicines across chemotherapy induced oral mucositis studies, assessing clinical effectiveness primarily using TER80. However, due to heterogeneity in study designs and the wide variety of herbal components, the authors did not perform a meta-analysis, highlighting concerns regarding risk of bias and the limited applicability of findings to standardized clinical prescriptions. Another, more recent review published in 2025 specifically evaluated studies using modified Xiexin decoction (加減瀉心湯), considering outcomes such as incidence, TER, and symptom scores including TCM symptom score, NRS, and VAS81. While this review provided quantitative synthesis for a single prescription, its scope was restricted to a single formula and did not encompass the broader range of herbal prescriptions commonly used in East Asian clinical practice.
In comparison, the present study integrates data from 63 RCTs using multiple herbal prescriptions, assessing both preventive and therapeutic outcomes, including incidence, TER, pain, and duration of oral mucositis. This broader scope allows for a more comprehensive evaluation of the clinical utility of herbal medicine in chemoradiation-induced oral mucositis, while also enabling preliminary insights into the potential mechanisms associated with frequently used prescriptions and shared bioactive components. The findings of the current meta-analysis thus complement and extend previous evidence by combining quantitative synthesis with prescription-level analysis, providing a more clinically applicable overview of herbal medicine interventions in East Asian contexts.
The incidence of oral mucositis after herbal medicine intervention can be considered a preventive effect, whereas improvements in TER, pain, and duration may reflect therapeutic effects after mucositis onset.
In this study, herbal medicine significantly reduced the incidence of overall oral mucositis and, notably, the incidence of severe oral mucositis of Grade III or Ⅳ was 16% lower than that in control group. Considering that severe oral mucositis often leads to dose reduction or delay of subsequent chemotherapy, even a relatively modest reduction like 5-15% in incidence may have substantial clinical implications7. Therefore, the observed preventive effect of herbal medicine against severe oral mucositis is of great clinical significance.
With respect to therapeutic outcomes, the herbal medicine group showed a significantly higher TER and showed meaningful improvements in pain intensity and duration of oral mucositis compared with the control group. Although substantial heterogeneity was observed in the meta-analyses of pain and duration, all included studies consistently reported favorable outcomes in the herbal medicine group. The magnitude of pain reduction, as measured by the VAS, ranged from approximately 1.4 to 1.6mm, indicating clinically meaningful alleviation of oral mucositis related discomfort. However, the timing of herbal medicine administration was not uniformly reported across studies, which should be considered when interpreting the distinction between preventive and therapeutic effects. The overall consistency of directionality across outcomes supports the potential role of herbal medicine in both the prevention and management of chemoradiation-induced oral mucositis.
This systematic review and meta-analysis has several limitations that should be considered when interpreting the results.
First, a substantial proportion of the included studies were conducted in China and published in Chinese. Although no language restrictions were applied to minimize publication bias, this regional concentration may limit the generalizability of the findings to other populations and healthcare settings.
Second, the methodological quality of the included studies was generally low. Many studies did not clearly report key aspects of trial design, such as allocation concealment, blinding of participants or outcome assessors, and pre-registered study protocols. As reflected in the risk-of-bias assessment and GRADE evaluation, these limitations resulted in low or very low certainty of evidence for most outcomes. Therefore, the observed effects should be interpreted with caution.
Third, considerable heterogeneity was observed in outcomes related to pain intensity and duration of oral mucositis. This heterogeneity may be attributable to variations in outcome assessment methods (e.g., different pain scales or grading systems), patient characteristics (such as cancer type and treatment modality), and differences in herbal medicine compositions, dosage forms, and duration of administration across studies. Although subgroup analyses were conducted to explore potential sources of heterogeneity, substantial heterogeneity remained, limiting the robustness of pooled estimates.
Finally, there was marked variability in the composition and clinical application of herbal medicine interventions. Because this review aimed to comprehensively evaluate the potential of herbal medicine for chemoradiation-induced oral mucositis, no restrictions were placed on specific prescriptions. While this approach reflects real clinical practice, it also hinders the identification of standardized treatment strategies. Future well-designed randomized controlled trials using standardized herbal interventions are warranted to strengthen the evidence.
This study provides comprehensive evidence suggesting that herbal medicine may have both preventive and therapeutic benefits for chemoradiation-induced oral mucositis. By considering clinical outcomes alongside commonly used prescriptions and findings from previous preclinical studies, this study offers insights into the potential role of herbal medicine as a complementary approach in the management of oral mucositis. Further rigorously designed randomized controlled trials with standardized interventions are needed to confirm these findings and to establish optimal clinical strategies.
