The efficacy of herbal medicine in the management of oral stomatitis in head and neck cancer patients undergoing radiotherapy: A systematic review

Abstract

Radiotherapy for head-and-neck cancer (HNC) frequently causes oral mucositis, a painful and debilitating condition often leading to treatment interruption, poor quality of life, and increased healthcare costs. Various herbal medicines such as Glycyrrhiza glabra (Yashtimadhu), Plantago major L. syrup, green tea mouthwash, and Hangeshashinto have been proposed for studies to explore the possibility of alleviating radiation-induced oral mucositis, with promising results serving as alternatives to conventional medication. This review assesses the effectiveness of Herbal preparations such as G. glabra (Yashtimadhu), P. major L., and traditional Chinese formulations like Chining decoction and Hangeshashinto which have shown promise in both preclinical and clinical studies in reducing the risk and impact of oral mucositis under radiation therapy. The results showed a wide variation in the efficacy of herbal treatments. Herbal medicine offers a promising adjunctive approach in the management of oral mucositis resulting from radiation therapy for HNC. Of all of these, Yashtimadhu, P. major, and Hangeshashinto were identified to demonstrate potential with statistically significant efficacy in reducing mucositis severity.

INTRODUCTION

Radiotherapy plays a crucial role. In treating head-and-neck cancer (HNC), providing local control and enhancing survival outcomes. Despite its benefits, radiotherapy often leads to oral mucositis, a debilitating side effect characterized by painful oral ulcers, inflammation, and swelling. In cases of HNCs, around 85%–100% are undergoing radiotherapy and developing some degree of mucositis, with up to 34% developing severe, Grade 3 or 4 mucositis.[1,2] This condition not only impacts the patient’s ability to eat, drink, and speak, moreover it also contributes to weight loss, malnutrition, and increased risks for infection.[3] Furthermore, severe cases of mucositis often require dose reductions or interruptions in radiotherapy, which may compromise treatment outcomes.[4]

Radiation-induced oral mucositis arises from a dynamic interplay between direct radiation effects and indirect cellular and molecular mechanisms, including damage to the basal epithelium and inflammation-mediated immune responses. The release of cytokines, including tumor necrosis factor-alpha and interleukins, exacerbates the injury and contributes to the disintegration of the epithelial layer.[5] Despite advances in supportive care, current treatment options for oral mucositis are largely palliative, including basic oral hygiene, pain management, and nutritional support.[6] This has driven research into alternative therapeutic strategies that could not only manage symptoms but also prevent the onset of severe mucositis.

There is growing interest in herbal medicine as a complementary approach to alleviate radiation-induced mucositis. Herbal preparations such as Glycyrrhiza glabra (Yashtimadhu), Plantago major L., and traditional Chinese formulations like Chining decoction and Hangeshashinto have shown promise in both preclinical and clinical studies.[1,2,3,4] The effects on inflammation, oxidation, and wound healing of these herbal remedies may provide protective benefits against radiation-induced mucosal injury. Research has shown that Yashtimadhu helps in lowering the risk of severe Grade 3 mucositis in patients with HNCs, whereas Plantago has been found effective to decrease both mucosal damage and related pain syndrome.[1,6]

However, despite the potential of these herbal interventions, the existing literature is characterized by small sample sizes and heterogeneous study designs. The consequence has been a persistent lack of large-scale, robust evidence to recommend the routine use of herbal medicines in clinical practice. This systematic review investigates how herbal interventions may contribute to reduce the incidence and severity of oral mucositis in HNC patients undergoing radiotherapy, through a critical systematic analysis of randomized controlled trials and cohort studies.

METHODS

Study design

This systematic review was conducted to evaluate the efficacy of herbal medicine in managing radiation-induced oral mucositis in HNC patients undergoing radiotherapy. The PRISMA framework guided this review to ensure transparency and rigor.

Search strategy

A thorough review of the existing literature was performed in electronic databases, including PubMed, Cochrane Library, Embase, and Google Scholar, from inception until [insert date]. Search terms were carefully chosen using the Population, Intervention, Comparison, Outcome framework. The following Boolean search strings were applied: (“head and neck cancer” OR “oropharyngeal cancer” OR “laryngeal cancer” OR “oral cancer”) AND (“radiotherapy” OR “radiation therapy”) AND (“oral mucositis” OR “oral stomatitis” OR “mouth sores”) AND (“herbal medicine” OR “phytotherapy” OR “traditional medicine” OR “natural remedies”). Hand-searching of reference lists from included studies and review articles was conducted to identify further relevant studies.

Inclusion and exclusion criteria

The following criteria were applied for the study eligibility:

• Population: Patients diagnosed with HNC undergoing radiotherapy, with radiation-induced oral mucositis as a primary or secondary outcome

• Intervention: Use of any herbal medicine or phytotherapy aimed at interventions for preventing or managing oral mucositis

• Only peer-reviewed randomized controlled trials (RCTs), cohort studies, and prospective observational designs were included

• Outcome: Primary outcomes included the severity of oral mucositis, measured using standardized scales (e.g., World Health Organization [WHO] mucositis grading scale), and other outcomes evaluated included pain relief, quality of life, and treatment interruptions. A thorough literature search was conducted in electronic databases such as PubMed and Cochrane.

Exclusion criteria were:

• Studies focused solely on chemotherapy-induced mucositis

• Case reports, review articles, conference abstracts, and letters to the editor

• Non-English language publications.

Data extraction

Two reviewers independently extracted the data. For each study, the following data were retrieved:

Study Design: Type of study (e.g., RCT, cohort study).

• Location: Geographical setting of the study

• Subjects: Number of participants, type of cancer, and treatment modality (e.g. radiotherapy)

• Intervention: Details of the herbal medicine used, including dosage, duration, and mode of administration

• Control: Description of control groups, including placebo or standard care treatments

• Outcomes: Severity of mucositis (graded according to WHO or Radiation Therapy Oncology Group scales), pain scores, treatment adherence, and adverse effects, if any.

A third reviewer facilitated the resolution of any discrepancies that arose during data extraction.

Quality assessment

The risk of bias in the selected randomized controlled trials was conducted using the Cochrane which examined:

• Generation of random allocation sequence

• Allocation masking

• Blinded trial: participants, staff, and outcome assessors

• Data loss due to participant dropout or incomplete follow-up

• Selective outcome reporting.

The quality of the cohort studies was assessed using the Newcastle-Ottawa Scale (NOS), assessing factors such as participant selection, cohort comparability, and outcome measurement.

Ethical considerations

This review did not require ethical approval.

RESULTS

Selection of studies

Following duplicate removal, 33 articles remained from the initial search yield of 50. Title and abstract screening resulted in 22 articles being selected for full-text review to determine eligibility. A total of 10 studies were selected for the systematic review after applying the predefined inclusion and exclusion criteria, including RCTs, cohort studies, and prospective observational studies published between 2015 and 2023. A PRISMA flow diagram illustrating the study selection process is presented in Figure 1.

Figure 1.

PRISMA flow diagram

Study characteristics

The selected studies were carried out across multiple countries, including India, China, Germany, Italy, Iran, Taiwan, and Japan. The number of participants in the included studies varied widely, with the smallest study having 26 participants and the largest having 561 diagnosis of HNC and undergoing radiotherapy. The interventions involved different herbal medicines, such as G. glabra (Yashtimadhu), P. major L. syrup, green tea mouthwash, and the traditional Japanese medicine Hangeshashinto (TJ-14).

Quality of studies

The quality of the randomized controlled trials (n = 7) was generally moderate to high. Three studies were judged to have minimal bias in all areas, as evaluated by the Cochrane Risk of Bias tool, while the remaining trials exhibited some risk due to unclear blinding procedures. For cohort studies (n = 3), the NOS indicated good quality, with all studies scoring 7–9 stars.

Efficacy of herbal interventions

Mucositis severity

The majority of the studies reported a statistically significant reduction in oral mucositis severity following treatment with herbal interventions. According to Mamgain et al., administration of Yashtimadhu lowered the incidence of Grade 3 mucositis from 42.85% in the standard care group to 15.5% in the intervention group (P < 0.05).[1] Similarly, Soltani et al. demonstrated that P. major L. syrup significantly reduced mucositis severity compared to the placebo group (P < 0.05), with fewer patients developing severe mucositis.[6]

Research by Li et al. (2021) revealed that traditional Chinese herbal medicine (CHM) decreased the risk of radiation-induced mucositis by 32%. However, a study by Ebert et al. (2021) found that Cystus tea and sage tea had similar effects on mucositis severity; the incidence of Grade 3 mucositis did not differ significantly between the treatment and control groups.[2]

Pain reduction

Several studies also evaluated the impact of herbal interventions on pain management. Wang et al. reported that patients receiving Chinese medicinal herb tea experienced significantly lower pain scores compared to those receiving recombinant human epidermal growth factor spray (P < 0.01).[4] Similarly, Ambili et al. found that the herbal mouthwash significantly reduced the need for analgesics in patients with radiation-induced mucositis; the data indicated a statistically significant difference from the control group (P < 0.05).[7]

Treatment adherence

Herbal treatments also appeared to enhance treatment adherence by reducing the need for treatment interruptions. Yamashita et al. observed that the use of Hangeshashinto improved treatment completion rates among patients receiving chemoradiotherapy with cisplatin (P = 0.002). The Orasol Plus (Lapacho-based) group showed no radiotherapy discontinuations due to mucositis, with mucositis severity limited to Grade 2 in 27.5% and Grade 3 in 10% of patients.[3,5]

Additional outcomes

Other studies explored various secondary outcomes, including oral health status and patient satisfaction. Liao et al. demonstrated that Green tea-based oral rinse significantly improved oral health status, with a reduction in Oral Assessment Guide scores by 1.71, 2.97, and 2.93 points at 4, 5, and 6 months, respectively, compared to the control group (P < 0.05).[8] Patients in the green tea participants also reported better satisfaction with their oral hygiene regimen.

Adverse events

The study found no evidence of serious adverse events reported across the studies, suggesting that herbal medicines were generally well-tolerated. In Sahebjamee et al., Aloe vera mouthwash demonstrated no notable difference side effects and was as effective as benzydamine in alleviating mucositis severity (P = 0.09).[9] Similarly, none of the studies reported allergic reactions or gastrointestinal disturbances related to the herbal interventions.

DISCUSSION

This systematic review suggests that herbal medicines may be effective in care strategies for radiation-induced oral mucositis. The results of several randomized controlled trials and cohort studies suggest that certain herbal preparations, including G. glabra (Yashtimadhu), P. major L. syrup, Hangeshashinto, and green tea, could provide significant benefits with regard to the reduction in severity, pain, and enhancing treatment adherence in oral mucositis.

Efficacy of herbal interventions

In this review, all the studies were indicating that herbal medicines were effective in decreasing the severity of mucositis. For instance, Yashtimadhu considerably reduced the frequency of severe mucositis, with only 15.5% of the patients developing Grade 3 mucositis, compared to 42.85% in the conventional treatment group.[1] Similarly, the syrup made from P. major L. reduced the severity of mucositis and pain, hence it can be an alternative treatment option with minor side effects.[6] Traditional CHM usage was correlated with a decreased risk of developing mucositis, lowered the incidence by 32% (aHR: 0.68).[10]

These findings are supported for the anti-inflammatory, antioxidant, and wound-healing properties of these herbal agents. As an example, G. glabra was reported to modulate pro-inflammatory cytokines that result in a reduction in the extent of radiation-induced mucosal injury.[1] Similarly, Hangeshashinto, a traditional Japanese Kampo medicine, is considered to express its anti-inflammatory effects via reducing neutrophil infiltration and the expression of cyclooxygenase-2 in tissues irradiated with radiation.[3] These biological mechanisms, thereby, probably contribute to the observed reduction in the severity of mucositis across studies.

Impact on pain and quality of life

Managing pain is an essential aspect of caring for patients with oral mucositis because severe pain can interfere with nutritional intake, oral hygiene, and overall quality of life. Several studies included in this review reported significant reductions in pain scores with the use of herbal interventions. For instance, the Chining decoction showed a significant decrease in pain levels in the treatment group compared to the control group, consistently across all time points, suggesting its utility as a complementary therapy to alleviate the discomfort associated with mucositis.[4] The green tea mouthwash study similarly demonstrated improvements in oral health and pain management, providing a simple, noninvasive method to improve patient outcomes.[8]

Although these are promising results, it must also be mentioned that few studies included validated pain scales or quality of life measures. Future studies should give first priority to the use of standardized tools in enhance the quantification of the effect of herbal treatments on patients’ pain and overall well-being.

Treatment adherence and continuation

The key observation of this review is the potential role herbal medicine could play in improving treatment adherence. Radiation-induced mucositis often leads to interruptions of treatments, which can compromise the efficacy of radiotherapy. Several studies reported a reduced need for treatment delays associated with herbal interventions. For instance, Hangeshashinto resulted in significantly higher completion rates of chemoradiotherapy in patients receiving cisplatin, thereby improving therapeutic outcomes by reducing disruptions to treatments.[3]

In the same way, the Orasol Plus (Lapacho-based) has been proven to reduce mucositis severity without causing any treatment interruptions.[5] Such results have suggested that herbal interventions might not only alleviate symptoms but also enable patients to continue with prescribed radiotherapy regimens, thereby improving overall cancer control.

Safety and tolerability

Herbal medicine is generally advantageous due to its favorable safety profile. All included studies in this review mentioned no significant adverse events. For example, Aloe vera oral rinse was proved to be as effective as benzydamine in mitigating mucositis degree, with a better safety profile due to the absence of reported side effects.[9] Similarly, patients using green tea mouthwash and Hangeshashinto reported no significant adverse reactions.[3,9] These discoveries have major implications for enhancing the safety and efficacy of herbal treatments when combined with standard care for radiation-induced mucositis.

However, despite these promising safety results, there is a need for caution in generalizing these findings. Herbal medicines are quite variable in quality and composition, depending on factors such as preparation methods and source materials. Furthermore, interactions between herbal treatments and conventional cancer therapies need further investigation to ensure safety in patients.

Study limitations and future directions

This review is strong evidence for the efficacy of herbal medicine that may help manage radiation-induced oral mucositis; several of the included studies exhibited some critical shortcomings. First, most studies showed moderate clinical heterogeneity regarding the herbal formulations, dosages applied, and outcome measures. Due to the significant heterogeneity of some outcomes, meta-analysis for all outcomes was impossible. In addition, most studies included small sample sizes; these limitations introduce some bias into the review results and therefore reduce their generalizability.

Second, most studies failed to evaluate long-term efficacy in terms of recurrence of mucositis or impact on cancer survival. Further studies should be large multicenter trials with longer periods of follow-up to improve the assessment of the durability of results with herbal interventions. Moreover, mechanisms of action for herbal medicines are only poorly understood, and further investigation into their pharmacological properties is necessary.

Lastly, heterogeneous outcome measures used in the studies pose a challenge for comparative analysis. Future studies should adopt consistent grading systems for mucositis severity, pain scales, and quality of life measures to facilitate more robust comparisons.

CONCLUSION

Herbal medicine shows potential as a complementary management of oral complications from radiation therapy in HNC treatment.

Agents such as G. glabra, P. major, and Hangeshashinto were identified to demonstrate significant efficacy in reducing mucositis severity, alleviating pain, and improving treatment adherence, all while exhibiting favorable safety profiles. Although the findings are encouraging, more robust, well-designed randomized controlled trials are required to validate these findings and establish standardized protocols for clinical practice.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.