Oral mucositis is an inflammation of the mucosa with a burning or tingling sensation. It is a common toxicity associated with both chemotherapy and head and neck radiation used for the treatment of cancer (Scully et al., 2006; Lalla et al., 2014a). Although many therapeutic strategies such as systemic chemotherapy and radiotherapy have improved survival rates for tumors, these treatments also cause several side effects, including a high risk of developing oral mucositis (Lalla et al., 2014b). Mucositis can be divided by treatment modality of cancer patients: radiotherapy to head and neck (H&N) cancer-induced (RT-induced), radiotherapy and chemotherapy to H&N cancer-induced (RT-CT-induced), chemotherapy-induced (CT-induced), and hematopoietic stem cell transplantation–induced (HSCT-induced). Mucositis has been consistently reported to occur in at least 75% of these cancer patients (Scully et al., 2006). RT-induced oral mucositis occurs in almost all patients who are treated for cancers of H&N; Grade 3 and 4 oral mucositis occurs in 56% (Jones et al., 2006; Maria et al., 2017). About 40% of patients treated with standard chemotherapy develop CT-induced oral mucositis. The situation can be even worse for the combining of different chemotherapeutic drugs, and the likelihood of oral mucositis increases with the number of chemotherapy cycles (Naidu et al., 2004; Scully et al., 2006). Mucositis presents as erythema and ulceration of the oral mucosa and is pathologically characterized by atrophy of the squamous epithelium, vascular damage, inflammatory infiltration, and ulceration. It causes severe discomfort and impairs patients’ ability to swallow, eat, and talk. The pain of oral mucositis increases the use of opioid analgesics, impairs nutritional intake, affecting the quality of life (Elting et al., 2008; Jensen and Peterson, 2014). Severe mucositis can necessitate cancer therapy, causing interruptions and/or dose reductions in cancer treatment protocols, and even negatively influence prognosis (Peterson et al., 2015).

Numerous strategies have been recommended by the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) for the prevention and treatment of radiotherapy and chemotherapy-induced oral mucositis. In the latest guideline conducted by the group in 2020, some natural agents, including herbal medicines, are included in the analysis. But due to the conflicting evidence, they are listed as having “no guideline possible” (Yarom et al., 2019; Yarom et al., 2020). Therefore, it is of great significance to assess their effects and thus lead to their appropriate clinical use. Chinese patent medicines (CPMs) are modern pharmaceutical preparations of traditional Chinese medicine (TCM) extracts, such as TCM pills, capsules, and injections, made mainly according to a standardized formulation of Chinese herbal medicines. The registration of CPMs is authorized by the China Food and Drug Administration (CDFA) and National Administration of Traditional Chinese Medicine (NATCM), with reference to laws such as Drug Administration Law of the People’s Republic of China and Provision for Drug Registration (Zhang, 2018). According to the TCM theory, CPMs with heat-clearing and detoxicating effects have become ideal options in the prevention and treatment of heat toxin syndrome, including redness, swelling, ulceration, and pain, which are also the main features of oral mucositis. In addition, unlike synthetic medicines, naturally originated CPMs are generally perceived to have a wider range of sources, fewer side effects, and multiple pharmacological targets (Lin et al., 2021). Therefore, CPMs are in wide clinical use to prevent or treat radiotherapy and chemotherapy-induced oral mucositis in China as important complementary alternative medicines (Zheng et al., 2011). However, as most articles relevant to CPMs are published in Chinese, their number and quality may be underestimated by clinicians and scientists outside China. Moreover, there has been no systematic review and meta-analysis evaluating the effectiveness of CPMs for radiotherapy and chemotherapy-induced oral mucositis currently. Therefore, with the inclusion of Chinese and English publications, a comprehensive assessment of the efficacy and safety of CPMs for the prevention and treatment of radiotherapy and chemotherapy-induced oral mucositis is conducted in this study to provide basic information for clinical practice.

In China, more and more patients receiving radiotherapy and chemotherapy choose CPMs to prevent or treat radiotherapy and chemotherapy-induced oral mucositis, but the application of CPMs is basically experience-based. Therefore, we tried to build its missing link to the evidence-based medical sciences in the present study. From the review, we found that CPMs were more frequently used in the prevention than the treatment of radiotherapy and chemotherapy-induced oral mucositis. That means the use of CPMs was usually begun before the onset of the disease, which may reduce the progression of the disease and thus had the effect of reducing the severity of radiotherapy and chemotherapy-induced oral mucositis. By meta-analysis, it was proved that CPMs could significantly reduce the prevalence, pain level, and severity of radiotherapy and chemotherapy-induced oral mucositis. As for the treatment, CPMs were effective in alleviating the symptoms, reducing the cure days, and thus improving the efficiency of clinical treatment for radiotherapy and chemotherapy-induced oral mucositis. We also found that the systemic administration of CPMs was more frequent than topical. Systemic CPMs could prevent and treat radiotherapy and chemotherapy-induced oral mucositis mainly by reducing the prevalence and severity of oral mucositis, and topical CPMs could play a role primarily through relieving the symptoms, promoting the healing of ulceration, and reducing the severity of oral mucositis.

According to the TCM theory, chemotherapy and radiotherapy belong to the “drug poison” and “evil poison” from the environment. The clinical feature of oral mucositis, including redness, swelling, ulceration, and pain, are the characteristics of TCM heat toxin syndrome ((Lin et al., 2021)). Heat clearing and detoxicating are classic TCM treatments for heat toxin syndrome (Jin et al., 2009). Therefore, CPMs with the above-mentioned effects have become our ideal option in the prevention and treatment of oral mucositis. The possible mechanisms of CPMs related to their main active components, such as matrine and cockroach extract, mainly attribute to the antioxidant, radical scavenging, anti-inflammatory, antimicrobial, and immunostimulatory properties. More specifically, matrine, as a primary component of Compound Kushen injection, could exert anti-inflammatory effects via lowering the expression of MyD88, NLRP3, and caspase-1, inhibiting the phosphorylation of I-κB α, and affecting the translocation of NF-κB from the cytoplasm to nucleus (Li et al., 2021). Cockroach extract, as the major component of Kangfuxin solution, could relieve the symptoms of oral mucositis by inhibiting the opening of the calcium-dependent potassium channel, promoting granulation tissue growth and angiogenesis, improving the phagocytic ability of macrophages and lymphocytes (Luo et al., 2016). Xihuang capsules, consisting of four ingredients extracted from natural herbs, including Bovis Calculus artifactus, Moschus, Olibanum, and Myrrha, were proved to reduce the levels of TNF-α and IL-6 detected by enzyme-linked immunosorbent assay (ELISA) in patients’ saliva (Dong et al., 2017). Moreover, Yangyin Shengxue Mixture, Kouyanqing Granules, Mailuoning injection, Kangfuxin solution, and Xipayi mouth rinse were also reported to have the effects of promoting microcirculation, reducing local vascular occlusion, and thus accelerating mucosal repair (Wang W. M. et al., 2010; Zhao et al., 2010; Ding and Gu, 2011; Li, 2011; Li and Tan, 2012; Wang and Ma, 2014; Ding and Xu, 2015; Xia et al., 2015; Bai et al., 2017; Wang et al., 2017; Yan et al., 2017). Therefore the mechanism of CPMs in the prevention and treatment of oral mucositis is not only in accordance with the TCM theory, but also related to the anti-inflammatory mechanism of its main active components, and the two complement and promote each other.

The courses of CPMs for the prevention of radiotherapy and chemotherapy-induced oral mucositis were basically the same as that of the chemotherapy or radiotherapy, and the courses for the treatment were about 1–2 weeks. Regarding safety evaluation, five trials reported the occurrence of adverse effects. The most frequently reported adverse effects were gastrointestinal reactions, which involved Zhenhuang pills, Yangyin Shengxue Mixture, Kouyanqing Granules, Compound Kushen injection, and Shuanghua Baihe tablets (Wang W. M. et al., 2010; Xu et al., 2013; Lian et al., 2017; Yan et al., 2017; Zheng et al., 2018). Specifically, Zhenhuang pills would cause loose stools; Yangyin Shengxue Mixture may lead to mild nausea or diarrhea; Kouyanqing granules could cause mild nausea and vomiting; Compound Kushen injection would sometimes induce mild diarrhea and bitter taste; Shuanghua Baihe tablets may bring about mild or moderate gastrectasia reactions. In the TCM theory, Chinese medicines are divided into four properties, including cold, hot, warm, and cool (Yang et al., 2013). Among the main active components of the above-mentioned CPMs, Rehmannia glutinosa, Asparagus, Sophora flavescens, Coptis chinensis, Bezoar, and Scutellaria baicalensis belong to cold or cool Chinese medicines, and these cold or cool components may cause gastrointestinal reactions such as loose stool, diarrhea, and vomiting due to the patients’ asthenia of spleen and stomach, and heavy dampness (Wang W. M. et al., 2010; Xu et al., 2013; Lian et al., 2017; Yan et al., 2017; Zheng et al., 2018). These adverse reactions are all closely related to the patients’ individual “cold” or “heat” constitution, gastrointestinal environment, and the underlying diseases. However, as the adverse effects of CPMs in the experimental groups were all mild and could disappear after stopping drugs, and fewer people were affected as the drug was discontinued, the statistical difference between the control and experimental groups was not clinically meaningful. Therefore, CPMs could still be considered safe in the prevention and treatment of radiotherapy and chemotherapy-induced oral mucositis.

Nevertheless, there are still some limitations in this study. First, as the study only included Chinese and English literature, and most articles relevant to CPMs are published in Chinese, it may lead to potential language bias and citation bias. Second, since most of the original literatures only showed the min-max age range without detailed age grouping, the patients’ age is a major confounding factor, and as the clinical data for each patient in the original RCT studies are inaccessible, it is impossible for this study to further perform subgroup analysis according to the patients’ age. Therefore, age grouping to reduce confounding bias in future studies was recommended. In addition, due to the application of CPMs depends on the identification of their effective chemical components, and the laboratory evidence was still lacking for most of the CPMs, more high-quality laboratory and animal experiments are still needed. Furthermore, due to the limited number of eligible studies and the publication bias, more high-quality, double-blinded, placebo-controlled RCTs are still needed to confirm the efficacy and safety of CPMs for the prevention and treatment of radiotherapy and chemotherapy-induced oral mucositis in future research.

This systematic review and meta-analysis indicated CPMs were more frequently used in the prevention than the treatment of radiotherapy and chemotherapy-induced oral mucositis. CPMs such as Compound Kushen injection, Kouyanqing Granules, and Shuanghua Baihe tablets may be effective for the prevention of radiotherapy and chemotherapy-induced oral mucositis through reducing the prevalence, relieving the pain level, and decreasing the occurrence of severe oral mucositis. As for the treatment, CPMs such as Xipayi mouth rinse, Sai wei’an, oral ulcer powder, and Kangfuxin solution may be superior in alleviating the symptoms, reducing the cure days than controls like normal saline, vitamin tablets, and antiseptic or anesthetic mouthwash. More high-quality, double-blinded, placebo-controlled RCTs are still warranted to verify and extend the present results to optimize CPMs for the prevention and treatment of radiotherapy and chemotherapy-induced oral mucositis.