Cancer-related Fever (CRF) is defined as a fever directly associated with cancer, excluding instances caused by infection or treatment during tumor progression (H. Zhang et al., 2019). As a primary cause of non-infectious fever in patients with tumors, CRF is typically linked to the autonomous production of cytokines by cancer cells. These small proteins, endowed with diverse biological properties, can act as pyrogens, directly inducing fever by influencing the thermoregulatory centers in the hypothalamus (Toussaint et al., 2006).

Patients experiencing CRF generally display a persistent, low-grade fever, with temperatures ranging from 37.5°C to 38°C. The fever tends to manifest in an irregular or intermittent pattern (Cador-Rousseau, Cazalets-Lacoste and Grosbois, 2002). CRF is a tricky symptom, Warburg et al. (2008) proposed that tumor cells primarily ferment glucose, leading to an accelerated metabolism and an increase in body temperature (Majerović et al., 2008). Notably, for every 1°C increase in body temperature, there is a 13% rise in the basal metabolic rate, intensifying the consumption of nutrients such as sugar, protein, and fat in febrile patients, thereby augmenting stress on the body (S. Li, 2013). Furthermore, fever ca adversely impact digestion by impairing the secretion of digestive juices and reduces the activity of digestive enzymes, leading to symptoms such as appetite loss. It can also elevate heart and respiratory rates, imposing additional physical strain on cancer patients. Beyond the physical discomfort, CRF significantly affects patients’ psychological wellbeing, inducing anxiety, irritability, and other negative emotions, which severely impact their quality of life (Cai et al., 2021).

While non-steroidal anti-inflammatory drugs such as naproxen, indomethacin, and ibuprofen have demonstrated effectiveness in managing CRF (Johnson, 1996), the use of naproxen in CRF may lead to increased sweating, and some patients may experience a recurrence of the fever after discontinuing the drug (Chang and Gross, 1985). Prolonged use of naproxen for CRF can cause adverse reactions, including gastritis, gastrointestinal bleeding, and notably, thrombocytopenia. Furthermore, naproxen is contraindicated in CRF patients with cardiac, hepatic, and renal insufficiency (Süleyman, Demircan and Karagöz, 2007). Indomethacin provides an alternative for treating CRF, though its use warrants attention due to potential adverse effects on the gastrointestinal tract, central nervous system, and hematopoietic system (Hur et al., 2009).

Chinese botanical drugs have demonstrated unique potential in the treatment of tumors (Ling, Yue and Ling, 2014; Y; Wang et al., 2020; Y; Zhang, Lou, Wang, Yu and Shen, 2020), showcasing anti-tumor effects that can be beneficial in managing CRF (X. Z. Chen and Li, 2012). One such botanical drug formula is Xiaochaihu Decoction, initially described in traditional Chinese Medicine (TCM) classic Treatise on Typhoid Fever wrote by famous ancient TCM practitioner Zhang Zhongjing for febrile illnesses. This decoction comprises Bupleurum chinense DC. [Apiaceae; Bupleuri radix], Scutellaria baicalensis Georgi [Lamiaceae; Scutellariae radix], Pinellia ternata (Thunb.) Makino [Araceae; Pinelliae rhizoma], Panax ginseng C.A.Mey. [Araliaceae; Ginseng radix et rhizoma], Ziziphus jujuba Mill. [Rhamnaceae; Jujubae fructus], Glycyrrhiza uralensis Fisch. ex DC. [Fabaceae; Glycyrrhizae radix et rhizoma], and Zingiber officinale Roscoe [Zingiberaceae; Zingiberis rhizoma recens] (Sun, Gao and Qiao, 2023). The conventional method for preparing a decoction involves placing a specified quantity of medicinal metabolites into a pot, adding sufficient water to submerge them, and allowing them to macerate for 30–60 min. Following maceration, the mixture is heated to boiling point using a high flame before being lowered to a simmer for 20–45 min. The resultant decoction, yielding approximately 300–400 mL, should then be divided into two equal portions to be consumed in the morning and evening, respectively (J. Wang, 2020). Prolonged boiling or ‘decocting’ is the earliest and most popular method of preparing botanical drugs in the practice of traditional Chinese medicine (TCM) (H. Luo, Li, Flower, Lewith and Liu, 2012). Modern pharmacological studies have revealed that Xiaochaihu Decoction can mitigate inflammatory responses and alleviate liver fibrosis through multiple targets (S. J. Wang et al., 2023). Clinical trials further support its efficacy by showing that Xiaochaihu Decoction modulates the tumor microenvironment, inhibits tumor markers, prolongs survival, and holds a distinct advantage in treating CRF (Bao et al., 2020; W. Y; Zhang et al., 2022). Notably, Xiaochaihu Decoction exhibits a long-lasting effect, with a low rate of temperature rebound after discontinuation and few notable side effects. Its positive impact on relieving symptoms, controlling tumors, improving patients’ quality of life, and prolonging survival make it a promising therapeutic option (Z. J. Wu, 2004).

While randomized controlled trials (RCTs) in China have investigated the use of Xiaochaihu Decoction for CRF, a comprehensive systematic review of its clinical effectiveness and safety is currently lacking. Meta-analysis, recognized as the superior method for synthesizing research findings across various disciplines, becomes indispensable in overcoming the limitations of independent studies due to diverse conditions and potential biases in their results. These biases, when collectively analysed, may reveal a common underlying truth. Therefore, statistical analysis is crucial in exposing this truth. For the first time, our study systematically evaluated the clinical effectiveness and safety of Xiaochaihu Decoction in treating CRF using meta-analysis. Our objective is to provide evidence-based medical support for the safety and clinical effectiveness of Xiaochaihu Decoction in treating CRF. By employing this meta-analytical approach, we aimed to offer essential insights for clinicians (Puhan et al., 2014; Hernandez, Marti and Roman, 2020). The expected outcome will assist clinicians in devising appropriate treatment plans for CRF patients, ultimately benefiting these individuals.

Our study was registered with International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42023484068. Following this, a meta-analysis was carried out in accordance with the guidelines stipulated in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 (Page et al., 2021), and the Cochrane Handbook for Systematic Reviews of Interventions (Higgins et al., 2011). The completed PRISMA checklist is provided in Supplementary Appendix SA.

In China, Xiaochaihu Decoction is widely used and has shown effectiveness in treating acute upper respiratory tract infections (AURTI), as substantiated by a meta-analysis conducted by Yan, LJ et al. (2021) (Yan et al., 2021). Additionally, Wang, SJ et al. (2023), employing network pharmacology and in vitro experiments, have proposed Xiaochaihu Decoction as a potential therapeutic agent for liver fibrosis (S. J. Wang et al., 2023). Recent studies have investigated the efficacy of Xiaochaihu Decoction in managing CRF through RCTs. Preliminary findings suggested that patients with CRF might benefit from Xiaochaihu Decoction. However, as of now, no comprehensive reviews or meta-analyses have been conducted to evaluate the effectiveness and safety of Xiaochaihu Decoction in this context of CRF.

Our study aimed to further substantiate the potential and safety of Xiaochaihu Decoction in managing CRF. Through a systematic review of eight domestic and international databases, 18 RCTs were included, involving 1,424 patients with CRF. The most prevalent cancers among these patients were liver and lung cancer, suggesting that Xiaochaihu Decoction may be particularly effective for patients with these types of cancer. The 18 RCTs encompassed 12 different treatment modalities for CRF in both traditional Chinese and Western medicine. Frequently used treatments included Xiaochaihu Decoction, antipyretics in conjunction with antibiotics, indomethacin, and ponatinib. Our meta-analysis corroborated that Xiaochaihu Decoction significantly ameliorated the clinical effectiveness rate in patients with CRF (RR = 1.24, 95%CI: 1.17,1.32). Moreover, Xiaochaihu Decoction expedited the normalization of body temperature by an average of 5.29 days compared to the control group. Additionally, it significantly influenced TNF-α, IL-1β, and COX-2 levels, providing valuable insights to its therapeutic impact.

TNF-α, predominantly produced by mononuclear phagocytes, has the capability to induce the secretion of substantial amounts of cytokines, including IL-1 and IL-1β. These cytokines, acting as endogenous pyrogens, influence the body’s temperature center, resulting in fever (Yang, Song, Hu, Hua and Li, 2009). IL-2 plays a crucial role in modulating the body’s immune response, promoting the activation and proliferation of T cells, NK cells, and B cells. It enhances cytokine and corresponding antibody levels while exerting inhibitory effects on tumor cells (B. H. Zhang et al., 2011). COX-2, an inducible enzyme, can participate in tumor development through various pathways. Its overexpression can lead to increased PGE2, causing fever and inducing high expression of leukocyte interleukins (Shen and Feng, 1989). Our data analysis revealed that Xiaochaihu Decoction reduced the levels of inflammatory factors TNF-α, IL-1β and COX-2, while increasing IL-2 levels in patients with CRF. Quality of life indices (KPS and QOL) suggested that Xiaochaihu Decoction significantly improved the quality of life indices for patients with CRF. Furthermore, the meta-analysis and three-dimensional diagram analysis results showed a lower incidence of adverse events in the Xiaochaihu Decoction group compared to the control group, implying that Xiaochaihu Decoction is both effective and safe in treating CRF.

Xiao Chaihu Decoction, a TCM formula, is frequently employed to manage febrile conditions. Its primary composition is Bupleurum chinense DC. [Apiaceae; Bupleuri radix] contains complex chemical metabolites, including saponins, volatile oils, flavonoids, and polysaccharides. These metabolites play a pivotal role in its pharmacological effects, contributing to immune regulation, anti-depression, anti-tumor, and anti-inflammatory properties (Kato et al., 1994; Zell and Chang, 2005; Foggo and Cavenagh, 2015; Fang, Wang, Yang, You and Xing, 2022; Sun et al., 2023). Bupleurum chinense DC. [Apiaceae; Bupleuri radix] and Scutellaria baicalensis Georgi [Lamiaceae; Scutellariae radix] constitute the key medicinal pair in Xiao Chaihu Decoction. Their primary active metabolites, quercetin, bergenin, isorhamnetin, baicalein, and wogonin, demonstrate the ability to inhibit the expression of PTGS2 and PTGS1 genes, consequently reducing prostaglandin synthesis. Moreover, they suppress the expression of PRSS1, Caspase-3, and AKT1 genes, contributing to tumor growth inhibition. These metabolites function by blocking the activation of cancer-related pathways, such as the TNF and IL-17 pathways, ultimately reducing the release of fever-inducing cytokines like IL-1, IL-6, and TNF-α.

Quercetin, a flavonoid metabolite, is believed to exhibit a spectrum of beneficial effects, including antioxidant, antiviral, anti-inflammatory, anti-tumor, and immune regulatory effects (Liu and Liu, 2020). Bergenin considered a safe and potential radiosensitizer, enhances radiation damage to tumor cells both in vitro and in vivo by inhibiting the AKT/PI3K and ERK pathways and activating the mitochondrial apoptosis pathway (Pei et al., 2022). Inducible PTGS2 contributes to the production of inflammatory prostaglandins, and its upregulation is linked with increased cell adhesion, phenotype alterations, anti-apoptosis, and tumor angiogenesis (X. H. Wang et al., 2021). The serine/threonine kinase encoded by AKT1 prevents cell apoptosis by phosphorylating and inactivating metabolites of the apoptosis mechanism (G. L. Li, Liu, Xie, Yu and Hu, 2020). Additionally, the protein encoded by IL-6 is proven to be an endogenous pyrogen capable of inducing fever in patients with autoimmune diseases or infections (Kang et al., 2023).

Jiang and Wang, (2015) conducted an observational study on the clinical effectiveness of Xiao Chaihu Decoction in 47 patients with CRF. The study revealed satisfactory results in managing CRF, with no severe adverse reactions observed during the treatment, suggesting its potential for broader use (Jiang and Wang, 2015). Similarly, Zhang, (2013) employed Xiao Chaihu Decoction in patients with CRF and found that 83.3% of patients reported symptom relief and maintained a body temperature below 37.0°C for three consecutive days (L. K. Zhang, 2013). However, its important to note that current empirical studies on Xiao Chaihu Decoction for treating CRF primarily rely on small sample sizes. Therefore, larger-scale and more rigorously designed clinical trials are essential to validate the efficacy and safety of Xiao Chaihu Decoction. Encouraging more researchers and institutions to participate in empirical investigation of Xiao Chaihu Decoction for treating CRF will contribute valuable evidence to support its application in this context.

Our research possesses several noteworthy strengths. Notably, we conducted a pioneering comprehensive meta-analysis of previously published RCTs. The outcomes, characterized by low heterogeneity, demonstrate consistency among the studies, bolstering the credibility of our conclusions. To ensure robust results, we performed meticulous sensitivity checks, publication bias checks, subgroup analysis, and employed the Egger test to detect potential publication bias. Methodological rigor was further ensured by utilizing the Risk of Bias 2.0 tool to evaluate each study. However, our evaluation revealed certain issues with the overall literature. The absence of blinding implementation in the 18 RCTs might be attributed to the inherent challenges of creating a placebo for Xiao Chaihu Decoction, adding complexity to the blinding process. While challenging, blinding is a crucial for ensuring trial fairness and reduce bias. We encourage future research to address these challenges. Additionally, none of the 18 RCTs registered their protocols, leading to a lack of transparency in the trial design, implementation, and completion, which poses a challenge for Podetial replication and potentially contributes to selective reporting bias. (X. X. Li, Han, Wang and Liu, 2013). Moreover, according to GRADE evaluation, most studies were rated as low quality, underscoring of the need for improvement in the quality and methodology of current RCTs. The relatively low sample size analyzed in our study may affect the generalizability and stability of results. Thus, we expect for large-sample studies to further validate our findings. We also recommend that future researchers prioritize implementing blinded and registered clinical trials to enhance the quality and credibility of their studies. In addition, although Xiao Chaihu Decoction is commonly employed in clinical settings and is generally regarded as safe, there are indications from some research studies that it can occasionally lead to interstitial pneumonia, acute hepatitis, and liver damage (Murakami, Okajima, Sakata and Takatsuki, 1995; Hsu, Huang, Tsay, Chang and Lee, 2006; Teschke, 2014). These severe adverse reactions, though rare, underscore the necessity of conducting regular medical examinations to ensure the safe use of Xiao Chaihu Decoction.

In conclusion, current evidence suggests that Xiao Chaihu Decoction may enhance clinical effectiveness in CRF patients, expedite temperature normalization, ameliorate inflammatory markers, improve quality of life, and minimize adverse reactions. However, to strengthen these findings, future research should focus on conducting high-quality, large-scale RCTs. Additionally, further support for these evidence-based discoveries could be derived from complementary pharmacological experiments.