Introduction
Febrile neutropenia (FN) is a common acute condition during tumor treatment. There is a clear international consensus on its diagnostic criteria: a single oral temperature ≥38.3°C or a sustained temperature ≥38.0°C for more than 1 h (defined by the European Society for Medical Oncology as 2 h), and an absolute neutrophil count of <0.5 × 109/L or expected to fall to <0.5 × 109/L within 48 h.1–3 Despite advances in prevention and treatment, FN remains one of the most serious complications of oncologic chemotherapy. Epidemiologic data show that FN occurs in seven to eight cases per 1,000 cancer patients receiving chemotherapy.4 A U.S. study that included 41,779 hospitalized FN patients showed an in-hospital mortality rate of 9.5%.5 The multiple burdens of FN on tumor patients cannot be ignored. Firstly, as the primary line of defense against infection, the absence of neutrophils significantly increases the risk of serious infections, endangering patients’ lives. Secondly, it affects the process of anti-tumor therapy, which may lead to a reduction or delay in the chemotherapy dose, thus affecting therapeutic efficacy and survival prognosis.6,7 Furthermore, FN seriously affects the quality of life of patients. From a health economics perspective, FN significantly increases the medical burden, with studies indicating an average length of stay of six days and an average hospitalization cost of up to 40,000 dollars, and has become a significant public health problem.8,9
Considering the hazardous nature of FN, it is important to find effective management options. Presently, the Multinational Association for Supportive Care in Cancer scoring system is the main clinical tool for FN risk assessment, which is effective in identifying low-risk patients.10 Recent guidelines indicate that risk factors for FN include advanced age, advanced disease, poor physical status, a history of neutropenia/FN, infections, recent surgery or open wounds, prior chemotherapy, myelosuppression, and the presence of pulmonary, renal, hepatic, or cardiovascular comorbidities. The incidence of FN can be effectively reduced by identifying these risk factors and implementing preventive measures.1,11,12
The current prevention and treatment of FN rely mainly on antibiotics and granulocyte colony-stimulating factor (G-CSF).9,13 Although studies have confirmed that antibiotics and G-CSF show good efficacy and can reduce the incidence of FN and mortality,14–17 there are still obvious limitations: antibiotic use can trigger drug resistance,18 while G-CSF can cause adverse effects such as skeletal muscle pain, vasculitis, and an increased risk of secondary tumors.19–21 Therefore, there is an urgent need to explore new adjuvant therapeutic strategies to optimize existing regimens.
Traditional Chinese medicine (TCM), as a complementary treatment for FN, demonstrates unique advantages. In contrast to the direct intervention mode of modern medical therapies, TCM emphasizes integrated regulation and dialectical treatment to improve symptoms and quality of life by restoring the balance of yin and yang (yin and yang are regulatory systems that describe the mutual antagonism and dynamic balance within the human body) in the body.22 A plethora of extant studies have demonstrated that TCM, whether employed as a standalone modality or in conjunction with modern medicine, has yielded favorable outcomes in enhancing the number of granulocytes and regulating fever.23–25 These findings provide a novel framework for the combined treatment of FN with TCM and modern medicine. However, further research is required to fully explore this potential. There is a lack of systematic reviews on the treatment of FN with TCM. This review aims to summarize the etiology, pathogenesis, and treatment principles of FN in TCM, to sort out clinical practice experience, and to explore its prospects, in order to provide a new theoretical basis and practical guidance for optimizing the treatment protocols of FN.
Theoretical basis for the treatment of FN in TCM
TCM is a systemized medical practice that has been developed and refined over millennia. It draws upon a rich tapestry of traditional Chinese cultural and medical knowledge, resulting in a unique theoretical framework, diagnostic methodologies, and therapeutic approaches.26 As one of the complementary and alternative medicine systems recognized by the World Health Organization, TCM has demonstrated unique advantages in the treatment of complex diseases.27 Records of FN can be traced back to the Chinese medical text Huang Di Nei Jing, which was written more than 2,000 years ago. FN can be categorized as “fatigue” and “fever”. Ancient physicians, through long-term clinical observation, categorized the causes of FN as external evils, improper diet, and internal injuries to emotions. These pathogenic factors work together to disrupt the balance of yin and yang in the human body, impairing the function of the internal organs and leading to weakness of qi and blood (qi and blood refer to the energy substances that maintain life activities), which in turn triggers a series of clinical manifestations of FN. It is worth noting that this pathological process often forms a vicious circle: weakness of qi and blood leads to a decline in the body’s ability to resist disease and evil, while the invasion of external evil further depletes qi and blood, and so on, aggravating the condition. Despite the absence of a contemporary notion of micro-medicine within the framework of TCM, this medical system accurately identified the fundamental pathological characteristics of FN through the diagnostic and therapeutic method of “external and internal”. The “fever from internal injuries” mentioned in the Shanghan Zabing Lun provided an important idea for the treatment of FN. The theories of “fever due to qi deficiency” and “fever due to blood deficiency,” put forward by Zhang Jingyue, a physician of the Ming Dynasty, are highly consistent with the pathogenesis of modern FN.28,29 These ancient wisdoms have laid a solid theoretical foundation for modern Chinese medicine in the diagnosis and treatment of FN.
With the development of modern medicine, the name, diagnostic criteria, and pathogenesis of FN have been clarified. On this basis, modern TCM, combined with Western medical theories, elaborates the etiology and pathogenesis of FN more systematically. The first factor is drug toxicity (mainly referring to the toxicity of chemotherapy drugs), the second is the invasion of external evil (i.e., pathogen infection), and the remaining factors include internal injury of emotion and spirit (including psychological factors such as emotional disorders) and improper diet.28,30 Within this theoretical framework, contemporary renowned Chinese medicine practitioners have proposed distinctive treatment principles. Prof. Bingkui Piao pointed out through in-depth research that most toxic effects after chemotherapy are caused by loss of qi and blood, disorders of the spleen and stomach, and deficiencies of the liver and kidneys, and advocated tonifying qi and blood.31 Prof. Daihan Zhou, based on the theory of “Wei qi and Ying blood”, believes that the essence of granulocyte decline is that “Wei qi is not solid and Yang qi is deficient”, and advocates the therapeutic principle of warming Yang and benefiting Qi.32 Prof. Rencun Yu paid special attention to the key role of the spleen and kidney in the prevention and treatment of FN and proposed the treatment method of strengthening the spleen and kidney.33
In clinical treatment, TCM is characterized by its adherence to the holistic concept and dialectical treatment (Fig. 1). The holistic concept views the human body as an organically connected system, and treatment focuses on regulating the entire system. When prescribing a prescription, doctors not only need to consider the symptoms of FN itself, but also many other factors, such as the patient’s primary tumor condition, the functional status of the relevant organs, and the Western treatment protocols that the patient is undergoing. This holistic treatment concept aims to restore the dynamic balance between the body’s various organ systems and provide each patient with a comprehensive treatment strategy. At the same time, dialectical treatment, as another major feature of TCM, emphasizes precise interventions targeting the patient’s core disease mechanism. It is a clinical decision-making model that involves a comprehensive analysis of an individual’s overall functional status, personalized diagnosis, and dynamic treatment adjustment. For example, qi deficiency is treated by qi tonification, blood deficiency is treated by blood tonification, and blood stasis is treated by blood activation. This individualized approach ensures that the treatment plan is precisely tailored to the patient’s condition. Studies have shown that this TCM mode, which combines holistic regulation and dialectical treatment, demonstrates unique advantages in the prevention and treatment of FN.34 As modern medicine has deepened its understanding of FN, theories developed in TCM have evolved and advanced, thus offering increased potential for addressing this clinical challenge.
Clinical evidence of TCM in FN treatment
In recent years, with increasing research on the modernization of TCM, the clinical efficacy of TCM in FN treatment has been increasingly reported in international medical journals. However, in most cases, TCM is still mainly used as part of an integrated treatment approach to enhance overall FN management. Clinical data have shown that the combination of TCM and modern medicine can significantly reduce the incidence of FN, as well as enhance the number of granulocytes, shorten the duration of fever, improve the quality of life of patients, and reduce other toxic effects of chemotherapy (Fig. 2).34 More importantly, TCM intervention can often regulate the overall functional status of the body rather than just targeting a single symptom, which reflects the TCM treatment concept of “treating the disease at its root”. To accurately evaluate the effectiveness of TCM in treating FN, we conducted a comprehensive search of the PubMed, Web of Science, and CNKI databases, covering the period from their establishment to May 2025, and summarized clinical studies on FN treated with TCM. The search terms included TS1 = “Medicine, Chinese Traditional” OR “Traditional Chinese Medicine”, and TS2 = “Febrile Neutropenia”. We screened the titles and full texts and ultimately obtained three studies. Table 1 summarizes the existing clinical studies.34–36
Table 1Clinical study on the treatment of FN with TCM
| Author, year | TCM Type | Clinical Application | Methods | sample sizes | Major findings |
|---|
| Wang, 202334 | The formula of benefiting qi and nourishing yin (the main ingredients of which are huangqi, codonopsis pilosula, radix pseudostellariae, etc.) | Combined with bianpenem and rhG-CSF | RCT | 64 | The average time for the body temperature to return to normal was shortened by 52 hours, the recovery time of neutrophils was advanced by 4 days, the total effective rate of clinical symptom improvement was increased by 26.67% (96.67% vs. 70.00%), and the improvement of the quality of life scores was significantly greater. |
| Tian et al., 201535 | TCM intervention (with spleen strengthening, qi nourishing and blood regeneration for marrow production as the basic treatment) | Combined with chemotherapy | retrospective study | 792 | The incidence of FN has significantly decreased. |
| Chen et al., 202436 | TCM intervention (tonify the spleen and stomach, clear Yin Fire, and support Yang) | Combined with antibiotics and G-CSF | case report | 1 | After 10 days of intervention, her absolute neutrophil count had gradually increased. Additionally, after two weeks of treatment, her fever subsided. |
TCM treatment reduces the incidence of FN, enhances the number of granulocytes, and shortens the duration of fever
The standard modern medical treatment regimen for FN relies on the combination of antibiotics and G-CSF.37 Antibiotics are used to control infection, while G-CSF promotes neutrophil production. However, as clinical practice evolves, mounting evidence suggests that integrating TCM with this established treatment protocol may yield substantial synergistic effects and offer more comprehensive therapeutic benefits for patients with FN.38 Several clinical studies have provided strong evidence for this combined TCM and modern medicine treatment model. A rigorously designed randomized controlled trial (RCT) included 64 patients with FN. The control group was treated with standard antibacterial therapy using biapenem combined with recombinant human G-CSF, while the observation group was treated with a formula for benefiting qi and nourishing yin (the main ingredients of which are huangqi, Codonopsis pilosula, Radix Pseudostellariae, etc.) based on the standard therapy. The results of the study showed that the combined TCM and modern medicine group was significantly better than the control group in several efficacy indices: the average time for body temperature to return to normal was shortened by 52 h, the recovery time of neutrophils was advanced by four days, the total effective rate of clinical symptom improvement was increased by 26.67% (96.67% vs. 70.00%), and improvement in quality-of-life scores was significantly greater.34 These data fully demonstrate the added value of TCM in accelerating FN recovery and improving patient symptoms. More noteworthy is the unique advantage of TCM in FN prevention. A large-scale retrospective study that included 792 patients undergoing chemotherapy for tumors showed that the incidence of FN was significantly lower in the group of patients who started TCM intervention (with spleen strengthening, qi nourishing, and blood regeneration for marrow production as the basic treatment) immediately before the chemotherapy cycle than in the control group (43% vs. 71%). An in-depth subgroup analysis further confirmed that this protective effect was observed in different chemotherapy regimens (such as those containing anthracyclines, paclitaxel, and docetaxel).35 This finding provides an important basis for the wide application of TCM in tumor supportive therapy. TCM also shows unique therapeutic potential for G-CSF–insensitive cases, which are more difficult to treat in clinical practice. A case report provided evidence for this potential. An 18-year-old woman with cancer developed FN after chemotherapy. Despite the use of antibiotics and G-CSF, FN persisted for two months. After approximately 10 days of treatment with TCM decoctions (tonifying the spleen and stomach, clearing yin fire, and invigorating yang), the absolute neutrophil count gradually increased. Two weeks later, the patient’s fever also subsided.36 Although limited by sample size, these clinical observations provide new ideas and options for the treatment of refractory FN. Synthesizing the available clinical evidence shows that the combined application of TCM and standard modern medical treatments can improve FN outcomes in multiple dimensions. Effective formulas include the Benefiting Qi and Nourishing Yin Decoction and the Shengyang Sanhuo Decoction. These formulas contain commonly used herbs such as huangqi, Codonopsis pilosula, Radix Pseudostellariae, Cimicifugae Rhizoma, and Bupleuri Radix. These findings provide a reference for the clinical treatment of FN using TCM. However, methodological limitations must also be acknowledged, including modest sample sizes and inadequate implementation of randomization methods and blinding. These factors affect the reliability and extrapolation of the study findings to a certain extent. Consequently, the need for high-quality clinical studies in this domain remains paramount.
TCM treatment to alleviate other symptoms associated with FN
In addition to FN, tumor patients experience a range of other toxic effects during chemotherapy, such as thrombocytopenia, erythrocytopenia, gastrointestinal reactions (nausea, vomiting, diarrhea), peripheral neuropathy (numbness of the hands and feet), and cardiotoxicity (cardiac arrhythmias, myocardial damage).39 Notably, TCM has demonstrated unique advantages in comprehensive conditioning for these concomitant symptoms while combating FN. Several systematic reviews and meta-analyses (including only RCTs) have confirmed that the combined application of TCM and chemotherapy can significantly reduce the incidence of leukopenia, erythrocytopenia, and thrombocytopenia compared with chemotherapy alone.40,41 The sample sizes covered by these meta-analyses all exceeded 1,500, further supporting the reliability of this conclusion. This result reflects the comprehensive protective effect of TCM on the hematopoietic system. In terms of gastrointestinal adverse reactions, multiple reviews have shown that Chinese herbs such as Pinellia ternata and ginger can effectively alleviate digestive symptoms, including nausea, vomiting, bloating, and loss of appetite. Multiple clinical trials have validated this conclusion, and the mechanisms have been preliminarily revealed in animal experiments.39,42,43 For chemotherapy-induced peripheral neuropathy and cardiotoxicity, TCM has also shown good results in prevention and treatment. A meta-analysis involving 2,356 patients found that external TCM treatment reduced the incidence of peripheral neuropathy by 20%, increased the overall recovery rate by 30%, and increased the effective rate of symptom severity scores by 35%.44 A review showed that qi- and heart-nourishing prescriptions can significantly reduce abnormal elevations of cardiotoxicity indicators (such as troponin and BNP) and protect cardiac function.45 These clinical benefits are achieved because of the guiding advantage of the holistic concept of TCM. Rather than targeting the isolated symptom of FN, TCM treatment improves the overall functional status of the body by regulating internal balance, thereby achieving multi-system and multi-target comprehensive regulation and a beneficial transformation of the treatment model. This therapeutic feature of holistic regulation aligns with the needs of modern tumor supportive therapy.46 With continued research, the comprehensive value of TCM in tumor supportive therapy is expected to be more fully demonstrated.
The safety of TCM in FN treatment
Existing studies have shown that, with regulated medication use, TCM interventions for FN have a good safety and tolerability profile.35 Clinical data show that adverse reactions to TCM compound preparations are generally low. They are dominated by mild gastrointestinal discomfort (such as nausea and abdominal distension), which can be relieved on its own within a short period without special treatment.47 From the perspective of long-term drug safety, the incidence of liver and kidney function abnormalities was not statistically different from that of the control group in patients who continued to use TCM for three to six months.48 In the treatment of FN with TCM, clinical data show that, compared with drugs such as G-CSF, TCM does not cause significant adverse reactions such as bone pain and vasculitis, nor does it increase the risk of secondary tumors.35 The good safety characteristics of TCM are mainly due to the treatment concept of “dialectical treatment”. This approach allows adjustment of the medication plan according to the patient’s constitution and condition characteristics, thus avoiding adverse drug reactions to the greatest extent possible. However, to ensure medication safety, drug interactions need to be guarded against in elderly patients receiving multiple medications. Special herbs, such as insects and minerals, should also be strictly controlled with regard to indications.49,50 In short, TCM is a low-risk therapy that can be applied to FN.
Strengths, challenges, and prospects
TCM for FN has unique clinical value and development potential. Its core advantages are mainly reflected in the overall regulatory effect of multiple targets, the individualized advantage of dialectical treatment, and the preventive health care value associated with high safety. Nevertheless, the efficacy of TCM is often questioned. Therefore, this review aims to evaluate the effectiveness of TCM within an evidence-based medicine framework by synthesizing existing clinical evidence, including systematic reviews and meta-analyses, RCTs, retrospective studies, case-control studies, and safety data. The results suggest that an integrated approach combining TCM and modern medicine is more effective than modern medicine alone. However, the treatment of FN with TCM still faces many challenges. Firstly, the criteria for dialectical treatment have not been fully unified, which affects the reproducibility of treatment protocols. Secondly, the quality of existing clinical studies varies, and large-sample, multicenter, high-quality studies are still insufficient. Thirdly, current research suggests that TCM may play a role through multiple pathways and targets, including immune regulation, improvement of the hematopoietic microenvironment, and anti-inflammatory and antiviral.51,52 However, there is still a relative lack of basic experimental research on the treatment of FN with TCM. These mechanisms are mostly based on preliminary speculation and have not yet been fully validated by solid experimental data. In addition, the components of TCM compound formulas are complex, and their effective ingredients and mechanisms of action remain unclear. Systematic research on the material basis and pharmacological mechanisms still needs to be further explored. Finally, in the treatment of acute and severe FN, the positioning, timing, and mode of TCM intervention still need to be further clarified, and the synergistic approach with Western medicine treatment requires optimization. Future development of TCM for FN should focus on the following directions. First, diagnostic and therapeutic norms should be established based on evidence-based medicine, with unified dialectical criteria formulated. Second, multicenter clinical trials conducted in accordance with international norms should be carried out to provide higher-level evidence. Third, the optimal mode of combining TCM and modern medicine should be explored to form therapeutic plans with complementary advantages. Fourth, modern scientific and technological methods, such as network pharmacology,53,54 should be used to further elucidate the mechanisms of TCM compounding. At the same time, research on drug interactions between TCM and modern drugs should be strengthened to promote the modernization and internationalization of TCM.
Conclusions
This review systematically analyzes the application value of TCM in the treatment of FN. The results show that TCM, as a promising and safe complementary therapy, exhibits unique clinical advantages in the comprehensive treatment of FN. Existing clinical evidence demonstrates that the combination of TCM and modern medicine significantly reduces the incidence of FN, effectively increases granulocyte counts, shortens the duration of fever, improves patients’ quality-of-life scores, and attenuates other toxicities associated with chemotherapy compared with modern medicine alone. However, it should be emphasized that some current clinical studies have limitations, such as small sample sizes, irregular randomization methods, and non-strict implementation of blinding. These methodological shortcomings may affect the reliability of the study results. Therefore, there is an urgent need for large-sample, multicenter, randomized, double-blind, high-quality clinical trials to further validate the clinical efficacy of TCM for FN. With continuous improvement in study design and deeper exploration of underlying mechanisms, TCM is expected to play a more important role in the prevention and treatment of FN, ultimately benefiting patients worldwide.
Declarations
Acknowledgement
Thanks to Figdraw.
Funding
This work was supported by the Fundamental Research Funds for the Central Public Welfare Research Institutes (No. ZZ14-YQ-013); the National Key Research and Development Program of China (No. 2023YFC3503300 and No. 2023YFC3503301); and the High-Level Chinese Medical Hospital Promotion Project (No. HLCMHPP2023034 and No. HLCMHPP2023085).
Conflict of interest
The authors have no conflicts of interest related to this publication.
Authors’ contributions
Conceptualization (KDC, WH, XQW), data curation (KDC), formal analysis (KDC), investigation (KDC, JKW), project administration (KDC, WH, XQW), visualization (KDC, JKW), resources (WH, XQW), supervision (WH, XQW), writing – original draft (KDC, JKW, JWW, SWA, DWA, SHH, BJF, LXZ, XQW), writing – review and editing (KDC, JKW, JWW, SWA, DWA, SHH, BJF, LXZ, WH, XQW). All authors made significant contributions to this work and approved the final manuscript.