Combination of Danggui Buxue Tang and concurrent chemoradiotherapy improves treatment outcomes by strengthening B cell immunity in patients with nasopharyngeal carcinoma—a double-blind, randomized trial

Introduction

Nasopharyngeal carcinoma (NPC) is a relative uncommon cancer globally, but it is common and endemic in southern China, Hong Kong, Southeast Asia, North Africa, and the Middle East (1,2). Approximately 1,500 new cases are reported annually in Taiwan (3), and the standard treatment options for NPC are radiotherapy (RT) alone for stage I and definite concurrent chemoradiotherapy (CCRT) for stages II–IVB (4). Patients with NPC experience many treatment-related acute or late toxicities, such as loss of taste, dry mouth, oral mucositis, sore throat, dysphagia, and radiation dermatitis. However, no standard management options are available for these adverse effects (5-11).

Adjunctive traditional Chinese medicines (TCMs) are now widely used for NPC and have been demonstrated to decrease treatment-related adverse effects and improve survival outcomes (12-20). Previous studies have reported the effect of TCMs in resolving the adverse effects of CCRT in patients with NPC (12,13,15,16); however, rigorous clinical trials are needed. In addition, several aspects should be considered. First, few randomized trials were found, and the articles were published in the early twentieth century, when CCRT was not the standard treatment for NPC. Second, the TCMs used in these studies were usually composed of many herbal drugs, and different drugs were used according to the patients’ clinical symptoms (12-16,18,19), limiting their routine use in clinical practice. Third, some adjunctive TCMs are prescribed as injections, which is inconvenient in clinical use. Therefore, readily available medicine with simple composition and oral form, such as scientific Chinese medicine, is more suitable for clinical practice.

In addition, patients with NPC experience fatigue, shortness of breath, flushing sensation, dry skin/mouth, and constipation during RT/CCRT (21). Per the Chinese medical syndrome differentiation and treatment model, deficiency of both qi and yin caused by the “heat poison” of RT/CCRT leads to these symptoms. Danggui Buxue Tang (DBT) is composed of only two drugs, Astragali Radix (Huang-Qi) and Angelica, which can supplement both qi and yin. The DBT formula has been found to act as a sensitizer for RT or chemotherapy in colorectal cancer cell lines (22). Moreover, addition of DBT has been proven to be effective in the prevention of chemotherapy-induced myelosuppression in patients with breast cancer (23).

The botanically derived drug PG2, an extract from Astragali Radix, modulates the immune response, ameliorates inflammation, and improves cancer-related fatigue (24-26). Despite the growing interest in DBT, current evidence supporting its clinical effectiveness remains limited and inconclusive, highlighting an urgent need for further comprehensive research to establish its therapeutic value and long-term impact on patient outcomes.

In addition, the anticancer effects of DBT are reportedly achieved through the modulation of different mechanisms and pathways (22,27,28). In vitro evidence has shown that DBT can sensitize the murine colon carcinoma cell line (CT26) to RT and increase the therapeutic effect of CCRT in CT26 cells (22) and is capable of inducing autophagy-associated cell death in CT26 cells by triggering the mTOR/p70^s6k signaling pathway, leading to the activation of Atg7 (an autophagy-related protein) (27). In an in vivo experiment, DBT inhibited metastatic colon cancer by upregulating the expression of Bax, caspase-3, and cleaved caspase-3 and by downregulating the expression of Bcl 2 (28). Therefore, we investigated whether a combination of DBT and CCRT for treating NPC could influence the patients’ immunity and explored the possible modulated signaling pathways using next-generation mRNA sequencing. We present this article in accordance with the CONSORT reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-406/rc).

Methods

Patients, study design, and treatment

This double-blind, randomized trial was performed in two high-volume medical centers (Taichung Veterans General Hospital and China Medical University Hospital). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Human Research Ethics committee of the China Medical University Hospital (No. CMUH106-REC1-068) and Taichung Veterans General Hospital (TCVGH-IRB No. SG20126A) and informed consent was obtained from all individual participants. The eligible criteria were as follows: (I) age 20–70 years; (II) previous untreated, biopsy-proved NPC; (III) clinical stage II–IVA according to American Joint Committee on Cancer, 8^th edition; (IV) Eastern Cooperative Oncology Group performance status 0–2; and (V) planned to receive CCRT. All patients received pretreatment staging workup including physical examination, medical history taking, baseline blood count, serologic biochemistry test (liver and renal function), chest radiography, abdominal ultrasonography, magnetic resonance imaging of head and neck, whole body bone scan, and ¹⁸F-fluorodeoxyglucose positron emission tomography scan. The exclusion criteria were as follows: (I) pregnant or lactating women; (II) distant metastatic disease at initial diagnosis; (III) received neoadjuvant chemotherapy followed by RT/CCRT; (IV) received anticoagulant or antiplatelet agents, such as aspirin or warfarin; and (V) unable to cooperate with the research protocol.

This study was initiated on July 26, 2018, and discontinued in February 2021 because of the DBT expiration date. Each group was expected to include approximately 60 patients. However, due to the impact of the COVID-19 endemic, patient recruitment was unsatisfactory. Finally, a total of 28 patients were randomly assigned at a 1:1 ratio to receive DBT or placebo with CCRT. The randomization process was integrated with drug preparation, using permuted block randomization to assign participants to either the experimental or control group, with good manufacturing practices-certified pharmaceutical factory labeling and packaging of the drugs. To preserve the double-blind design, individual emergency decoding envelopes were prepared and securely stored by the principal investigator, while the randomization documents were held in the dispensing unit. Furthermore, to achieve a double-blind design and mask the distinctive flavor of DBT, the placebo was formulated by spraying caramel coloring with corn starch and adding 1/20th of the DBT dose, followed by thorough mixing. Once the patients were enrolled in this study, pretreatment blood sampling for mRNA sequencing and a questionnaire survey to determine the TCM constitution were performed. The start date of RT was defined as day 1, week 1, and the patients would repeat the above examinations again at week 12. Thereafter, the questionnaire for TCM constitution was administered every 3 months for 2 years. Evaluable data were obtained from 24 patients who completed the pre- and post-treatment blood tests and TCM constitution questionnaires. A detailed flow chart of enrollment is shown in Figure 1.

Figure 1 Flow chart of patient enrollment. CCRT, concurrent chemoradiotherapy; DBT, Danggui Buxue Tang; NPC, nasopharyngeal carcinoma; RT, radiotherapy.

CCRT was delivered by a 6-MV photon beam (either intensity-modulated RT, volumetric arc therapy or TomoTherapy) with a total radiation dose of 70 Gy in 35 fractions (2 Gy per fraction, once daily, five fractions per week) in combination with platinum-based regimen (the most commonly used regimen was weekly cisplatin 30–40 mg/m²). The DBT or placebo was prescribed three times a day after meals for 12 weeks from the start date of RT.

TCM constitution definition

The patients’ TCM constitution were classified into nine categories according to Wang Qi’s “Classification and Judgment Form of TCM Physique” (29), including peace (normal constitution), phlegm-dampness, damp-heat, yin deficiency, qi deficiency, blood stasis, stagnation of qi, yang deficiency, and special characteristics. The TCM constitution was based on the patient’s subjective symptom description in the Constitution in Chinese Medicine Questionnaire (CCMQ). The corresponding symptoms for different TCM constitutions are described as follows: chest tightness, abdominal fullness, heavy body sensation, or much sputum production for phlegm-dampness; acne formation or sticky feeling after defecation for damp-heat; flushes, dry skin/mouth, or easy constipation for yin deficiency; fatigue or shortness of breath for qi deficiency; unnoticed ecchymoses or body pain for blood stasis; sighing often, depressed or anxious mood for stagnation of qi; afraid of cold or easily catching a cold for yang deficiency; and allergic constitution for special characteristics.

RNA extraction, library preparation, and transcriptome sequencing

Every enrolled patient underwent blood testing at two time-points: at week 0 (before RT) and at week 12 after the start date of RT. The blood samples were saved in Tempus^TM blood RNA tubes that were shaken at least 10 times to mix the blood and buffer completely. After incubation at room temperature for at least 2 hours, it was stored at 4 ℃. Total RNA was extracted using Tri Reagent (Ambion, Austin, TX, USA). RNA concentration and quality were determined using a NanoDrop ND-1000 spectrophotometer (Thermo Scientific, Waltham, USA) and Agilent 2100 Bioanalyzer (Agilent Technologies, Palo Alto, CA), which calculates the RNA integrity number (RIN). Criteria for total RNA included the following: A260/A280 =1.8–2.0, and RIN >8.0.

We used 2 µg of RNA for library construction. RNA library preparation consisted of the following steps: RNA purification and fragmentation, first strand cDNA synthesis, second strand cDNA synthesis, 3' end adenylation, adapter ligation, and DNA fragment enrichment. Sequencing was performed on NextSeq500 (v2, 1×75 bp, Illumina Inc., San Diego, CA, USA) to generate 75-bp paired-end reads.

Data processing

We used FastQC (version: 0.11.8) to perform quality control assessments on raw data arising from high-throughput sequencing pipelines; Trimmomatic (version: 0.39), to remove low-quality reads, eliminate poor-quality bases, and trim adaptor sequences from raw data; HISAT2 (version: 2.1.0), to map the reads to the Homo sapiens reference genome (hg38); and Rsubread (version: 1.32.4), to quantify expression at the gene, transcript, and exon levels. Gene count was normalized using the trimmed mean of M value.

Follow-up, end points, and statistical analysis

The post-treatment follow-up (physical examinations, routine complete blood cell count, serologic biochemistry data of liver and kidney, and fiberscope) was scheduled monthly for 3–6 months, at 3-month intervals for 3 years, and every 4–6 months thereafter. Computed tomography of the head and neck was conducted every 3–6 months for 3 years and annually thereafter.

The primary end point was to determine whether the combination of DBT and CCRT could improve treatment-related adverse effects and compliance of patients with NPC. The secondary end points were to determine (I) whether the patients’ TCM constitution and clinical discomfort could be improved in the DBT group and (II) the differentially expressed genes (DEGs) and possible signaling pathways in the two groups. Due to patient withdrawal and the resulting incomplete questionnaire data, per-protocol analysis method was adopted to ensure the validity of the findings by including only those participants who fully adhered to the study protocol. This approach allows for a more accurate assessment of the intervention’s effect among compliant participants, although it may limit the generalizability of the results. Acute toxicities were recorded every week during CCRT based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 (30). According to the Chinese medical syndrome differentiation and treatment model, we focused on pre- and post-treatment change in TCM constitutions of the qi and yin, respectively. Patient characteristics, treatment-related adverse effects, and compliance rates between the groups were compared using Fisher’s exact test. The changes in pre- and post-treatment TCM constitutions between the two groups were compared using McNemar’s test. All statistical analyses were performed using SAS version 9.4, and a two-sided P<0.05 was considered statistically significant.

DEG analysis was performed using the DESeq2 R package. We compared the DBT and placebo groups to determine the upregulated and downregulated DEGs. The DEGs were screened, and the adjusted P value was set at <0.1. The functions of these DEGs were further analyzed by gene set enrichment analysis. Gene Ontology (GO), including biological process (BP), cellular component (CC), molecular function (MF) terms, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using Database for Annotation, Visualization and Integrated Discovery (DAVID). P<0.05 was considered statistically significant.

Results

Patient characteristics

This double-blind, randomized trial aimed to determine whether a combination of DBT and CCRT for NPC can improve the treatment outcomes and patients’ TCM constitutions. The patients’ clinical characteristics were similar between the two groups (Table 1). The DBT group was younger, possibly owing to bimodal distribution of predisposing age for NPC, but this did not interfere with the study outcomes (31). The majority of the enrolled patients were male (75%). Half of the enrolled patients had disease of clinical stage III (stage II vs. stage III vs. stage IV =41.7% vs. 54.2% vs. 4.2%). The proportions of pretreatment qi deficiency and yin deficiency were similar between the groups.

Alleviation of treatment-related adverse effects and compliance with DBT

All patients were alive for the median follow-up duration of 18.5 months (range, 6–39 months). Four patients experienced locoregional recurrence (three patients in the CCRT + placebo group and one patient in the CCRT + DBT group), and none of them experienced distant metastasis.

Patients with NPC treated with CCRT + DBT had lower treatment-related adverse effects. Patients in the DBT group did not experience ≥ grade 2 neutropenia (P=0.1), and only one patient had grade 1 anemia (P=0.3) (Table 2). In contrast, four patients in the placebo group had ≥ grade 2 neutropenia, and four patients had grade 1 anemia. Patients in the DBT group had a higher incidence of ≥ grade 2 anorexia (P=0.01). No difference was observed between the two groups in terms of body weight loss, oral mucositis, radiation dermatitis, renal and hepatic toxicities.

Our study also showed improved treatment compliance among patients with NPC treated with CCRT + DBT. Only one patient (9.1%) in the DBT group received a CCRT dose of cisplatin <200 mg/m² compared with three patients (23.1%) in the placebo group. Patients in both groups received the planned radiation dose of 70 Gy in the same median treatment duration of 48 days. The median medication compliance rates were 83.3% (DBT) and 48.4% (placebo) (P=0.93).

Improved post-CCRT qi and yin deficiency for NPC treated with DBT

Patients with NPC treated with CCRT + DBT had decreased treatment-related adverse effects and improved compliance. We further displayed the changes in TCM constitutions after CCRT using the CCMQ questionnaire data. The qi deficiency and yin deficiency before and after CCRT in patients in the DBT group were similar (P=0.18 and 0.99, respectively). In contrast, patients in the placebo group had significantly increased incidences of qi and yin deficiency after treatment (both P<0.05), as shown in Table 3. The detailed scores on qi deficiency and yin deficiency are also displayed in Table 3; higher scores indicate the presence of more serious clinical symptoms.

DEGs and possible signaling pathways in patients with NPC who received CCRT + DBT

The transcriptomic results of the DBT and placebo groups were compared. The leading upregulated DEGs in both groups are displayed in Figure 2A. The majority of the upregulated DEGs were associated with B cell receptor signaling and development, such as BLK, CD72, CD22, CD79A, FCER2, PAX5, EBF1, and VPREB3. One downregulated DEG (LOC122526776) was found, but it was a novel gene without clear function. Furthermore, functional and enrichment analyses of these upregulated DEGs were performed using DAVID (Figure 2B). The predominant BPs were B cell receptor signaling pathway, adaptive immune response, B cell differentiation, immune response, and B cell activation. The possible mechanism by which DBT exerted its effect was through the B cell receptor signaling pathway. Therefore, DBT could modulate patients’ immunity through the B cell receptor signaling pathway.

Figure 2 Comparisons of post-treatment transcriptomic data between the groups. (A) Leading upregulated DEGs identified in both groups. (B) GO enrichment and KEGG pathway analyses. GO enrichment analysis classified the DEGs under three terms: BP, CC, and MF. The count indicated the number of pathway genes. All P values (DEGs and pathway) were <0.05. BP, biological process; CC, cellular component; DEGs, differentially expressed genes; FC, fold change; GO, Gene ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; MF, molecular function.

Discussion

To our knowledge, this is the first multicenter, double-blind, randomized trial to investigate whether a combination of DBT and CCRT for NPC can improve the treatment outcomes, patients’ TCM constitution, and related clinical discomfort, as well as the signaling pathways involved. Our results showed that the addition of DBT decreased the occurrence of treatment-related adverse effects, enhanced compliance, and improved patients’ clinical symptoms related to both the qi and yin deficiency after CCRT. Besides, DBT enabled the patients’ B cell immunity to recover persistently even after the medication period. According to our results, addition of DBT is a feasible adjunctive treatment modality for patients with NPC who receive standard CCRT.

Many supportive management approaches are used to improve the RT/CCRT-related adverse effects in patients with head and neck cancer, but a standard treatment protocol is lacking (5-11). Many adjunctive TCMs have been reported to be beneficial in relieving RT/CCRT-related adverse effects in NPC (12-20). However, the composition of these medicines is usually complex; the additions and subtractions make it difficult to use in Western medicine, and there is limited evidence on their effectiveness during the period of CCRT. In current study, the composition of DBT was simple with only two drugs, Astragali Radix (Huang-Qi) and Angelica, which are easily available. The DBT treatment did not interrupt the CCRT treatment course. Instead, more patients in the DBT group received high cumulative doses of concurrent chemotherapy, and fewer patients experienced ≥ grade 2 neutropenia and ≥ grade 1 anemia.

In view of the Chinese medical syndrome differentiation and treatment model, CCRT is a “heat poison” that leads to deficiencies of both qi and yin. The clinical symptoms include feeling tired, shortness of breath, sweating with slightly increased physical activity, weakness when talking, hot flashes, hot sensation on the face/palms of hands or soles, dry skin/mouth, or constipation during or after CCRT.

A botanically derived drug of PG2, an extract from Huang-Qi, can modulate immune response, alleviate inflammatory reaction, and improve cancer-related fatigue (24-26). In the current study, the DBT group had significantly improved TCM constitutions of both qi and yin deficiency compared with that in the placebo group. We also found that 10 patients in the DBT group experienced ≥ grade 2 anorexia, but six of them had a medication rate >80%. Patients who develop mucositis during CCRT might be feel an uncomfortable sensation on consuming the powdery oral DBT, which might exacerbate anorexia. However, most of our patients could keep taking medication, possibly because of the decreased extent of clinical discomfort, as stated in the CCMQ questionnaire.

Astragali Radix (Huang-Qi) and Angelica have been demonstrated to be immunomodulatory herbal medicines that can affect immune organs and innate and acquired immunity (32,33). In Chen’s studies, DBT functioned as a chemotherapy or RT sensitizer in colorectal cancer treatment and induced autophagy-associated cell death in a murine colon carcinoma cell line via the upregulation of Atg7 and modulation of the mTOR/p70s6k signaling pathway (22,27). Furthermore, Deng et al. used DBT in an immune-induced aplastic anemia mouse model and found that it could attenuate immune-mediated bone marrow failure (34). In our study, several upregulated DEGs associated with B cell immunity were found, such as the B cell receptor signaling pathway, transmembrane signaling receptor activity, adaptive immune response, B cell differentiation, and B cell receptor complex. Our results suggest that DBT could aid in the recovery of B cell immunity in patients with NPC who undergo CCRT.

The limitations of this study are as follows: (I) lack of stratification of pretreatment TCM constitutions and clinical stage of NPC; (II) small sample size; (III) lack of blood sampling at week 7 (at the completion of CCRT), a timepoint associated with the most dramatic change in TCM constitution; (IV) lack of blood sampling during the DBT medication period, which could not provide the direct therapeutic effect; and (V) NPC is strongly associated with Epstein-Barr virus infection, and this might have interfered with the outcome of mRNA sequencing.

Conclusions

The combination of DBT and CCRT for NPC helped reduce the occurrence of treatment-related adverse effects, increase compliance, and improve patients’ clinical symptoms by improving their TCM constitutions. Furthermore, the addition of DBT to the treatment modality promoted post-treatment immunity by means of B cell immunity.

Acknowledgments

We thank Dr. Ming-Hsui Tsai (Department of Otorhinolaryngology Head & Neck Surgery, China Medical University Hospital, Taichung 404327), Dr. Chun-Hung Hua (Department of Otorhinolaryngology Head & Neck Surgery, China Medical University Hospital, Taichung 404327) and Dr. K. S. Clifford Chao (Department of Radiation Oncology, Taichung Veterans General Hospital, Taichung 40705) for their kind support on this study.

Footnote

Reporting Checklist: The authors have completed the CONSORT reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-406/rc

Trial Protocol: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-406/tp

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-406/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-406/prf

Funding: This work was financially supported by the Ministry of Science and Technology (No. 106-2320-B-039-018-MY3), Taiwan, and the “Chinese Medicine Research Center, China Medical University” from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan (No. CMRC-CMA-6).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-406/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Human Research Ethics committee of the China Medical University Hospital (No. CMUH106-REC1-068) and Taichung Veterans General Hospital (TCVGH-IRB No. SG20126A) and informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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