This study is a prospective, randomized, controlled, multicenter clinical trial evaluating the efficacy of BTG in combination with chemotherapy for the treatment of CRLM characterized by spleen deficiency and liver depression, stasis, and toxin interpunction type. Participants will be divided into two distinct groups: the treatment group, which will receive conventional first-line antitumor therapy in combination with BTG, and the control group, which will receive conventional first-line antitumor therapy alone. Patients will be treated until disease progression is observed, at which point they will be followed up until death. The trial design is presented in Figure 1 and the schedule in Table 1, respectively.

This randomized controlled trial has been approved by the Human Research Ethics Committee of Shanxi hospital of Traditional Chinese medicine (approval No. 2024KY-07020) and registered in the Chinese Clinical Trial Registry (No. ChiCTR2400084861). Prior to participation in any aspect of the study, all participants will be required to provide written informed consent. Moreover, participants may withdraw from the study at any point. Following the assessment of relevant entry criteria within a week preceding the commencement of the intervention, enrolment will be confirmed. At this point, baseline characteristics, including sex, age, body mass index (BMI), pathological type, Eastern Cooperative Oncology Group (ECOG) performance status score, and disease history, will be recorded. A series of tests will be conducted on each participant, including full blood count, urine analysis, tumor markers analysis (e.g., CEA and CA19–9), liver and renal function tests. These tests will be performed at the baseline, treatment weeks 3, 6, 9, and 12.

Participants will be included if they meet the diagnosis criteria of the 2023 edition of the Colorectal Cancer Diagnosis and Treatment Guidelines issued by the Chinese Society of Clinical Oncology (CSCO) (25) and the 2008 edition of the Guidelines for the Diagnosis and Treatment of Cancer in TCM issued by the Chinese Association of Traditional Chinese Medicine (26).

Participants are eligible to participate in this study after meeting all of the following criteria: (a) aged 18–80 years, male or female, with an expected survival of ≥3 months; (b) diagnosed with colorectal adenocarcinoma, deemed unresectable by multidisciplinary assessment, with liver-only or liver-based metastasis; (c) evaluable liver metastases (maximum diameter ≥ 10 mm) unsuitable for surgical resection or local ablation; (d) no prior advanced systemic or local therapy for liver metastases; (e) diagnosed with spleen deficiency and liver depression, stasis, and toxin interpunction per TCM criteria; (f) Karnofsky Performance Status (KPS) score ≥ 60; (g) voluntarily participate in the study, and patients or their immediate relatives are able and willing to sign the informed consent.

Participants who meet any of the following criteria will be excluded from this study: (a) non-primary colorectal cancer with an unclear diagnosis; (b) with polygenic carcinoma or other malignant neoplasms; (c) extensive peritoneal metastases, MSI-H/dMMR, or other targeted therapies; (d) presenting with severe hepatic or renal insufficiency, intestinal obstruction, perforation, jaundice, or bleeding; (e) unwilling or unable to accept TCM treatment; (f) allergy to one or more of the Chinese herbs included in this protocol; (g) pregnancy or lactation in women; (h) poor compliance or inability to commit to completing the protocol; (i) participation in other clinical trials within the previous 3 months.

Participants will freely withdraw (discontinue participation) from the trial at any time and for any reason. Researchers should meet all research expectations, including regulatory requirements in the current trial and the Guidelines for Good Clinical Practice. Researchers should prevent patients from the situation such as (but not limited to): occurrence of an unexpected serious concomitant disease.

A review of previous literature indicates that the median progression-free survival (PFS) of the control group is estimated to be 6.1 months. With a significance level of α = 0.05 (two-sided), a power of 0.9.

Sample size is calculated according to the following formula:

n = Z 1 − α + Z 1 − β 2 × π 1 × 1 − π 1 + π 2 × 1 − π 2 / π 1 − π 2 2 .

Considering a dropout rate controlled within 10%, the sample size calculation indicates that 105 cases per group, totaling 210 cases, are required.

Participants will be randomly assigned to treatment and control groups in a 1:1 ratio using SAS9.3 software to generate the random sequence in blocks of 6 with no stratification. An independent researcher, not involved in treatment or data analysis, will generate the sequence. Randomization assignments were concealed in opaque, sealed envelopes, which were distributed sequentially to participants after informed consent was obtained and baseline measurements were completed. Randomization will be managed through a central system, with clinical investigators accessing it by telephone or online to obtain randomization numbers. This study employed a single-blind design. The investigator responsible for patient assignment was not involved in patient recruitment, assessment, treatment, or data analysis. Study evaluators remained blinded to patient allocation throughout the study.

All patients will receive a standard chemotherapy regimen following the initial treatment. The chemotherapy regimen is XELOX (capecitabine plus oxaliplatin), administered over four cycles spanning 12 weeks, with each cycle lasting 3 weeks. The XELOX regimen is as follows: oxaliplatin will be administered intravenously at a dose of 150 mg/m² on Day 1 of each 3-week cycle, and capecitabine will be administered orally at a dose of 1,000 mg/m², twice daily, from Day 1 to Day 14 of each 3-week cycle. The control group will receive only the standard XELOX chemotherapy regimen. In contrast, the treatment group will receive the standard XELOX chemotherapy along with BTG. BTG will be administered orally at a dose of 10 g, twice daily, from Day 1 to Day 14 of each 3-week cycle. Chemotherapy will be administered in the outpatient clinic, and patients will undergo follow-up assessments at three-week intervals. All patients will have weekly clinical evaluations and routine blood tests throughout the chemotherapy course. Supportive therapies, including myocardial protection, liver protection, acid inhibition, and antiemetic treatments, will be provided as needed to manage potential adverse effects.

The primary outcomes will be the PFS, with quality of life as a co-primary outcome. PFS will be calculated as the time from randomization to the first recurrence, metastasis, progression, or death from any cause, in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Quality of life will be assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30).

Secondary outcomes will include the overall survival (OS), objective response rate (ORR), disease control rate (DCR), liver-specific progression-free survival, efficacy of TCM syndrome, piper fatigue scale, and Karnofsky performance status (KPS) score. OS is analyzed by calculating the time interval from the date of inclusion to the date of death from any cause or the date of the last follow-up for surviving patients, and then estimated using the Kaplan–Meier method. Objective tumor responses were evaluated based on complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). ORR is defined as the proportion of patients achieving CR and PR. DCR is calculated as the combined proportion of patients with CR, PR, and SD. Liver-specific progression-free survival is defined as the time from randomization to radiological liver progression. The TCM syndrome therapeutic effect referred to the judgment standard of TCM syndromes of cancer-related fatigue according to the Principles of Clinical Research Guidelines for New Chinese Drugs (27). The therapeutic effect index = (pretreatment total score − posttreatment total score)/pre-treatment total score × 100%. The definitions of clinical efficacy included healed (efficacy index ≥90%), markedly effective (efficacy index <90% and ≥ 70%), effective (efficacy index <70% and ≥ 30%) and ineffective (efficacy index <30%). The therapeutic effect was evaluated by the percentage of TCM syndrome scoring of the patients. Total efficiency = (healed number + markedly effective number + effective number)/total number × 100%.

All adverse events (AEs) will be recorded and assessed. AEs occurring during the course of treatment will be classified in accordance with the US National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) or World Health Organization (WHO) grading. Once grade 3–4 AEs occur, a comprehensive account will be compiled, including the time of occurrence, clinical manifestations, duration, physical examination results, laboratory findings, interventions and outcome. Researchers will discuss the causal relationship with the testing treatment and decide whether participation in the trial should continue.

In all centers, we intend to conduct long-term follow-up (12–24 weeks post-treatment) beyond the duration of this project to monitor metastasis development in accordance with current standards. Data on disease-free survival, cancer-specific survival, and overall survival will be recorded.

All study data will be entered into electronic case report forms within the study’s electronic data capture system to facilitate data integration and management. The system includes a complete audit trail, utilizing anonymous subject identification numbers. The principal study site will establish a unified data processing agreement with collaborating centers and ensure strict adherence to its implementation. Any amendments to the protocol must be submitted to and approved by the Ethics Committee of Shanxi hospital of traditional Chinese medicine. At the end of the study, the database will be locked and analyzed in accordance with the agreement between the principal investigator and statistician, who will be granted access to the final trial dataset.

The EpiData 3.0 software will be employed for the management of the database, while the SAS 9.2 software will be utilized for the statistical analysis. The study is conducted in accordance with intention-to-treat (ITT) analysis principles. Continuous data that conforms to a normal distribution will be represented by the mean ± standard deviation. Hypothesis testing will be conducted using an independent sample t-test. In the event that the data does not conform to a normal distribution, it will be represented by the median (interquartile range) and analyzed using the Kruskal-Wallis test. In the context of multicenter analysis, the CMH chi-squared test and covariance analysis will be employed. PFS will be analyzed using Cox regression, while TCM symptom scores, quality of life scores, and Piper Fatigue Scale data will be analyzed using covariance analysis. The Wilcoxon rank-sum test will be employed to assess the efficacy of TCM symptoms. The differences between the treatment and control groups will be quantified using the log-rank method. Missing data were addressed using a simple imputation method. No interim analyses were planned or conducted. Subgroups analysis will be carried out by the left or right colon, stages of CRLM, sex, and age. A p-value of less than 0.05 will indicate statistical significance.

Currently, participant recruitment is ongoing.