Malignant tumors represent the second leading cause of global mortality, posing a paramount public health concern. According to the latest 2020 global cancer burden data released by the International Agency for Research on Cancer, there were 19.29 million newly diagnosed cancer cases and 9.96 million deaths worldwide in 2020. CRC accounted for 10% of the global cancer incidence and a mortality rate of 9%, highlighting a formidable challenge in the global landscape of cancer prevention and control (Sung et al., 2021). CRC, characterized by its heterogeneous nature, often arises from the intricate interplay of genetic and environmental factors. Current research emphasizes the role of mutations in APC, CHEK2, MLH1, MUTYH, and PTEN in increasing the risk of CRC (Seagle et al., 2023). Over half of the new cases may be linked to modifiable risk factors such as smoking, excessive alcohol consumption, antibiotic usage, sedentary lifestyle, and obesity (Zhou et al., 2023; Wu J. et al., 2023; Iwasaka et al., 2023; Zhai et al., 2023). Approximately 25% of all patients with CRC receive a diagnosis of metastatic CRC (mCRC), and 25%–30% of patients with an initial diagnosis of stage I–III CRC eventually develop mCRC within 5 years (Mousa et al., 2015; Cartwright, 2012; Shah et al., 2016; Arnold and Stein, 2013). The clinical treatment of CRC is mainly surgical treatment, while chemotherapy is a widely used adjuvant treatment for patients with middle-advanced CRC. According to the literature, approximately 80% of all recurrences manifest within the initial 3 years after surgery, with 95% occurring within 5 years (Sargent et al., 2009; Seo et al., 2013). Systemic therapy for metastatic colorectal cancer (mCRC) typically begins with chemotherapy regimens that combine a fluoropyrimidine with either oxaliplatin or irinotecan. Although immunotherapy shows potential for treating advanced CRC, it faces challenges such as immunotherapy resistance and a limited population of beneficiaries (Adebayo et al., 2023; Tan and Sahin, 2021). For mCRC that progresses despite these treatments, three oral drugs have been researched and approved: regorafenib (Grothey et al., 2013), fruquintinib (Dasari et al., 2023), and trifluridine/tipiracil (TAS-102) (Mayer et al., 2015). These medications are considered standard later-line treatments and have been shown to extend survival in patients with resistant mCRC. However, the benefits are not universal, as evidenced by the FRESCO study, which reported an objective response rate of only 4.7% for fruquintinib monotherapy.

Traditional Chinese medicine exhibits a range of pharmacological effects and plays a therapeutic role in many critical aspects of diseases. Brucea javanica, a medicinal plant found throughout Asia in open areas and secondary forests (Ye et al., 2015), has demonstrated significant potential in this regard. Extracts from its fruit have been shown to possess anti-proliferative and pro-apoptotic properties on human carcinoma cells (Man et al., 2012).BJOEI comprises oil-soluble components formulated into a water-in-oil emulsion with refined Brucea javanica, purified lecithin, glycerol, and injectable water. Widely employed as an anti-tumor Chinese herbal injection, BJOEI has obtained approval from the China Food and Drug Administration (China drug approval number: Z 19993152) for the treatment of lung cancer, brain metastases from lung cancer, and digestive system tumors. Recent studies investigated cytotoxicity effects of Brucea javanica on tumor such as lung (Xie et al., 2021), liver (Chen et al., 2016), colorectal (Bagheri et al., 2018a), gastric (Li et al., 2020), esophageal (Qiu et al., 2019), and pancreatic cancers (Wu Y. et al., 2023). Primarily, it initiates the activation of caspase-8/9 and concurrently modulates apoptosis-associated proteins. This coordinated modulation leads to the initiation of apoptotic pathways in HT29 and HCT116 CRC cells. Additionally, it exerts a direct inhibitory effect on HCT116 CRC cell proliferation by facilitating cellular autophagy (Bagheri et al., 2018a; Bagheri et al., 2018b; Yan et al., 2015). Besides, BJOEI as adjuvant therapy also showed superiority in efficacy and safety for cancer treatment in clinical practice (Chen et al., 2022). BJOEI plus chemoradiotherapy may have positive effects on lung cancer, gastric cancer and CRC (Nie et al., 2012; Wang et al., 2021; Gao and Zhang, 2023). It is very important to improve quality of life and reduce incidences of some adverse effects compared with chemoradiotherapy alone. This study is principally aimed at acquiring preliminary insights that will underpin a phase III clinical trial focused on the assessment of BJOEI’s efficacy and safety, administered in conjunction with optimal supportive care, for patients afflicted with mCRC who exhibit resistance to all prevailing therapeutic options.

CRC stand as a significant global health burden, ranking as the third most prevalent malignancy. Substantial evidence indicates that 90% of CRC cases are diagnosed in individuals aged 50 and above. Alarmingly, the incidence of CRC among younger populations is increasing (Penz et al., 2023). The 5-year survival rate for mCRC remains dishearteningly low at 6% (Coco et al., 2012). The most effective treatment for mCRC is 5-FU-based regimens. However, disease progression after two lines of doublet chemotherapy remains inevitable. Although several drugs are the standard third-line treatment of mCRC in guidelines (Grothey et al., 2013; Dasari et al., 2023; Mayer et al., 2015), they yield minimal response rate and short PFS and OS. In general, the efficacy of third-line and subsequent treatments is unsatisfactory. Few treatment options exist for this population of patients. Traditional Chinese Medicine (TCM) theories and treatment approaches are gaining global acceptance, with integrative Chinese and Western medicine emerging as a novel avenue in cancer therapy. TCM demonstrates unique advantages in tumor treatment. BJOEI have been widely used for the treatment of cancer in China. Numerous clinical studies have shown that BJOEI when combined with FOLFOX/FOLFIRI regimens, enhances tumor treatment efficacy, improves patients' quality of life, and mitigates adverse reactions (Gao and Zhang, 2023).

In prior studies of BJOEI on CRC, the primary endpoint was the ORR. However, this measure alone cannot fully capture the clinical benefits of the trial drug. PFS is utilized both as a surrogate end-point for OS and as a primary trial end-point in itself (Robinson et al., 2014). Therefore, we hope to further objectively evaluate the clinical effectiveness of BJOEI combined with BSC from the PFS status. In addition, Safety assessments will include the incidence, nature, and severity of adverse events; serious adverse events and laboratory abnormalities. Laboratory safety assessments will include the regular monitoring of hematology and blood chemistry.

However, the study design has several limitations. Firstly, obtaining a placebo for BJOEI in China is challenging, making it impossible to blind the study. Secondly, this study is a small-scale trial intended to provide effect size data for calculating sample sizes in future large-scale randomized controlled trials. Thirdly, since the experiment will be conducted in five centers within China, we now clearly state that the findings may primarily reflect outcomes in the Chinese population and that caution should be exercised when extrapolating results to other ethnic groups due to potential pharmacogenomic differences.

The present findings will be hypothesis-generating and will supply the parameters necessary for a rigorously powered confirmatory phase III trial. We anticipate that this trial will offer a new treatment option for advanced CRC patients who are unresponsive to standard therapies.