Qu-Shi-Jie-Du decoction for prevention of recurrence and metastasis in high-risk stage II/III colon cancer: Study protocol for a double-blind, randomized, placebo-controlled trial

Qu-Shi-Jie-Du decoction for prevention of recurrence and metastasis in high-risk stage II/III colon cancer: Study protocol for a double-blind, randomized, placebo-controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol Qu-Shi-Jie-Du decoction for prevention of recurrence and metastasis in high-risk stage II/III colon cancer: Study protocol for a double-blind, randomized, placebo-controlled trial Ya-dong Chen, Zi-yan He, Wen-jie Zhao, Yi-han He, Yi-hong Liu, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5908874/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Colorectal cancer is one of the most common and fatal cancers worldwide. Despite therapeutic advancements, patients with stage II and III colon cancer often experience recurrences and metastases, particularly to the liver, leading to suboptimal disease-free survival rates and decreased long-term survival. Qu-Shi-Jie-Du decoction (QSJDD), a traditional Chinese herbal formula, may prevent cancer recurrence and spread by boosting immunity, reducing inflammation, and inhibiting tumour growth. Preliminary studies have demonstrated that QSJDD reduces liver metastasis in patients with colon cancer. However, robust clinical evidence is required to confirm its efficacy and safety. This study aims to evaluate the safety and efficacy of QSJDD in preventing colon cancer recurrence and liver metastasis, thereby offering a potential adjunctive therapy to improve patient outcomes. Methods This multicentre, double-blind, randomised, placebo-controlled trial includes 336 high-risk patients with stage II or III colon cancer from 10 hospitals across China. After surgery and chemotherapy (fluorouracil monotherapy, CAPEOX or mFOLFOX6), 168 patients will be randomised to either the intervention (QSJDD compound granules) or placebo group. The treatment lasts for 6 months, followed by a 3-year follow-up period with assessments conducted every 6 months. The primary endpoint is the 3-year disease-free survival rate, whereas the secondary endpoints include 1- and 2-year relapse rates, overall survival, and variations in the Traditional Chinese Medicine Dampness Syndrome Scale. Safety outcomes including adverse events, will also be monitored. Additionally, the blood and gut microbiomes of patients will be analysed to investigate the effect of QSJDD in delaying the metastasis of colon cancer. Discussion This trial will determine the efficacy and safety of QSJDD and provide evidence regarding its role in the adjuvant treatment of colon cancer. Trial registration Chictr.org.cn Identifier: ChiCTR2300078971. Registered on 22nd December 2023. Qu-Shi-Jie-Du decoction Colon cancer Chinese herbal medicine Protocol Randomized controlled trial Figures Figure 1 Figure 2 Figure 3 BACKGROUND Colorectal cancer (CRC) is a common malignancy, with over 1.9 million cases and 900 thousands deaths in 2022, accounting for nearly 10% of all cancer cases and deaths. 1 In China, over 60% of patients with primary colon cancer are diagnosed at stage II or III. 2 For resectable colon cancer, surgery-based multidisciplinary treatment is preferred, with adjuvant therapy guided by the surgical pathological stage. 3 According to the National Comprehensive Cancer Network (NCCN) guidelines, adjuvant therapy for patients with high-risk stage II and III colon cancer is recommended for either 3 or 6 months. Treatment options include fluorouracil (5-FU) and leucovorin, folinic acid, fluorouracil, and oxaliplatin (FOLFOX), oxaliplatin and capecitabine (CAPEOX), or single-agent capecitabine. 4 Despite standard adjuvant chemotherapy, 20–40% of patients experience recurrences and metastases within 3 years post-surgery. The recurrence rates are 10, 20, and 25% at 1, 2, and 3 years, respectively. 5 Additionally, the 5-year survival rate for metastatic colon cancer is 10%. 6 Reducing recurrences and metastases by enhancing treatment effectiveness for colon cancer remains a significant clinical challenge. Traditional Chinese medicine (TCM) has been used in China for over 2,000 years to treat various diseases and is an integral part of Chinese culture. Consequently, many patients receive TCM herbal treatments during or after adjuvant chemotherapy. Long-term TCM herbal treatment can enhance disease-free survival (DFS) in stage II and III colorectal cancer patients. 7 – 9 Use of TCM medication after surgery significantly enhanced DFS in patients with stage III colorectal cancer. 10 Advancements in molecular mechanism research have demonstrated that TCM, including formulas, single herbs, and monomers, can regulate CD4 + and CD8 + T cells, NK cells, regulatory T cells, tumour-associated macrophages (TAMs), hypoxic microenvironments, cancer-associated fibroblasts, angiogenesis, and the extracellular matrix. 11 – 13 Furthermore TCM can exert anti-CRLM (colorectal cancer liver metastasis) effects by modulating signalling pathways such as Hippo, Wnt/β-catenin, HGF/c-Met, PI3K/AKT, IGF/IGF1R, and AMPK. 14 – 15 Ke Cai et al. 16 demonstrated that the Xianlian Jiedu formula hinders colorectal cancer metastasis, possibly by reducing inflammation, correcting gut microbiota imbalances, addressing metabolic disorders, and lowering the infiltration of TAMs in the tumour environment. Ji Lv et al. 17 reported that combining Gegen Qinlian decoction with anti-mouse PD-1 therapy boosts CD8 + T cells in the blood and tumours, increases IFN-γ, reduces PD-1, and increases IL-2 levels, indicating improved T-cell function by blocking immune checkpoints. Through clinical practice, we observed that Dampness Syndrome is the most prevalent TCM syndrome in colorectal cancer, 18 – 19 for which Professor Haibo Zhang developed QSJDD. The herbal ingredients used in QSJDD are listed in Table 1 . This decoction boosts the spleen Qi, removes dampness, and has antitumour properties, aiding colon cancer prognosis post-surgery. In a single-arm trial at our centre, 45 high-risk stage III colon cancer patients received QSJDD following adjuvant chemotherapy. After 2 years of follow-up, the DFS rate was at 82.2%, outperforming the 70–75% rate in the International Duration Evaluation of Adjuvant Therapy (IDEA) trial. 3 This observation indicates that QSJDD may enhance DFS in these patients. Based on this previous work, we propose a multicentre, double-blind, placebo-controlled clinical trial to assess the impact of QSJDD on DFS and postoperative prognosis in patients with high-risk stage II or III colon cancer. Table 1 Standard formulation of Qu-Shi-Jie-Du Decoction (QSJDD) Pinyin name Latin name Dose (g) Monarch Dangshen Codonopsis pilosula 20 Fuling Poria cocos (Schw.) Wolf 20 Baizhu Atractylodis Macrocephalae Rhizoma 20 Chaihu Bupleuri radix 15 Minister Shanyao Dioscorea opposita 20 Lianzi Nelumbinis semen 15 Baibiandou Dolichos lablab L. 15 Yiyiren Coicis Semen 20 Chishao Paeoniae Radix Rubra 15 Assistant Sharen Amomum villosum Lour. 5 Qianshi Semen Euryales 20 Zhiqiao Aurantii Fructus 10 Baihuasheshecao Hedyotis diffusa Willd. 20 Baitouweng Pulsatilla chinensis (Bunge) Regel 15 Guide Gancao Glycyrrhiza uralensis 15 Table 1 . METHODS AND DESIGN Study design This multicentre, double-blind, randomised controlled trial is scheduled to be conducted between July 2022 and June 2026 at the Guangdong Provincial Hospital of Chinese Medicine and nine other major hospitals. The trial was registered with ClinicalTrials.gov (ChiCTR2300078971) and follows the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 20 and CONSORT (Consolidated Standards of Reporting Trials) CHM 21 guidelines for methodology and quality control. The trial flowchart is depicted in Fig. 1 . Inclusion criteria Patients eligible for the study must meet the following criteria: a. Diagnosis of colon cancer by tissue or cytopathology. b. Radical surgery with pathological staging of stage III or high-risk stage II (based on NCCN clinical practice guidelines for colorectal cancer [version 1. 2022]). 22 c. Completed adjuvant chemotherapy with 4–6 cycles of CAPEOX, 6–12 cycles of FOLFOX, or fluorouracil monotherapy, with no additional chemotherapy planned. d. Final chemotherapy treatment within 3 months prior to enrolment. e. Eastern Cooperative Oncology Group (ECOG) score of ≤ 2 points. f. Individuals aged 18–75 years. g. Normal hepatic and renal function. Normal renal function is defined as levels of serum creatinine ≤ 1.5 mg/dL (133 µmol/L) or creatinine clearance ≥ 60 mL/min. Normal liver function is defined as serum total bilirubin levels ≤ 1.5 times the upper limit of normal (ULN), and serum glutamic oxaloacetic transaminase (AST) and glutamic pyruvic transaminase (ALT) levels ≤ 2.5 times ULN. h. Signed informed consent, willingness to follow the treatment regimen, ability to adhere to prescription, and good compliance. Exclusion criteria Participants meeting any of the following will be excluded: a. Inability to complete the baseline assessment form. b. Complete or incomplete bowel obstruction. c. Other serious illnesses, including uncontrolled infection, severe electrolyte disturbances, and/or bleeding tendencies. d. Pregnant or lactating women. e. Comorbid depression, mania, obsessive-compulsive disorder, or schizophrenia. f. History of autoimmune disease, haematological disease, organ transplantation, or long-term use of hormones or immunosuppressive agents. g. Other uncontrolled tumours. h. Received or are scheduled to receive preoperative neoadjuvant radiotherapy. i. Severe brain or psychiatric disorders that affect the ability to self-report. j. History of organ transplantation (including bone marrow auto transplantation and peripheral stem cell transplantation). k. Individuals without legal capacity, medical, or ethical concerns that may impact the study. Elimination criteria Participants meeting any of the following criteria will be excluded from the analysis: a. Withdrawal of informed consent by the participant. b. Other explicit request to exclude data from the analysis. c. Erroneous enrolment of a participant. Withdrawal criteria The investigator may discontinue a participant from the study under the following circumstances while continuing to record follow-up data: a. Severe adverse reactions or disease progression during treatment. b. Protocol violations including discontinuing the study medication for over two months, using traditional Chinese medicines outside the study for more than two months, and receiving anti-tumour therapies (such as chemotherapy, biological agents, radiotherapy, targeted therapy, or immunotherapy) for two months or longer. Participants This study will be conducted at ten medical institutions in China. Guangdong Provincial Hospital of Chinese Medicine is leading the research and the others include: Sun Yat-sen University Cancer Center, The Sixth Affiliated Hospital of Sun Yat-sen University, The First Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial People's Hospital, Zhujiang Hospital of Southern Medical University, Dongguan People's Hospital, The First People’s Hospital of Foshan, Mei Zhou Hospital of Traditional Chinese Medicine, and Guangdong Provincial Agricultural Reclamation Central Hospital. All centres are Grade A general or tumour specialty hospitals who adhere to the NCCN guidelines for colon cancer. Inpatient and outpatient participants will voluntarily complete an informed consent form. Interventions Intervention group Patients in the intervention group will receive QSJDD granules daily for 6 months or until tumour recurrence or metastasis are detected, or intolerable side effects occur. Treatment starts within 3 months of completion of standard adjuvant chemotherapy with continuous compliance monitoring. QSJDD is administered once daily with warm water. Control group Patients in the control group will receive a placebo (QSJDD mimetic agent) consisting of 5% QSJDD granules and other ingredients such as colour and taste correctors and malt dextrin. The placebo granules will match the test drugs in appearance, dosage form, weight, colour, and odour. The duration of the placebo treatment will be identical to that of the intervention group. (Further details on the preparation process of the treatment drug and placebo are available in Supplement 1). Procedure Figure 1 displays the study flowchart and Table 2 details the measurement methods and data collection timelines. Treatment starts within 3 days of randomization and lasts 6 months. Patients will be assessed every 3 months during treatment, and then every 6 months after surgery, until death or study conclusion at 3 years. Patient and treatment details, along with demographic information, such as age, sex, and living conditions, will be obtained from medical records and baseline questionnaires. Medical data will be obtained from the patients’ medical records. Table 2 Measurement methods and data collection timeline Study Phase Baseline 3 Months Post-Enrolment 6 Months Post-Enrolment 1.5 Years Post-Surgery 2 Years Post-Surgery 2.5 Years Post-Surgery 3 Years Post-Surgery Follow-up Visits Clinical Visit / Visit 1 Visit 2 Follow-up 1 Follow-up 2 Follow-up 3 Follow-up 4 / Inclusion/Exclusion Criteria, Informed Consent, Randomization, Basic Information ● / / / / / / / General Condition ● ● ● ● ● ● ● / Tumour-Related Information ● / / / / / / / Treatment-Related Information ● / / / / / / / Treatment Traditional Chinese Medicine Treatment ● ● ● ◎ ◎ ◎ ◎ / Concomitant Medications ● ● ● ◎ ◎ ◎ ◎ / Completion Status / ● ● / / / / / Safety Complete Blood Count ● ● ● / / / / / Stool and Urine Routine (CBC) ◎ ◎ ◎ / / / / / Electrocardiogram ◎ ◎ ◎ / / / / / Blood Biochemical Tests ● ● ● / / / / / Adverse Events / ● ● / / / / / Efficacy Outcomes CT or MRI ● ◎ ● ● ● ● ● ◎ Colonoscopy ◎ / / ◎ ◎ / ◎ ◎ Tumour Markers ● ● ● / / / / / CTC ● ● ● / / / / / Immune Factors ● ● ● / / / / / Plasma Storage ● ● ● / / / / / Stool Storage ● ● ● / / / / / Dampness Syndrome Scale ● ● ● ◎ ◎ ◎ ◎ ◎ ●: Mandatory Item, ◎༚Non-Mandatory Item CT = computed tomography; MRI = magnetic resonance imaging; CTC = circulating tumour cells Table 2 CTC and CIC Isolations by microfluidic chips A total of 5 mL peripheral blood (PB) samples from cancer patients were collected in EDTA-containing tubes, stored at room temperature, and processed within 4 hours of collection. PB samples were diluted with same volume of phosphate buffered solution (PBS), and the mixture was processed through the cascaded filter deterministic lateral displacement microfluidic chip (CFD-Chip) 23 – 24 . The obtained cell suspensions consisting of CTCs, circulating cell-in-cell tumor cells (CICs) and leukocytes were centrifuged at 250 g for 10 min and resuspended in PBS. Detection of CTCs and CICs using the immunofluorescence The cell suspensions after CFD-Chip separation were seed onto 96-well plates. Cells were fixed for 15 min with 4% paraformaldehyde (Affymetrix, Santa Clara, CA) at room temperature. Fixed cells were washed four times using PBS, and then permeabilized by 0.1% TritonX-100 (Sigma-Aldrich, St. Louis, MO) for 10 min at room temperature. After blocking with 3% BSA solution for 1 h, cells were incubated with a cocktail of antibodies containing PE anti-CD45 antibody (1:100, BD Biosciences), 488 anti-pan cytokeratin antibody (1:500, Thermo Fisher Scientific) overnight at 4°C. After washing six times, cells were stained with 15 µL 1 mg/ml DAPI solution (Solarbio, Cat# C0060, Beijing, China) for 10 min. After washing two times by PBS, cells were observed using a fluorescence microscope. The numbers of CTCs were manually counted which were determined by DAPI+/CD45-/CK + immunofluorescence staining cells with integrated neoplastic cell morphology. The numbers of CICs were determined by DAPI+/CD45+/CK + immunofluorescence staining tumor cells with mononuclear but double-layered cell membrane morphology 25 . Primary outcome The primary endpoint is the 3-year DFS rate. Clinicians will monitor the development and timing of recurrences and metastases using imaging and cancer markers. Secondary outcomes Secondary endpoints include 1- and 2-year DFS rates and median DFS. Additional secondary endpoints include recurrence rates (RR) and overall survival (OS) at 1 and 2 years. The intestinal microbiota, circulating tumour cells (CTCs), peripheral blood immune cells, and cytokines will be assessed at three time points randomisation, the third, and sixth month of treatment. These secondary endpoints will also serve as indicators for exploring the mechanisms by which QSJDD prevents liver metastases. Additionally, the Dampness Syndrome Scale provided by the State Key Laboratory of Dampness Syndrome of Chinese Medicine under the joint establishment of the Ministry of Provincial Affairs of the People's Republic of China will be used to evaluate TCM-related symptoms and changes (refer Figs. 2 and 3 ). Surrogate outcome The enrolment of 60 patients in the pre-trial phase will likely be finalised within a 12-month period. Throughout this phase, alterations in CTC counts will serve as surrogate markers for DFS. Safety outcomes Adverse events and postoperative complications will be evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, established by the National Cancer Institute (NCI). 26 Safety assessments include: complete blood count, urinalysis, biochemical tests, electrocardiogram, general physical examination, and documentation of other adverse events. Randomization and blinding This double-blind study uses central randomisation at the Guangdong Provincial Hospital of the Chinese Medicine Methodology Group. The participants are randomly assigned in a 1:1 ratio to either the QSJDD or placebo group, with both the participants and researchers remaining blinded. Guangdong YiFang Pharmaceutical Co., Ltd., China, manufactures and supplies QSJDD compound and placebo granules. Data collection and monitoring Participants will provide baseline information before the first treatment, and the Dampness Syndrome Scale will be assessed at randomisation and during follow-up at 3 and 6 months. Data will be recorded in the case report form (CRF) by trained investigators, with any revisions noted, including the reason and date. Two data managers will document the information using EpiData software (version 3.1), and the data will be locked after verification. Sample size calculation This study aims to assess the 3-year recurrence and metastasis rates. Based on the MOSAIC 27 and NSABP C-07 trials, 28 this rate is approximately 30% for high-risk patients with stage II/III colon cancer after surgery. We hypothesize that the QSJDD group will see a reduction to 15% compared to 30% in the placebo group. Hence, 268 patients (134 per group) are required, with a 5% alpha level and 0.8 power. Accounting for a 20% dropout rate, 336 participants are required (168 per group). Statistical analysis Data will be analysed using SPSS 17.0 and Stata 11.0 software. For normally-distributed quantitative data, the results will be presented as mean ± standard deviation. For non-normal distributions, the data will be described using the median, lower quartile (Q1), upper quartile (Q3), minimum and maximum values. Intergroup comparisons will be conducted using the t-test. For non-normal data distributions or unequal variances, the Wilcoxon rank-sum test will be applied. Categorical data will be described using proportions and ratios, and inter-group comparisons will be performed using the χ² test or Fisher's exact test. The Kaplan–Meier method will be used to analyse and calculate cumulative DFS and OS, with comparison using the log-rank test. A multivariate analysis will be performed using the Cox regression model. All tests will be two-sided, and the significance level (α) will be set at 0.05. DISCUSSION Postoperative recurrence and metastasis have always been key prognostic issues after radical resection of colon cancer. 29 – 32 Data indicate that 15–25% of patients with colon cancer develop liver metastases, 33 – 34 and over 40% of them die from these metastases. 35 Liver resection is feasible for approximately 20% of patients. For those with unresectable liver metastases, palliative chemotherapy offers a median survival of 2 years, with a 5-year survival rate of 10%. 36–39 Prior to this clinical study, we conducted a small-sample single-arm clinical trial of QSJDD with a follow-up over 2 years. The results showed that no liver metastasis occurred in 12 patients with recurrence and metastases, suggesting that QSJDD may prevent liver metastases in colon cancer. Compared to rectal cancer, colon cancer presents an approximately 50% higher incidence and risk of mortality, underscoring the severity of colon cancer. 40 Our study focuses on colon cancer, allowing for precise analysis and understanding of its distinct characteristics and treatment needs. In addition to regular monitoring, new treatment strategies aimed at reducing the risk of liver metastases are required after adjuvant chemotherapy to improve patient prognosis. To address the challenge of reducing metastasis in colon cancer, several adjunctive therapies have been studied. Rebersek 41 proposed that gut microbiota is a screening, prognostic, and predictive biomarker. The gut microbiota may represent a modifiable factor influencing the prevention of metastasis and enhancing the effectiveness of therapy in colon cancer. Moreover, low-dose non-steroidal anti-inflammatories, particularly aspirin, may lower the risk of postoperative recurrence and mortality in colon cancer 42 – 45 . However, it has not yet been confirmed by a large randomized controlled trial. 46 TCM improves overall health and enhances immune function. 47 In China, approximately 80% of patients with cancer use TCM, particularly herbal remedies, during treatment. 48 – 49 Combining TCM with chemotherapy extends progression-free survival, 50 rendering it a promising adjunctive postoperative therapy for colon cancer. When monitoring postoperative recurrence in colon cancer, liquid biopsy using circulating tumour DNA can detect hidden metastatic lesions after surgery. 51 – 52 However, its clinical application has been limited owing to its lower sensitivity to fusion events and copy number alterations, as well as its high costs. Therefore, current research is focused on identifying effective biomarkers and interventions for predicting and controlling postoperative recurrence and metastasis in colon cancer. CTCs shed from a primary tumour into the vasculature with an intact viable nucleus, a positive cytokeratin, an epithelial cell adhesion molecule (EpCAM) and a negative CD45 molecule. 53 Found in metastatic cancers, 54 CTCs, indicators of tumour spread, are used as liquid biopsy markers and are vital for prognosis and treatment monitoring. Wu et al. 55 classified CTCs into three subgroups: E-CTCs (EpCAM), M-CTCs (vimentin), and E/M-CTCs (both). They reported that M-CTCs and circulating tumour micro emboli were more strongly linked to tumour metastasis than other CTC subgroups. Similarly, Yuchen Zhong et al. 56 showed that M-CTCs correlate with tumour size, T stage, TNM stage, vascular invasion, and carcinoembryonic antigen levels, and demonstrated that M-CTCs > 1 were associated with poor DFS. Although some researchers have focused on CTC subgroup analyses, CTC cell subtypes have received limited focus in previous studies. We identified a new CTC subtype of circulating cell-in-cell tumour cell (CIC) using microfluidic detection technology. CICs have a single nucleus, but the cell membrane is double-layered and has neutrophil characteristics. The number of CICs usually exceeds the number of conventionally-defined CTCs, and may be more effective for monitoring prognosis. CICs have a significant regulatory effect on chemotaxis, epithelial-mesenchymal transition, and gene expression on immune checkpoints 57 . Therefore, these CTC will be used for secondary outcome measurement and for validating its feasibility and accuracy as a predictor. This multicentre, double-blind, randomised controlled trial evaluates the effectiveness and safety of QSJDD in preventing recurrence and metastasis in high-risk stage II/III colon cancer and evaluates the effectiveness of CTCs and their subtypes as indicators of recurrence and potential therapeutic targets. We will employ a standard RCT methodology to validate the efficacy of QSJDD, and this rigorous approach provides a solid foundation for our findings. However, this study has certain limitations. The treatment duration of QSJDD was limited. Considering that prolonged use of QSJDD may lead to decreased patient adherence and an increased follow-up loss rate, a 6-month treatment period was preferred, which is considered an effective duration for traditional Chinese medicine treatments. 58 Despite this limitation, our study assesses the benefits of TCM interventions, provides a TCM-based therapeutic strategy, and lays the groundwork for future large-scale studies. Abbreviations 5-FU: fluorouracil ALT: serum glutamic pyruvic transaminase Anti-CRLM: anti-colorectal cancer liver metastasis CAPE-OX: capecitabine and oxaliplatin CICs: circulating cell-in-cell tumour cells CONSORT : Consolidated Standards of Reporting Trials CRC: colorectal cancer CRF: case report form CTCAE: Common Terminology Criteria for Adverse Events CTCs: circulating tumour cells DFS: disease-free survival ECOG: Eastern Cooperative Oncology Group EpCAM: epithelial cell adhesion molecule FOLFOX: leucovorin (folinic acid), fluorouracil, and oxaliplatin mFOLFOX6: modified FOLFOX 6 regimens MOSAIC: Multicenter International Study of Oxaliplatin/ 5-Fluorouracil/ Leucovorin in the Adjuvant Treatment of Colon Cancer Study NCCN: National Comprehensive Cancer Network NCI: National Cancer Institute NSABP: National Surgical Adjuvant Breast and Bowel Project OS: overall survival QSJDD: Qu-Shi-Jie-Du decoction RCT: randomized, controlled trial RR: relapse rates SPIRIT: Standard Protocol Items: Recommendations for Interventional Trials TAM: Tumour-associated macrophage TCM: traditional Chinese medicine ULN: upper limit of normal Declarations Ethics Approval This study follows the Declaration of Helsinki and adheres to the SPIRIT guidelines. 59 It is registered with the Chinese Clinical Trial Registry (ChiCTR2300078971) and has received ethical approval from the Guangdong Provincial Hospital of Traditional Chinese Medicine's ethics committee (BF2021-204). Consent to Participate Eligible participants from inpatient and outpatient departments will voluntarily complete an informed consent form. Consent for Publication Not applicable. Trial Status The last updated protocol was version 3.0. Study execution period: Between 1 July 2021 and 30 June 2026; recruitment period: 24 August 2023 to 30 June 2026. At the time of manuscript submission, patient recruitment was ongoing, with a total of 336 patients expected to be recruited for both the intervention and control groups. Data Availability No datasets were generated or analysed during the current study. Competing Interests The authors have declared that no competing interests. Funding This study is funded by State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (grant number: SZ2021ZZ40, SZ2023ZZ14), Science and Technology Planning Project of Guangdong Province (No.2023B1212060063), Guangzhou Municipal Science and Technology Bureau, China (grant number: 2024A03J0709), The Traditional Chinese Medicine Bureau of Guangdong Province (grant number: 20231115), The Project of Guangdong Provincial Hospital of Chinese Medicine (grant number: YN2023MS32), and The Project of State Key Laboratory of Traditional Chinese Medicine Syndrome (grant number: SKLKY2024B0002Z). Acknowledgements We thank the Methodology Group of Guangdong Provincial Hospital of Chinese Medicine for providing the central randomisation method. In addition, we thank Shenzhen Zigzag Biotechnology Co., Ltd. for the CTCs sorting and detection technology used in this study. We extend our gratitude to all the healthcare professionals who provided support throughout the course of this study. We would like to thank Editage (www.editage.cn) for English language editing. Contributions YC and HZ conceived the study. YC, WZ, YH, YL, YZ, YY, ZX, XC and HZ participated in the study design and protocol development. YC, ZH and WZ wrote the manuscript. ZL provided testing techniques. HZ led the development of the proposal and protocol and applied for funding. All the authors have read and approved the final manuscript. References Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263. Zeng H, Ran X, An L, et al. Disparities in stage at diagnosis for five common cancers in China: a multicentre, hospital-based, observational study. Lancet Public Health. 2021;6(12):e877-e887. doi:10.1016/S2468-2667(21)00157-2. 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National Institutes of Health. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf. André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350(23):2343-2351. doi:10.1056/NEJMoa032709 Kuebler JP, Wieand HS, O'Connell MJ, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007;25(16):2198-2204. doi:10.1200/JCO.2006.08.2974 Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin, 2024, 74(1): 12-49. Han B, Zheng R, Zeng H, et al. Cancer incidence and mortality in China, 2022. J Natl Cancer Cent, 2024, 4(1): 47-53. Franken IA, van der Baan FH, Vink GR, et al. Survival and patient-reported outcomes of real-world high-risk stage II and stage III colon cancer patients after reduction of adjuvant CAPOX duration from 6 to 3 months. Eur J Cancer. 2024;208:114207. doi:10.1016/j.ejca.2024.114207 Nordlinger B., Panis Y., Puts J. P., Herve J. P., Delelo R., Ballet F. Experimental model of colon cancer: recurrences after surgery alone or associated with intraperitoneal 5-fluorouracil chemotherapy. Diseases of the Colon & Rectum. 1991;34(8):658–663. doi: 10.1007/bf02050346. Hackl C, Neumann P, Gerken M, et al. Treatment of colorectal liver metastases in Germany: a ten-year population-based analysis of 5772 cases of primary colorectal adenocarcinoma. BMC Cancer . 2014;14:810. Ren, Li, Dexiang Zhu, Jin Gu, Baoqing Jia, Jin Li, Xinyu Qin, Xishan Wang et al. "Chinese guidelines for the diagnosis and comprehensive treatment of colorectal liver metastases (V. 2023)." Clinical Surgical Oncology 2, no. 2 (2023): 100013. Tian, C. X., and L. Zhao. "Epidemiological characteristics of colorectal cancer and colorectal liver metastasis." Zhonghua Zhong Liu Fang Zhi Za Zhi 28.13 (2021): 1033-1038. Tomasello, Gianluca et al. “FOLFOXIRI Plus Bevacizumab as Conversion Therapy for Patients With Initially Unresectable Metastatic Colorectal Cancer: A Systematic Review and Pooled Analysis.” JAMA oncology vol. 3,7 (2017): e170278. doi:10.1001/jamaoncol.2017.0278 Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 2010; 28: 4706–4713. Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M et al. ; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381: 303–312. Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N et al. ; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 2015; 372: 1909–1919. Geng, X., Wang, Z., Feng, L. et al. Efficacy and safety of Xian-Lian-Jie-Du optimization decoction as an adjuvant treatment for prevention of recurrence in patients with stage IIIB/IIIC colon cancer: study protocol for a multicentre, randomized controlled trial. BMC Complement Med Ther 23, 239 (2023). https://doi.org/10.1186/s12906-023-04052-2 Rebersek M. Gut microbiome and its role in colorectal cancer. BMC Cancer. 2021;21(1):1325. Published 2021 Dec 11. doi:10.1186/s12885-021-09054-2 Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. JAMA. 2009;302(6):649–58. Rothwell P, Wilson M, Elwin C, Norrving B, Algra A, Warlow C, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet (London, England). 2010;376(9754):1741–50. Algra A, Rothwell P. Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncol. 2012;13(5):518–27. Rothwell P, Wilson M, Price J, Belch J, Meade T, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet (London, England). 2012;379(9826):1591–601. Meyerhardt JA, Shi Q, Fuchs CS, Meyer J, Niedzwiecki D, Zemla T, et al. Effect of celecoxib vs placebo added to standard adjuvant therapy on disease-free survival among patients with stage iii colon cancer: the CALGB/SWOG 80702 (Alliance) randomized clinical trial. JAMA. 2021;325(13):1277–86. Jia Q, Wang L, Zhang X, et al. Prevention and treatment of chronic heart failure through traditional Chinese medicine: Role of the gut microbiota. Pharmacol Res. 2020;151:104552. doi:10.1016/j.phrs.2019.104552 McQuade JL, Meng Z, Chen Z, et al. Utilization of and Attitudes towards Traditional Chinese Medicine Therapies in a Chinese Cancer Hospital: A Survey of Patients and Physicians. Evid Based Complement Alternat Med. 2012;2012:504507. doi:10.1155/2012/504507 Chen G, Qiao TT, Ding H, et al. Use of Chinese herbal medicine therapies in comprehensive hospitals in central China: A parallel survey in cancer patients and clinicians. J Huazhong Univ Sci Technolog Med Sci. 2015;35(6):808-814. doi:10.1007/s11596-015-1511-5 Liu N, Wu C, Jia R, et al. Traditional Chinese Medicine Combined With Chemotherapy and Cetuximab or Bevacizumab for Metastatic Colorectal Cancer: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Front Pharmacol. 2020;11:478. Published 2020 Apr 21. doi:10.3389/fphar.2020.00478 Loft M, To YH, Gibbs P, et al. Clinical application of circulating tumour DNA in colorectal cancer. Lancet Gastroenterol Hepatol. 2023;8(9):837-852. Chen G, Peng J, Xiao Q, et al. Postoperative circulating tumor DNA as markers of recurrence risk in stages II to III colorectal cancer. J Hematol Oncol. 2021;14(1):80. Published 2021 May 17. doi:10.1186/s13045-021-01089-z Raza, A., Khan, A.Q., Inchakalody, V.P. et al. Dynamic liquid biopsy components as predictive and prognostic biomarkers in colorectal cancer. J Exp Clin Cancer Res 41, 99 (2022). https://doi.org/10.1186/s13046-022-02318-0 Allard WJ, Matera J, Miller MC, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res. 2004;10(20):6897-6904. doi:10.1158/1078-0432.CCR-04-0378 Wu F, Zhu J, Mao Y, Li X, Hu B, Zhang D. Associations between the epithelial-mesenchymal transition phenotypes of circulating tumor cells and the Clinicopathological features of patients with colorectal Cancer. Dis Markers. 2017;2017:9474532. Zhong Y, Ma T, Qiao T, Hu H, Li Z, Luo K, et al. Role of phenotypes of circulating tumor cells in the diagnosis and treatment of colorectal Cancer. Cancer Manag Res. 2021;13:7077–85. Chen, Xiaowen, Yuan, Xiuli, Chen, Yixin ,Cui, Xiufang , Cao, Nianhua , Yi, Meng et al. Circulating Cell-in-Cell Tumor Cells with Neutrophil Signature are Hematogenous Metastasis-Initiating Cells. Available at SSRN: https://ssrn.com/abstract=4781922 or http://dx.doi.org/10.2139/ssrn.4781922 Shao C, Zuo Q, Lin J, Yu RJ, Fu Y, Xiao M, et al. Effect of Chinese herbal medicine on the survival of colorectal cancer patients with liver-limited metastases: a retrospective cohort study, 2008 to 2017. Integr Cancer Ther. 2019;18:1534735419883687. Chan AW, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013;158(3):200-207. doi:10.7326/0003-4819-158-3-201302050-00583 Lu, T., et al. "Development and preliminary optimization of the dampness syndrome scale of Chinese medicine." J. Trandit. Chin. Med 62.19 (2021): 1677-1638. Qian, L. I., W. U. Wenzhen, and Xiaobo Yang. "Research on Normatively Portraying the Symptom Terminology of the Dampness Syndrome." World Science and Technology-Modernization of Traditional Chinese Medicine 25, no. 7 (2023): 2281-2286. Additional Declarations No competing interests reported. Supplementary Files Supplementaryappendix.docx SPIRITFillablechecklist15Aug2013.doc Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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02:23:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5908874/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5908874/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":75189775,"identity":"56852c93-f19e-453e-b0a8-0325501ecbbe","added_by":"auto","created_at":"2025-01-31 18:05:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":177024,"visible":true,"origin":"","legend":"\u003cp\u003eTrial Flowchart\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-5908874/v1/6bb862950cb73d62eebe3843.png"},{"id":75189779,"identity":"29c04cfd-b36f-4d14-b4b4-ace36e5786c3","added_by":"auto","created_at":"2025-01-31 18:05:04","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":451849,"visible":true,"origin":"","legend":"\u003cp\u003eDampness Syndrome Assessment Scale\u003csup\u003e60\u003c/sup\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-5908874/v1/9e38ec94d49b1e3cd34d760d.png"},{"id":75189783,"identity":"bd672f3e-e547-4d6a-a610-6bfa6cecf6e2","added_by":"auto","created_at":"2025-01-31 18:05:04","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":443758,"visible":true,"origin":"","legend":"\u003cp\u003eDampness Clinical Diagnosis Scale\u003csup\u003e61\u003c/sup\u003e\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-5908874/v1/95696a5c1e3f673795265357.png"},{"id":78002806,"identity":"26787734-4f3b-4ebd-97e7-801944502719","added_by":"auto","created_at":"2025-03-07 17:31:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2011589,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5908874/v1/683156ff-ef0b-47d8-8cba-be20b6ccea5b.pdf"},{"id":75189774,"identity":"2361ae17-9738-484c-b452-1de91b4bf7ec","added_by":"auto","created_at":"2025-01-31 18:05:04","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":352017,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryappendix.docx","url":"https://assets-eu.researchsquare.com/files/rs-5908874/v1/a62b5f30f7b3af1fc998d9c4.docx"},{"id":75189777,"identity":"2a971465-407e-4e99-a3b2-9abc331c6eec","added_by":"auto","created_at":"2025-01-31 18:05:04","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":128000,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITFillablechecklist15Aug2013.doc","url":"https://assets-eu.researchsquare.com/files/rs-5908874/v1/44b7fc6741ac1dd885f4e317.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Qu-Shi-Jie-Du decoction for prevention of recurrence and metastasis in high-risk stage II/III colon cancer: Study protocol for a double-blind, randomized, placebo-controlled trial","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eColorectal cancer (CRC) is a common malignancy, with over 1.9\u0026nbsp;million cases and 900 thousands deaths in 2022, accounting for nearly 10% of all cancer cases and deaths.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e In China, over 60% of patients with primary colon cancer are diagnosed at stage II or III.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e For resectable colon cancer, surgery-based multidisciplinary treatment is preferred, with adjuvant therapy guided by the surgical pathological stage.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e According to the National Comprehensive Cancer Network (NCCN) guidelines, adjuvant therapy for patients with high-risk stage II and III colon cancer is recommended for either 3 or 6 months. Treatment options include fluorouracil (5-FU) and leucovorin, folinic acid, fluorouracil, and oxaliplatin (FOLFOX), oxaliplatin and capecitabine (CAPEOX), or single-agent capecitabine.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Despite standard adjuvant chemotherapy, 20\u0026ndash;40% of patients experience recurrences and metastases within 3 years post-surgery. The recurrence rates are 10, 20, and 25% at 1, 2, and 3 years, respectively.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Additionally, the 5-year survival rate for metastatic colon cancer is 10%.\u003csup\u003e6\u003c/sup\u003e Reducing recurrences and metastases by enhancing treatment effectiveness for colon cancer remains a significant clinical challenge. Traditional Chinese medicine (TCM) has been used in China for over 2,000 years to treat various diseases and is an integral part of Chinese culture. Consequently, many patients receive TCM herbal treatments during or after adjuvant chemotherapy. Long-term TCM herbal treatment can enhance disease-free survival (DFS) in stage II and III colorectal cancer patients.\u003csup\u003e\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Use of TCM medication after surgery significantly enhanced DFS in patients with stage III colorectal cancer.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Advancements in molecular mechanism research have demonstrated that TCM, including formulas, single herbs, and monomers, can regulate CD4\u0026thinsp;+\u0026thinsp;and CD8\u0026thinsp;+\u0026thinsp;T cells, NK cells, regulatory T cells, tumour-associated macrophages (TAMs), hypoxic microenvironments, cancer-associated fibroblasts, angiogenesis, and the extracellular matrix.\u003csup\u003e\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Furthermore TCM can exert anti-CRLM (colorectal cancer liver metastasis) effects by modulating signalling pathways such as Hippo, Wnt/β-catenin, HGF/c-Met, PI3K/AKT, IGF/IGF1R, and AMPK.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Ke Cai et al.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e demonstrated that the Xianlian Jiedu formula hinders colorectal cancer metastasis, possibly by reducing inflammation, correcting gut microbiota imbalances, addressing metabolic disorders, and lowering the infiltration of TAMs in the tumour environment. Ji Lv et al.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e reported that combining Gegen Qinlian decoction with anti-mouse PD-1 therapy boosts CD8\u0026thinsp;+\u0026thinsp;T cells in the blood and tumours, increases IFN-γ, reduces PD-1, and increases IL-2 levels, indicating improved T-cell function by blocking immune checkpoints. Through clinical practice, we observed that Dampness Syndrome is the most prevalent TCM syndrome in colorectal cancer,\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e for which Professor Haibo Zhang developed QSJDD. The herbal ingredients used in QSJDD are listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. This decoction boosts the spleen Qi, removes dampness, and has antitumour properties, aiding colon cancer prognosis post-surgery. In a single-arm trial at our centre, 45 high-risk stage III colon cancer patients received QSJDD following adjuvant chemotherapy. After 2 years of follow-up, the DFS rate was at 82.2%, outperforming the 70\u0026ndash;75% rate in the International Duration Evaluation of Adjuvant Therapy (IDEA) trial.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e This observation indicates that QSJDD may enhance DFS in these patients. Based on this previous work, we propose a multicentre, double-blind, placebo-controlled clinical trial to assess the impact of QSJDD on DFS and postoperative prognosis in patients with high-risk stage II or III colon cancer.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eStandard formulation of Qu-Shi-Jie-Du Decoction (QSJDD)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePinyin name\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLatin name\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDose (g)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eMonarch\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDangshen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eCodonopsis\u0026nbsp;pilosula\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFuling\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ePoria cocos (Schw.) Wolf\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBaizhu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eAtractylodis Macrocephalae Rhizoma\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChaihu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eBupleuri radix\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eMinister\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eShanyao\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eDioscorea opposita\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLianzi\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eNelumbinis semen\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBaibiandou\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eDolichos lablab L.\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYiyiren\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eCoicis Semen\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChishao\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ePaeoniae Radix Rubra\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eAssistant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSharen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eAmomum villosum Lour.\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eQianshi\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eSemen Euryales\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eZhiqiao\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eAurantii Fructus\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBaihuasheshecao\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eHedyotis diffusa Willd.\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBaitouweng\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ePulsatilla chinensis (Bunge) Regel\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGuide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGancao\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eGlycyrrhiza uralensis\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e"},{"header":"METHODS AND DESIGN","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy design\u003c/h2\u003e\n \u003cp\u003eThis multicentre, double-blind, randomised controlled trial is scheduled to be conducted between July 2022 and June 2026 at the Guangdong Provincial Hospital of Chinese Medicine and nine other major hospitals. The trial was registered with ClinicalTrials.gov (ChiCTR2300078971) and follows the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e and CONSORT (Consolidated Standards of Reporting Trials) CHM\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e guidelines for methodology and quality control. The trial flowchart is depicted in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eInclusion criteria\u003c/h3\u003e\n\u003cp\u003ePatients eligible for the study must meet the following criteria:\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea.\u003c/strong\u003e Diagnosis of colon cancer by tissue or cytopathology.\u003c/p\u003e\u003cspan\u003e\n \u003cp\u003e\u003cstrong\u003eb.\u003c/strong\u003e Radical surgery with pathological staging of stage III or high-risk stage II (based on NCCN clinical practice guidelines for colorectal cancer [version 1. 2022]). \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/span\u003e\u003cspan\u003e\n \u003cp\u003e\u003cstrong\u003ec.\u003c/strong\u003e Completed adjuvant chemotherapy with 4\u0026ndash;6 cycles of CAPEOX, 6\u0026ndash;12 cycles of FOLFOX, or fluorouracil monotherapy, with no additional chemotherapy planned.\u003c/p\u003e\n\u003c/span\u003e\u003cspan\u003e\n \u003cp\u003e\u003cstrong\u003ed.\u003c/strong\u003e Final chemotherapy treatment within 3 months prior to enrolment.\u003c/p\u003e\n\u003c/span\u003e\u003cspan\u003e\n \u003cp\u003e\u003cstrong\u003ee.\u003c/strong\u003e Eastern Cooperative Oncology Group (ECOG) score of \u0026le;\u0026thinsp;2 points.\u003c/p\u003e\n\u003c/span\u003e\u003cspan\u003e\n \u003cp\u003e\u003cstrong\u003ef.\u003c/strong\u003e Individuals aged 18\u0026ndash;75 years.\u003c/p\u003e\n\u003c/span\u003e\u003cspan\u003e\n \u003cp\u003e\u003cstrong\u003eg.\u003c/strong\u003e Normal hepatic and renal function. Normal renal function is defined as levels of serum creatinine\u0026thinsp;\u0026le;\u0026thinsp;1.5 mg/dL (133 \u0026micro;mol/L) or creatinine clearance\u0026thinsp;\u0026ge;\u0026thinsp;60 mL/min. Normal liver function is defined as serum total bilirubin levels\u0026thinsp;\u0026le;\u0026thinsp;1.5 times the upper limit of normal (ULN), and serum glutamic oxaloacetic transaminase (AST) and glutamic pyruvic transaminase (ALT) levels\u0026thinsp;\u0026le;\u0026thinsp;2.5 times ULN.\u003c/p\u003e\n\u003c/span\u003e\u003cspan\u003e\n \u003cp\u003e\u003cstrong\u003eh.\u003c/strong\u003e Signed informed consent, willingness to follow the treatment regimen, ability to adhere to prescription, and good compliance.\u003c/p\u003e\n\u003c/span\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eExclusion criteria\u003c/h3\u003e\n\u003cp\u003eParticipants meeting any of the following will be excluded:\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea.\u003c/strong\u003e Inability to complete the baseline assessment form.\u003c/p\u003e\u003cspan\u003e\n \u003cp\u003e\u003cstrong\u003eb.\u003c/strong\u003e Complete or incomplete bowel obstruction.\u003c/p\u003e\n\u003c/span\u003e\u003cspan\u003e\n \u003cp\u003e\u003cstrong\u003ec.\u003c/strong\u003e Other serious illnesses, including uncontrolled infection, severe electrolyte disturbances, and/or bleeding tendencies.\u003c/p\u003e\n\u003c/span\u003e\u003cspan\u003e\n \u003cp\u003e\u003cstrong\u003ed.\u003c/strong\u003e Pregnant or lactating women.\u003c/p\u003e\n\u003c/span\u003e\u003cspan\u003e\n \u003cp\u003e\u003cstrong\u003ee.\u003c/strong\u003e Comorbid depression, mania, obsessive-compulsive disorder, or schizophrenia.\u003c/p\u003e\n\u003c/span\u003e\u003cspan\u003e\n \u003cp\u003e\u003cstrong\u003ef.\u003c/strong\u003e History of autoimmune disease, haematological disease, organ transplantation, or long-term use of hormones or immunosuppressive agents.\u003c/p\u003e\n\u003c/span\u003e\u003cspan\u003e\n \u003cp\u003e\u003cstrong\u003eg.\u003c/strong\u003e Other uncontrolled tumours.\u003c/p\u003e\n\u003c/span\u003e\u003cspan\u003e\n \u003cp\u003e\u003cstrong\u003eh.\u003c/strong\u003e Received or are scheduled to receive preoperative neoadjuvant radiotherapy.\u003c/p\u003e\n\u003c/span\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ei.\u003c/strong\u003e Severe brain or psychiatric disorders that affect the ability to self-report.\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ej.\u003c/strong\u003e History of organ transplantation (including bone marrow auto transplantation and peripheral stem cell transplantation).\u003c/p\u003e\u003cspan\u003e\n \u003cp\u003e\u003cstrong\u003ek.\u003c/strong\u003e Individuals without legal capacity, medical, or ethical concerns that may impact the study.\u003c/p\u003e\n\u003c/span\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eElimination criteria\u003c/h3\u003e\n\u003cp\u003eParticipants meeting any of the following criteria will be excluded from the analysis:\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea.\u003c/strong\u003e Withdrawal of informed consent by the participant.\u003c/p\u003e\u003cspan\u003e\n \u003cp\u003e\u003cstrong\u003eb.\u003c/strong\u003e Other explicit request to exclude data from the analysis.\u003c/p\u003e\n\u003c/span\u003e\u003cspan\u003e\n \u003cp\u003e\u003cstrong\u003ec.\u003c/strong\u003e Erroneous enrolment of a participant.\u003c/p\u003e\n\u003c/span\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eWithdrawal criteria\u003c/h3\u003e\n\u003cp\u003eThe investigator may discontinue a participant from the study under the following circumstances while continuing to record follow-up data:\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea.\u003c/strong\u003e Severe adverse reactions or disease progression during treatment.\u003c/p\u003e\u003cspan\u003e\n \u003cp\u003e\u003cstrong\u003eb.\u003c/strong\u003e Protocol violations including discontinuing the study medication for over two months, using traditional Chinese medicines outside the study for more than two months, and receiving anti-tumour therapies (such as chemotherapy, biological agents, radiotherapy, targeted therapy, or immunotherapy) for two months or longer.\u003c/p\u003e\n\u003c/span\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eParticipants\u003c/h2\u003e\n \u003cp\u003eThis study will be conducted at ten medical institutions in China. Guangdong Provincial Hospital of Chinese Medicine is leading the research and the others include: Sun Yat-sen University Cancer Center, The Sixth Affiliated Hospital of Sun Yat-sen University, The First Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial People\u0026apos;s Hospital, Zhujiang Hospital of Southern Medical University, Dongguan People\u0026apos;s Hospital, The First People\u0026rsquo;s Hospital of Foshan, Mei Zhou Hospital of Traditional Chinese Medicine, and Guangdong Provincial Agricultural Reclamation Central Hospital. All centres are Grade A general or tumour specialty hospitals who adhere to the NCCN guidelines for colon cancer. Inpatient and outpatient participants will voluntarily complete an informed consent form.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eInterventions\u003c/h3\u003e\n\u003cp\u003eIntervention group\u003c/p\u003e\n\u003cp\u003ePatients in the intervention group will receive QSJDD granules daily for 6 months or until tumour recurrence or metastasis are detected, or intolerable side effects occur. Treatment starts within 3 months of completion of standard adjuvant chemotherapy with continuous compliance monitoring. QSJDD is administered once daily with warm water.\u003c/p\u003e\n\u003cp\u003eControl group\u003c/p\u003e\n\u003cp\u003ePatients in the control group will receive a placebo (QSJDD mimetic agent) consisting of 5% QSJDD granules and other ingredients such as colour and taste correctors and malt dextrin. The placebo granules will match the test drugs in appearance, dosage form, weight, colour, and odour. The duration of the placebo treatment will be identical to that of the intervention group. (Further details on the preparation process of the treatment drug and placebo are available in Supplement 1).\u003c/p\u003e\n\u003ch3\u003eProcedure\u003c/h3\u003e\n\u003cp\u003eFigure \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e displays the study flowchart and Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e details the measurement methods and data collection timelines. Treatment starts within 3 days of randomization and lasts 6 months. Patients will be assessed every 3 months during treatment, and then every 6 months after surgery, until death or study conclusion at 3 years. Patient and treatment details, along with demographic information, such as age, sex, and living conditions, will be obtained from medical records and baseline questionnaires. Medical data will be obtained from the patients\u0026rsquo; medical records.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMeasurement methods and data collection timeline\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"10\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eStudy Phase\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e3 Months Post-Enrolment\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e6 Months Post-Enrolment\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e1.5 Years Post-Surgery\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e2 Years Post-Surgery\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e2.5 Years Post-Surgery\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e3 Years Post-Surgery\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFollow-up Visits\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical Visit\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eVisit 1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eVisit 2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollow-up 1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollow-up 2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollow-up 3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollow-up 4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eInclusion/Exclusion Criteria, Informed Consent, Randomization, Basic Information\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eGeneral Condition\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eTumour-Related Information\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eTreatment-Related Information\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTraditional Chinese Medicine Treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConcomitant Medications\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCompletion Status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eSafety\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eComplete Blood Count\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStool and Urine Routine (CBC)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eElectrocardiogram\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBlood Biochemical Tests\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdverse Events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"8\"\u003e\n \u003cp\u003e\u003cstrong\u003eEfficacy Outcomes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCT or MRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eColonoscopy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTumour Markers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCTC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eImmune Factors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlasma Storage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStool Storage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDampness Syndrome Scale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e◎\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"10\"\u003e●: Mandatory Item, ◎༚Non-Mandatory Item\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"10\"\u003eCT\u0026thinsp;=\u0026thinsp;computed tomography; MRI\u0026thinsp;=\u0026thinsp;magnetic resonance imaging; CTC\u0026thinsp;=\u0026thinsp;circulating tumour cells\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eTable \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e\u003c/p\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eCTC and CIC Isolations by microfluidic chips\u003c/h2\u003e\n \u003cp\u003eA total of 5 mL peripheral blood (PB) samples from cancer patients were collected in EDTA-containing tubes, stored at room temperature, and processed within 4 hours of collection. PB samples were diluted with same volume of phosphate buffered solution (PBS), and the mixture was processed through the cascaded filter deterministic lateral displacement microfluidic chip (CFD-Chip)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. The obtained cell suspensions consisting of CTCs, circulating cell-in-cell tumor cells (CICs) and leukocytes were centrifuged at 250 g for 10 min and resuspended in PBS.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eDetection of CTCs and CICs using the immunofluorescence\u003c/h2\u003e\n \u003cp\u003eThe cell suspensions after CFD-Chip separation were seed onto 96-well plates. Cells were fixed for 15 min with 4% paraformaldehyde (Affymetrix, Santa Clara, CA) at room temperature. Fixed cells were washed four times using PBS, and then permeabilized by 0.1% TritonX-100 (Sigma-Aldrich, St. Louis, MO) for 10 min at room temperature. After blocking with 3% BSA solution for 1 h, cells were incubated with a cocktail of antibodies containing PE anti-CD45 antibody (1:100, BD Biosciences), 488 anti-pan cytokeratin antibody (1:500, Thermo Fisher Scientific) overnight at 4\u0026deg;C. After washing six times, cells were stained with 15 \u0026micro;L 1 mg/ml DAPI solution (Solarbio, Cat# C0060, Beijing, China) for 10 min. After washing two times by PBS, cells were observed using a fluorescence microscope. The numbers of CTCs were manually counted which were determined by DAPI+/CD45-/CK\u0026thinsp;+\u0026thinsp;immunofluorescence staining cells with integrated neoplastic cell morphology. The numbers of CICs were determined by DAPI+/CD45+/CK\u0026thinsp;+\u0026thinsp;immunofluorescence staining tumor cells with mononuclear but double-layered cell membrane morphology\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003ePrimary outcome\u003c/h2\u003e\n \u003cp\u003eThe primary endpoint is the 3-year DFS rate. Clinicians will monitor the development and timing of recurrences and metastases using imaging and cancer markers.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003eSecondary outcomes\u003c/h2\u003e\n \u003cp\u003eSecondary endpoints include 1- and 2-year DFS rates and median DFS. Additional secondary endpoints include recurrence rates (RR) and overall survival (OS) at 1 and 2 years. The intestinal microbiota, circulating tumour cells (CTCs), peripheral blood immune cells, and cytokines will be assessed at three time points randomisation, the third, and sixth month of treatment. These secondary endpoints will also serve as indicators for exploring the mechanisms by which QSJDD prevents liver metastases. Additionally, the Dampness Syndrome Scale provided by the State Key Laboratory of Dampness Syndrome of Chinese Medicine under the joint establishment of the Ministry of Provincial Affairs of the People\u0026apos;s Republic of China will be used to evaluate TCM-related symptoms and changes (refer Figs. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eSurrogate outcome\u003c/h2\u003e\n \u003cp\u003eThe enrolment of 60 patients in the pre-trial phase will likely be finalised within a 12-month period. Throughout this phase, alterations in CTC counts will serve as surrogate markers for DFS.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003ch2\u003eSafety outcomes\u003c/h2\u003e\n \u003cp\u003eAdverse events and postoperative complications will be evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, established by the National Cancer Institute (NCI).\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e Safety assessments include: complete blood count, urinalysis, biochemical tests, electrocardiogram, general physical examination, and documentation of other adverse events.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n \u003ch2\u003eRandomization and blinding\u003c/h2\u003e\n \u003cp\u003eThis double-blind study uses central randomisation at the Guangdong Provincial Hospital of the Chinese Medicine Methodology Group. The participants are randomly assigned in a 1:1 ratio to either the QSJDD or placebo group, with both the participants and researchers remaining blinded. Guangdong YiFang Pharmaceutical Co., Ltd., China, manufactures and supplies QSJDD compound and placebo granules.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\n \u003ch2\u003eData collection and monitoring\u003c/h2\u003e\n \u003cp\u003eParticipants will provide baseline information before the first treatment, and the Dampness Syndrome Scale will be assessed at randomisation and during follow-up at 3 and 6 months. Data will be recorded in the case report form (CRF) by trained investigators, with any revisions noted, including the reason and date. Two data managers will document the information using EpiData software (version 3.1), and the data will be locked after verification.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\n \u003ch2\u003eSample size calculation\u003c/h2\u003e\n \u003cp\u003eThis study aims to assess the 3-year recurrence and metastasis rates. Based on the MOSAIC\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e and NSABP C-07 trials,\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e this rate is approximately 30% for high-risk patients with stage II/III colon cancer after surgery. We hypothesize that the QSJDD group will see a reduction to 15% compared to 30% in the placebo group. Hence, 268 patients (134 per group) are required, with a 5% alpha level and 0.8 power. Accounting for a 20% dropout rate, 336 participants are required (168 per group).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical analysis\u003c/h2\u003e\n \u003cp\u003eData will be analysed using SPSS 17.0 and Stata 11.0 software. For normally-distributed quantitative data, the results will be presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. For non-normal distributions, the data will be described using the median, lower quartile (Q1), upper quartile (Q3), minimum and maximum values. Intergroup comparisons will be conducted using the t-test. For non-normal data distributions or unequal variances, the Wilcoxon rank-sum test will be applied. Categorical data will be described using proportions and ratios, and inter-group comparisons will be performed using the \u0026chi;\u0026sup2; test or Fisher\u0026apos;s exact test. The Kaplan\u0026ndash;Meier method will be used to analyse and calculate cumulative DFS and OS, with comparison using the log-rank test. A multivariate analysis will be performed using the Cox regression model. All tests will be two-sided, and the significance level (\u0026alpha;) will be set at 0.05.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003ePostoperative recurrence and metastasis have always been key prognostic issues after radical resection of colon cancer. \u003csup\u003e\u003cspan additionalcitationids=\"CR30 CR31\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e Data indicate that 15\u0026ndash;25% of patients with colon cancer develop liver metastases, \u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e and over 40% of them die from these metastases.\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e Liver resection is feasible for approximately 20% of patients. For those with unresectable liver metastases, palliative chemotherapy offers a median survival of 2 years, with a 5-year survival rate of 10%.\u003csup\u003e36\u0026ndash;39\u003c/sup\u003e Prior to this clinical study, we conducted a small-sample single-arm clinical trial of QSJDD with a follow-up over 2 years. The results showed that no liver metastasis occurred in 12 patients with recurrence and metastases, suggesting that QSJDD may prevent liver metastases in colon cancer. Compared to rectal cancer, colon cancer presents an approximately 50% higher incidence and risk of mortality, underscoring the severity of colon cancer.\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e Our study focuses on colon cancer, allowing for precise analysis and understanding of its distinct characteristics and treatment needs. In addition to regular monitoring, new treatment strategies aimed at reducing the risk of liver metastases are required after adjuvant chemotherapy to improve patient prognosis.\u003c/p\u003e \u003cp\u003eTo address the challenge of reducing metastasis in colon cancer, several adjunctive therapies have been studied. Rebersek\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e proposed that gut microbiota is a screening, prognostic, and predictive biomarker. The gut microbiota may represent a modifiable factor influencing the prevention of metastasis and enhancing the effectiveness of therapy in colon cancer. Moreover, low-dose non-steroidal anti-inflammatories, particularly aspirin, may lower the risk of postoperative recurrence and mortality in colon cancer \u003csup\u003e\u003cspan additionalcitationids=\"CR43 CR44\" citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. However, it has not yet been confirmed by a large randomized controlled trial.\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e TCM improves overall health and enhances immune function.\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e In China, approximately 80% of patients with cancer use TCM, particularly herbal remedies, during treatment.\u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e Combining TCM with chemotherapy extends progression-free survival, \u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e rendering it a promising adjunctive postoperative therapy for colon cancer.\u003c/p\u003e \u003cp\u003eWhen monitoring postoperative recurrence in colon cancer, liquid biopsy using circulating tumour DNA can detect hidden metastatic lesions after surgery. \u003csup\u003e\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e However, its clinical application has been limited owing to its lower sensitivity to fusion events and copy number alterations, as well as its high costs. Therefore, current research is focused on identifying effective biomarkers and interventions for predicting and controlling postoperative recurrence and metastasis in colon cancer. CTCs shed from a primary tumour into the vasculature with an intact viable nucleus, a positive cytokeratin, an epithelial cell adhesion molecule (EpCAM) and a negative CD45 molecule.\u003csup\u003e\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e Found in metastatic cancers,\u003csup\u003e\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e CTCs, indicators of tumour spread, are used as liquid biopsy markers and are vital for prognosis and treatment monitoring. Wu et al.\u003csup\u003e\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e classified CTCs into three subgroups: E-CTCs (EpCAM), M-CTCs (vimentin), and E/M-CTCs (both). They reported that M-CTCs and circulating tumour micro emboli were more strongly linked to tumour metastasis than other CTC subgroups. Similarly, Yuchen Zhong et al.\u003csup\u003e\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e showed that M-CTCs correlate with tumour size, T stage, TNM stage, vascular invasion, and carcinoembryonic antigen levels, and demonstrated that M-CTCs\u0026thinsp;\u0026gt;\u0026thinsp;1 were associated with poor DFS. Although some researchers have focused on CTC subgroup analyses, CTC cell subtypes have received limited focus in previous studies. We identified a new CTC subtype of circulating cell-in-cell tumour cell (CIC) using microfluidic detection technology. CICs have a single nucleus, but the cell membrane is double-layered and has neutrophil characteristics. The number of CICs usually exceeds the number of conventionally-defined CTCs, and may be more effective for monitoring prognosis. CICs have a significant regulatory effect on chemotaxis, epithelial-mesenchymal transition, and gene expression on immune checkpoints\u003csup\u003e\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u003c/sup\u003e. Therefore, these CTC will be used for secondary outcome measurement and for validating its feasibility and accuracy as a predictor.\u003c/p\u003e \u003cp\u003eThis multicentre, double-blind, randomised controlled trial evaluates the effectiveness and safety of QSJDD in preventing recurrence and metastasis in high-risk stage II/III colon cancer and evaluates the effectiveness of CTCs and their subtypes as indicators of recurrence and potential therapeutic targets. We will employ a standard RCT methodology to validate the efficacy of QSJDD, and this rigorous approach provides a solid foundation for our findings. However, this study has certain limitations. The treatment duration of QSJDD was limited. Considering that prolonged use of QSJDD may lead to decreased patient adherence and an increased follow-up loss rate, a 6-month treatment period was preferred, which is considered an effective duration for traditional Chinese medicine treatments.\u003csup\u003e\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u003c/sup\u003e Despite this limitation, our study assesses the benefits of TCM interventions, provides a TCM-based therapeutic strategy, and lays the groundwork for future large-scale studies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e5-FU: fluorouracil\u003c/p\u003e\n\u003cp\u003eALT: serum glutamic pyruvic transaminase\u003c/p\u003e\n\u003cp\u003eAnti-CRLM: anti-colorectal cancer liver metastasis\u003c/p\u003e\n\u003cp\u003eCAPE-OX: capecitabine and oxaliplatin\u003c/p\u003e\n\u003cp\u003eCICs: circulating cell-in-cell tumour cells\u003c/p\u003e\n\u003cp\u003eCONSORT : Consolidated Standards of Reporting Trials\u003c/p\u003e\n\u003cp\u003eCRC: colorectal cancer\u003c/p\u003e\n\u003cp\u003eCRF: case report form\u003c/p\u003e\n\u003cp\u003eCTCAE: Common Terminology Criteria for Adverse Events\u003c/p\u003e\n\u003cp\u003eCTCs: circulating tumour cells\u003c/p\u003e\n\u003cp\u003eDFS: disease-free survival\u003c/p\u003e\n\u003cp\u003eECOG: Eastern Cooperative Oncology Group\u003c/p\u003e\n\u003cp\u003eEpCAM: epithelial cell adhesion molecule\u003c/p\u003e\n\u003cp\u003eFOLFOX: leucovorin (folinic acid), fluorouracil, and oxaliplatin\u003c/p\u003e\n\u003cp\u003emFOLFOX6: modified FOLFOX 6 regimens\u003c/p\u003e\n\u003cp\u003eMOSAIC:\u0026nbsp;Multicenter International Study of Oxaliplatin/ 5-Fluorouracil/ Leucovorin in the Adjuvant Treatment of Colon Cancer Study\u003c/p\u003e\n\u003cp\u003eNCCN: National Comprehensive Cancer Network\u003c/p\u003e\n\u003cp\u003eNCI: National Cancer Institute\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNSABP: National Surgical Adjuvant Breast and Bowel Project\u003c/p\u003e\n\u003cp\u003eOS: overall survival\u003c/p\u003e\n\u003cp\u003eQSJDD: Qu-Shi-Jie-Du decoction\u003c/p\u003e\n\u003cp\u003eRCT: randomized, controlled trial\u003c/p\u003e\n\u003cp\u003eRR: relapse rates\u003c/p\u003e\n\u003cp\u003eSPIRIT: Standard Protocol Items: Recommendations for Interventional Trials\u003c/p\u003e\n\u003cp\u003eTAM: Tumour-associated macrophage\u003c/p\u003e\n\u003cp\u003eTCM: traditional Chinese medicine\u003c/p\u003e\n\u003cp\u003eULN: upper limit of normal\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics Approval\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study follows the Declaration of Helsinki and adheres to the SPIRIT guidelines.\u003csup\u003e59\u0026nbsp;\u003c/sup\u003eIt is registered with the Chinese Clinical Trial Registry (ChiCTR2300078971) and has received ethical approval from the Guangdong Provincial Hospital of Traditional Chinese Medicine\u0026apos;s ethics committee (BF2021-204).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eConsent to Participate\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eEligible participants from inpatient and outpatient departments will voluntarily complete an informed consent form.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for Publication \u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTrial Status\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe last updated protocol was version 3.0. Study execution period: Between 1 July 2021 and 30 June 2026; recruitment period: 24 August 2023 to 30 June 2026. At the time of manuscript submission, patient recruitment was ongoing, with a total of 336 patients expected to be recruited for both the intervention and control groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eData Availability\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo datasets were generated or analysed during the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting Interests\u003c/em\u003e\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors have declared that no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis study is funded by State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (grant number: SZ2021ZZ40, SZ2023ZZ14), Science and Technology Planning Project of Guangdong Province (No.2023B1212060063), Guangzhou Municipal Science and Technology Bureau, China (grant number: 2024A03J0709), The Traditional Chinese Medicine Bureau of Guangdong Province (grant number: 20231115), The Project of Guangdong Provincial Hospital of Chinese Medicine (grant number: YN2023MS32), and The Project of State Key Laboratory of Traditional Chinese Medicine Syndrome (grant number: SKLKY2024B0002Z).\u003c/p\u003e\n\u003ch1\u003e\u003cem\u003eAcknowledgements\u0026nbsp;\u003c/em\u003e\u003c/h1\u003e\n\u003cp\u003eWe thank the Methodology Group of Guangdong Provincial Hospital of Chinese Medicine for providing the central randomisation method. In addition, we thank Shenzhen Zigzag Biotechnology Co., Ltd. for the CTCs sorting and detection technology used in this study. We extend our gratitude to all the healthcare professionals who provided support throughout the course of this study.\u0026nbsp;We would like to thank Editage (www.editage.cn) for English language editing.\u003c/p\u003e\n\u003ch1\u003eContributions\u003c/h1\u003e\n\u003cp\u003eYC and HZ conceived the study. YC, WZ, YH, YL, YZ, YY, ZX, XC and HZ participated in the study design and protocol development. YC, ZH and WZ wrote the manuscript. ZL provided testing techniques. HZ led the development of the proposal and protocol and applied for funding. All the authors have read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. 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Published 2021 May 17. doi:10.1186/s13045-021-01089-z\u003c/li\u003e\n\u003cli\u003eRaza, A., Khan, A.Q., Inchakalody, V.P. et al. Dynamic liquid biopsy components as predictive and prognostic biomarkers in colorectal cancer. J Exp Clin Cancer Res 41, 99 (2022). https://doi.org/10.1186/s13046-022-02318-0\u003c/li\u003e\n\u003cli\u003eAllard WJ, Matera J, Miller MC, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res. 2004;10(20):6897-6904. doi:10.1158/1078-0432.CCR-04-0378\u003c/li\u003e\n\u003cli\u003eWu F, Zhu J, Mao Y, Li X, Hu B, Zhang D. Associations between the epithelial-mesenchymal transition phenotypes of circulating tumor cells and the Clinicopathological features of patients with colorectal Cancer. Dis Markers. 2017;2017:9474532.\u003c/li\u003e\n\u003cli\u003eZhong Y, Ma T, Qiao T, Hu H, Li Z, Luo K, et al. Role of phenotypes of circulating tumor cells in the diagnosis and treatment of colorectal Cancer. Cancer Manag Res. 2021;13:7077\u0026ndash;85.\u003c/li\u003e\n\u003cli\u003eChen, Xiaowen, Yuan, Xiuli, Chen, Yixin ,Cui, Xiufang , Cao, Nianhua , Yi, Meng et al. Circulating Cell-in-Cell Tumor Cells with Neutrophil Signature are Hematogenous Metastasis-Initiating Cells. Available at SSRN: https://ssrn.com/abstract=4781922 or http://dx.doi.org/10.2139/ssrn.4781922\u003c/li\u003e\n\u003cli\u003eShao C, Zuo Q, Lin J, Yu RJ, Fu Y, Xiao M, et al. Effect of Chinese herbal medicine on the survival of colorectal cancer patients with liver-limited metastases: a retrospective cohort study, 2008 to 2017. Integr Cancer Ther. 2019;18:1534735419883687.\u003c/li\u003e\n\u003cli\u003eChan AW, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013;158(3):200-207. doi:10.7326/0003-4819-158-3-201302050-00583\u003c/li\u003e\n\u003cli\u003eLu, T., et al. \u0026quot;Development and preliminary optimization of the dampness syndrome scale of Chinese medicine.\u0026quot; J. Trandit. Chin. Med 62.19 (2021): 1677-1638.\u003c/li\u003e\n\u003cli\u003eQian, L. I., W. U. Wenzhen, and Xiaobo Yang. \u0026quot;Research on Normatively Portraying the Symptom Terminology of the Dampness Syndrome.\u0026quot; World Science and Technology-Modernization of Traditional Chinese Medicine 25, no. 7 (2023): 2281-2286.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Qu-Shi-Jie-Du decoction, Colon cancer, Chinese herbal medicine, Protocol, Randomized controlled trial","lastPublishedDoi":"10.21203/rs.3.rs-5908874/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5908874/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eColorectal cancer is one of the most common and fatal cancers worldwide. Despite therapeutic advancements, patients with stage II and III colon cancer often experience recurrences and metastases, particularly to the liver, leading to suboptimal disease-free survival rates and decreased long-term survival. Qu-Shi-Jie-Du decoction (QSJDD), a traditional Chinese herbal formula, may prevent cancer recurrence and spread by boosting immunity, reducing inflammation, and inhibiting tumour growth. Preliminary studies have demonstrated that QSJDD reduces liver metastasis in patients with colon cancer. However, robust clinical evidence is required to confirm its efficacy and safety. This study aims to evaluate the safety and efficacy of QSJDD in preventing colon cancer recurrence and liver metastasis, thereby offering a potential adjunctive therapy to improve patient outcomes.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis multicentre, double-blind, randomised, placebo-controlled trial includes 336 high-risk patients with stage II or III colon cancer from 10 hospitals across China. After surgery and chemotherapy (fluorouracil monotherapy, CAPEOX or mFOLFOX6), 168 patients will be randomised to either the intervention (QSJDD compound granules) or placebo group. The treatment lasts for 6 months, followed by a 3-year follow-up period with assessments conducted every 6 months. The primary endpoint is the 3-year disease-free survival rate, whereas the secondary endpoints include 1- and 2-year relapse rates, overall survival, and variations in the Traditional Chinese Medicine Dampness Syndrome Scale. Safety outcomes including adverse events, will also be monitored. Additionally, the blood and gut microbiomes of patients will be analysed to investigate the effect of QSJDD in delaying the metastasis of colon cancer.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eThis trial will determine the efficacy and safety of QSJDD and provide evidence regarding its role in the adjuvant treatment of colon cancer.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003eChictr.org.cn Identifier: ChiCTR2300078971. Registered on 22nd December 2023.\u003c/p\u003e","manuscriptTitle":"Qu-Shi-Jie-Du decoction for prevention of recurrence and metastasis in high-risk stage II/III colon cancer: Study protocol for a double-blind, randomized, placebo-controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-31 18:04:59","doi":"10.21203/rs.3.rs-5908874/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f3fae1b8-61d9-4ad1-aee0-fdd8b7ef2a38","owner":[],"postedDate":"January 31st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-03-07T17:23:43+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-31 18:04:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5908874","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5908874","identity":"rs-5908874","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}