Capecitabine Metronomic Chemotherapy for Metastatic Colorectal Cancer Patients Reaching NED Status: A Protocol for a Prospective, Randomized, Controlled Trial

doi:10.21203/rs.3.rs-2203315/v1

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Capecitabine Metronomic Chemotherapy for Metastatic Colorectal Cancer Patients Reaching NED Status: A Protocol for a Prospective, Randomized, Controlled Trial

https://doi.org/10.21203/rs.3.rs-2203315/v1

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Background: A increasing number of patients with metastatic colorectal cancer (mCRC) have achieved no evidence of diseases (NED) status after surgery or other treatments. However, the latest guidelines for colorectal cancer do not recommend an appropriate treatment for patients with mCRC who achieve NED status. Capecitabine has the advantages of significant efficacy and minimal adverse reactions. Thus, capecitabine metronomic chemotherapy is a potential effective method for maintenance treatment for mCRC, but no relevant clinical studies have been reported. Therefore, we designed a randomized controlled trial to evaluate the efficacy and safety of capecitabine metronomic chemotherapy as maintenance treatment for mCRC patients who achieve NED.

Methods/design: This study is a prospective, randomized controlled study that evaluates the efficacy and safety of capecitabine metronomic chemotherapy for patients with mCRC who achieve NED status. Sixty eligible participants will be randomly assigned to either a capecitabine metronomic chemotherapy group or a “watch and wait” group at a 1:1 allocation ratio. Eligible patients diagnosed with stage IV mCRC, both the primary tumor and the metastases, are those who have achieved R0 resection (or complete destruction by ablation) and reached NED. Participants who are enrolled in the capecitabine group will receive capecitabine 500 mg/m2 (bid) for 2 years. Meanwhile, those who are assigned to the control group will receive regular imaging examination and follow-up only. All participants will follow up for one year after receiving 2 years of intervention. The primary outcomes will be progression-free survival (PFS) and overall survival (OS) from randomization. Secondary outcomes will include 2-year and 1-year survival, adverse reactions and quality of life scores.

Discussion: As a potentially effective treatment, low-dose capecitabine metronomic chemotherapy has been explored in clinical practice. The results of this trial will provide evidence on the efficacy and safety of capecitabine metronomic chemotherapy for patients with mCRC who have reached NED status.

Trial registration: Chinese Clinical Trial Registry (ChiCTR2100047149, protocol version number F2.0)

Capecitabine

metronomic chemotherapy

mCRC (metastatic colorectal cancer)

NED (no evidence of diseases)

maintenance treatment

Metastatic colorectal cancer (mCRC) accounts for more than 40% of the total colorectal cancer population [1–2]. In recent years, with the progress of surgery and a series of drugs to improve the objective response rate of tumors, more and more patients with mCRC can now receive surgical resection after conversion therapy, or achieving no evidence of disease (NED) status through local treatment such as ablation [3–4]. This has greatly improved survival for patients with mCRC. At present, a total of 6 months of perioperative chemotherapy is routinely recommended for patients with mCRC after resection, but many patients have postoperative recurrence and metastasis. For patients with mCRC who achieve NED status after resection after conversion therapy, how to avoid tumor recurrence and metastasis after surgery is an urgent clinical problem [5–6].

Fluorouracil (5 - FU) is the most important and basic drug used in chemotherapy for colorectal cancer. Capecitabine is an oral drug and a member of the fluorouracil class. The highly expressed thymidine phosphorylase in tumor tissue can degrade it into 5-FU, significantly increasing the drug concentration at the tumor site, and simulating continuous perfusion of 5-FU, so that it maintains a stable blood drug concentration at the action site [7]. Several clinical studies have confirmed that capecitabine has the advantages of significant efficacy and minimal adverse reactions. Single-agent capecitabine is suitable for patients with mCRC who need out-patient administration and cannot tolerate multi-drug combined chemotherapy [8–9].

Metronomic chemotherapy is a mode of small dose, continuous administration and oral administration which can maintain drug concentration at a low and effective blood drug concentration for a long time, prolong the disease control time, and mitigate the toxic side effects. Metronomic chemotherapy exerts an anti-tumor effect by inhibiting tumor angiogenesis, and can promote and induce anti-tumor immune response in the microenvironment. Its targets are vascular endothelium and tumor stromal cells, tumor stem cells and immune cells, but not the tumor itself. It can shorten the treatment interval, reduce the recovery time for tumor cells during the treatment interval, and inhibit tumor proliferation by anti-angiogenesis, immune activation, reducing drug resistance and inducing tumor dormancy to inhibit tumor proliferation [10–14] .

After multiple courses of combined chemotherapy for advanced colorectal cancer, patients’ sensitivity to drugs will decline, and the adverse reactions of the chemotherapy drugs will continue to accumulate. For patients who achieve NED after surgery or ablation, most tumor lesions are removed, and quality of life becomes the focus of the next stage of treatment.

It is necessary to balance the anti-tumor effect while reducing the treatment-related adverse reactions. Capecitabine metronomic chemotherapy has shown good efficacy in breast cancer and head and neck cancer [15]. The SYSUC-001 study [16] analyzed the efficacy of capecitabine metronomic chemotherapy after standard treatment in patients with triple-negative breast cancer. 434 patients were randomized to either a capecitabine metronomic chemotherapy group (650 mg/m² twice daily for 1 year) or an observation group. The findings showed that 5-year DFS significantly improved in the capecitabine metronomic chemotherapy group versus the observation group (83% vs. 73%). This regimen has the characteristics of low toxicity and high efficiency, and is well-tolerated by most patients. However, more clinical data are needed to evaluate the efficacy and safety of single-agent capecitabine metronomic chemotherapy in the treatment of mCRC after NED status, and prospective RCT clinical studies are needed to verify the efficacy and safety of capecitabine metronomic chemotherapy.

Study design

This study is a prospective, randomized controlled study of capecitabine metronomic chemotherapy for maintenance therapy after reaching NED for metastatic colorectal cancer. All eligible individuals (60) will be randomly assigned to either a capecitabine metronomic chemotherapy group (n = 30) or a “watch-and-wait” group (n = 30) at a 1:1 ratio. This study protocol has been approved by the Ethics Committee at Zhongshan Affiliated Hospital, Guangzhou University of Chinese Medicine (No. 2021ZSZY-LLK-354) and registered in the Chinese Clinical Trial Registry (ChiCTR2100047149). All eligible participants will be required to sign an informed consent form prior to random grouping. The study flowchart is shown in Fig. 1.

Study Subjects

All subjects will be recruited through posters at Zhongshan Affiliated Hospital, Guangzhou University of Chinese Medicine, and all subjects must be medically fit patients with mCRC advanced colon cancer who had achieved NED status after surgery or ablation, aged 18–80 years, and with an ECOG score of 0–1. Major exclusion criteria are multiple primary carcinoma patients; pregnant women; mentally ill patients; patients with other serious underlying diseases. Complete inclusion and exclusion criteria are outlined in Table 1.

Table 1

Study inclusion and exclusion criteria
Inclusion criteria	Exclusion criteria
(1) Male or female aged 18–70 years.	(1) Patients diagnosed with more than one malignancy.
(2) Pathologically confirmed metastatic colorectal adenocarcinoma.	(2) Pregnant or lactating women.
(3) Contrast-enhanced CT or MRI of the chest and abdomen at the initial diagnosis, clinical stage IV colon cancer with liver and/or lung metastasis, and potentially curative R0 resection (including local therapy such as radiofrequency ablation) for the primary tumor and metastatic lesions, have completed perioperative chemotherapy, and achieved NED status on chest and abdomen CT or MRI within 4 weeks before enrollment.	(3) Patients with mental illness.
(4) ECOG score of 0–1.	(4) Combined with coronary heart disease, myocardial infarction, renal failure, pulmonary embolism and other diseases that may affect the survival of patients.
(5) There were no other underlying diseases affecting organ function.	(5) Patients with poor compliance can not cooperate with the treatment.
(6) Understand, be willing to give consent, and sign the written ICF prior to undergoing any study-specific procedure.	(6) There is a known deficiency of DPD, or Capecitabine intolerance.
Abbreviation: NED, no evidence of disease; ECOG, Eastern Co-operative Oncology Group; ICF, informed consent form; DPD, dihydropyrimidine dehydrogenase

Randomization, Allocation And Blinding

Eligible patients will be randomly assigned to either a watch-and-wait group or a capecitabine metronomic chemotherapy group in equal proportions via the random number table method. After the participants sign the informed consent form and complete the baseline assessment, the investigators will assign them a random number and assign the participants to the appropriate group. Participants will be informed that they have an equal chance of being assigned to the capecitabine metronomic chemotherapy group or to the watch-and-wait group. Subject assignment will be performed by an independent investigator in the clinical department who will not be involved in the evaluation of the results. The assigned group will be known to the practitioners, but the patients participating in the study will be unaware of their group assignments, while outcome assessors, data collectors, and statisticians will be blinded to group assignment throughout the course of the study. In addition, the blinding is allowed to be revealed when the patient has an intolerable adverse reaction.

Intervention

The interventions studied will be implemented by attending physicians with at least 3 years of clinical experience in the Oncology Department at Zhongshan Affiliated Hospital, Guangzhou University of Chinese Medicine. Based on chemotherapy theory for metastatic colorectal cancer and previous randomized controlled trials, capecitabine chemotherapy process interventions will be developed under the consensus of colorectal cancer oncology experts. Prior to initiating the study, the clinical practitioner will receive specialized training to gain a comprehensive understanding of capecitabine metronomic chemotherapy, and to administer treatment in accordance with the specific requirements of the investigator's manual. All eligible patients in both groups will have been diagnosed with stage IV colon cancer with hepatic and/or lung metastases, have potentially cured R0 resection of the primary tumor and metastatic lesion (including local treatments such as radiofrequency ablation), have completed perioperative chemotherapy, and have reached NED status on computed tomography (CT) or MRI within 4 weeks of enrollment. The study will be conducted over a 3-year period, with all treatments completed within 2 years, followed by a 1-year follow-up period. The study schedule is shown in Fig. 2.

Capecitabine metronomic chemotherapy group

All eligible patients will have been diagnosed with Stage IV mCRC according to the 2022 National Cancer Network (NCCN) colorectal cancer diagnosis and treatment guidelines. They also will have achieved NED after local treatment such as surgery or ablation and completed perioperative 6-month chemotherapy.

In the capecitabine metronomic chemotherapy group, after chemotherapy ends, patients will continue to take capecitabine 500 mg/m2 (bid) for 2 years, or until the disease progresses or the patient develops intolerable side effects. During the trial period, each observation index will be re-visited every 2 months, and imaging and tumor markers will be reviewed every 3 months from postoperative intervals to determine whether there is any recurrent metastasis of the tumor. The follow-up will last for 1 year, and the observation indicators will be re-visited every 3 months. The enhanced CT will be reviewed every 6 months to assess whether the tumor has recurred or metastasized.

Watch-and-wait group

Eligible patients diagnosed with stage IV mCRC, both the primary tumor and the metastases, have achieved R0 resection (or complete destruction by ablation) and reached NED. After completing 6 months of perioperative chemotherapy, they will enter observational waiting.

The observation period will be 2 years, and the observation indicators will be re-visited every 3 months; the follow-up period will be 1 year, and the observation indicators will be re-visited every 3 months during the period. The enrolled patients will be reexamined with enhanced CT or MR every 3 months during the observation period and every 6 months during the follow-up period to determine whether there is any recurrence or metastasis of the tumor.

The primary endpoints progression-free survival (PFS) and overall survival (OS)will be analyzed by using intention-to-treat (ITT) data set from randomization. Secondary endpoints will include 1- and 2-year survival and quality of life scores. The adverse reactions will be counted, and the bone marrow suppression rate and the incidence of digestive tract reactions will be used as safety evaluations.

Primary outcomes

Progression-free Survival (Pfs)

Progression-free survival (PFS) refers to the survival time calculated from randomization without any locoregional progressive disease, distant metastasis, recurrence or secondary colorectal cancer. Death from any cause will also be considered an event for this endpoint.

The enrolled patients will be assessed every 3 months starting from the baseline (Month 0). At the same time, the enhanced CT or MR will be reexamined, and combined with the tumor marker level to evaluate the recurrence and metastasis of the tumor, to observe patient survival, and to calculate the PFS.

Overall Survival (Os)

Another primary outcome is patient overall survival (OS), which is the time from randomization to death from any cause. For patients who are lost to follow-up before death, the time of last follow-up will be calculated as the time of death.

Participating patients will be recorded from baseline (month 0), with visits every 3 months to document patient survival.

Secondary outcome

Survival Rate

After visits at the time nodes specified in the trial, patient survival will be calculated at the time nodes of the 1st year and the 2nd year after randomization.

Quality Of Life

The Eastern Cancer Cooperation Group (ECOG) scoring system will be used to evaluate the patient's postoperative physical condition. Both the 2-year trial period and the 1-year follow-up period will be recorded every 3 months.

Safety

All participants will undergo physical tests to evaluate their bodies before screening enrolling and after treatment. These tests will include the function of the heart, liver, kidneys, and other organs, including cardiac ultrasound, ECG, white blood cell count, hematocrit, platelets, aspartate aminotransferase/alanine transaminase, blood urea nitrogen, creatinine, γ-glutamyl transpeptidase, and erythrocyte sedimentation rate.

Adverse events (AEs) are any unexpected adverse conditions, symptoms, or sensations that occur in subjects throughout the trial period, whether or not they are associated with capecitabine treatment. AE will be graded using the Common Terminology Standard (CTCAE) 4.0.3 [17]. A serious adverse event (SAE) will be defined as any of grade 3, 4, or 5 adverse events. Each AE will be recorded on the case report form (CRF). SAE will be reported to the Competent Authorities and the Ethics Committee. Initiators must submit annual safety reports to Competent Authorities and Ethics Committees during clinical trials. At the same time, the incidence of bone marrow suppression and the incidence of gastrointestinal responses will be counted to assess the safety of capecitabine metronomic chemotherapy.

Quality Control, Data Management And Monitoring

Prior to recruitment, research team members will be required to attend a training workshop to ensure their strict adherence to the research protocol, and that they have a comprehensive understanding of the trial management process. The intervention will be implemented by attending physicians with at least 3 years of hospital experience. The trial process will be conducted in accordance with a researcher's manual of standard operating procedures developed in consultation with experts with extensive therapeutic experience. To improve compliance, we maintained contact with the subjects and at least one family member of the subjects, and regular telephone follow-up was conducted.

This data will be collected and recorded on CRF. All data will be input to a password-protected computer by a staff member who does not know how the group assignments were made. It will be checked twice by investigators after the data is entered. The collected clinical data will be entered into the database and the database will be regularly updated according to follow-up timing. The original CRF and all database data will be securely stored in the Oncology Department building at Zhongshan Hospital of Traditional Chinese Medicine affiliated to Guangzhou University of Chinese Medicine. Throughout the trial, two trained, qualified, and independent supervisors will regularly visit the trial center to be responsible for data monitoring, regulatory management, and to conduct a trial audit every 3 months, independent of the investigator and the organizer. This will include specification of the random inspection program, the reasonableness of the inclusion and exclusion criteria, the proper implementation, the implementation of informed consent procedures, the specification of the CRF, the confidential updating of the database, and SAE reporting, and also determining whether to terminate the study prematurely. For any cases in which there is shedding or loss of visit, it will be necessary to explain the reasons for the shedding and the loss of visit, and calculate the proportion of cases in which there was shedding and loss of visit relative to the total number of observed cases.

Sample Size Calculation

As this is an innovative study, no data are available for reference. After reviewing the literature on sample size estimation in pilot studies, Browne pointed out that a sample size of 30 subjects was needed to estimate parameters [18]. In recent years, several scholars have suggested that the minimum sample size for each treatment group should be 12 subjects [19]. In the proposed study, in order to mitigate the imprecision of standard deviation estimates for future expanded trials {20], statisticians combined the specific circumstances of the proposed study to estimate that 30 subjects were expected to be enrolled in each group, and 60 subjects in both groups.

Statistical analysis

The statistical analysis will use SPSS version 26.0 (IBM SPSS Statistics, New York, USA). All analysis will be based on the ITT dataset. Missing data will be supplemented with the principle of multiple interpolation. All statistical tests will use a two-side test, and P < 0.05 will be considered statistically significant for the difference being tested.

Baseline data comparisons between the two groups will be based on data type, χ² test will be used for counting data, and t-test (consistent with normal distribution) or rank test (not normally distributed) will be used for measurement data. Descriptive statistics will be presented for each group as the mean change (SD, 95% confidence intervals), and P < 0.05 (two-side) will be considered statistically significant.

The survival analysis will use the Kaplan-Meier method for one-factor survival, calculating the median disease PFS and OS of the two groups, and comparing the survival curves by the Logrank test. P < 0.05 will be considered statistically significant.

In the past, mCRC was generally regarded as an unresectable disease with no chance of cure. Conversion therapy refers to the treatment of initially unresectable mCRC patients, through effective chemotherapy and targeted therapy so that the tumor will retreat to the condition of surgical resection. Several clinical studies have used chemotherapy combined with targeted therapy for patients with initially unresectable metastatic colorectal cancer. In these studies, patients’ NED, tumor regression depth, objective response rate (ORR) and radical surgery resection rate have significantly improved, such that more and more patients with mCRC have the opportunity to receive radical surgery [21–23] .

For patients with mCRC who achieve NED in the tumor-free state after radical surgery, there are no RCT study data to address whether to continue to use chemotherapy, which treatment regimen to use, or the duration of chemotherapy. Based on expert opinion and research data on postoperative adjuvant chemotherapy for stage III colorectal cancer, 6 months of perioperative chemotherapy and watch-and-wait after chemotherapy are generally recommended [24–25]. However, in clinical practice, it has been found that some patients with mCRC still have recurrence and metastasis within a short time after reaching NED. Thus, there is an urgent need for an effective treatment strategy with low toxicity and long-term drug tolerance. Metronomic low dose capecitabine chemotherapy has the advantages of minimal side effects, convenient long-term administration, and a clear anti-tumor effect. Moreover, the efficacy of metronomic capecitabine chemotherapy has been verified in breast cancer and nasopharyngeal carcinoma. As a potentially effective treatment, low-dose capecitabine metronomic chemotherapy has been explored in clinical practice. The purpose of this proposed clinical study is to verify the treatment efficacy by evidence-based medicine.

mCRC patients after reaching NED state still lack an effective standard therapy, and thus the proposed study will primarily observe capecitabine metronomic chemotherapy for mCRC after reaching NED state maintenance treatment regarding the PFS, OS, the quality of life score and adverse reaction data. This study is expected to change clinical guidelines, to provide high-quality clinical research data for clinical practice of such patients.

Trial status

This trial is currently recruiting patients, which started on 1 February 2022 and is anticipated to end on 1 February 2025. The protocol is Version 2.0 dated 2022/01/24.

mCRC

metastatic colorectal cancer

NED

no evidence of disease (NED)

computed tomography

PFS

progression-free survival

overall survival

ECOG

Eastern Cancer Cooperation Group

adverse event

SAE

serious adverse event

CRF

case report form

ORR

objective response ratery

Authors’ contributions

JMW, CTF, JCM and HTZ conceived this trial. JMW and YD were responsible for planning the draft and revising the manuscript. JMW, LXW and JCM were responsible for recruiting and treating the patients. JCM and LZL were involved in collecting the data. The authors read and approved the final manuscript.

Funding

This study is funded by the Scientific Research Project of the Guangdong Provincial Administration of Traditional Chinese Medicine (20202231), Medical Research Foundation of Guangdong Province(B2022284) and The Zhongshan Social Public Welfare Science and Technology Research Project (2021B1062).

Ethics approval and consent to participate

This study protocol has been approved by the Ethics Committee at Zhongshan Affiliated Hospital, Guangzhou University of Chinese Medicine (No. 2021ZSZY-LLK-354). The study coordinator will obtain consent from eligible patients, who will request permission from the research team to share relevant data and inform that there is neither anticipated harm nor compensation for participating in the trial.

Availability of data and materials

The full protocol of this study will be provided by the corresponding author. Datasets generated or analyzed during the current study will be available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Acknowledgements

We would like to thank the staff working at Zhongshan Affiliated Hospital, Guangzhou University of Chinese Medicine for their help with subject recruitment.

Consent for publication

Not Applicable.

Additional file 1. Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Checklist.

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Capecitabine Metronomic Chemotherapy for Metastatic Colorectal Cancer Patients Reaching NED Status: A Protocol for a Prospective, Randomized, Controlled Trial

Status:

Version 1

Abstract

Figures

Introduction

Methods

Study design

Study Subjects

Randomization, Allocation And Blinding

Intervention

Capecitabine metronomic chemotherapy group

Watch-and-wait group

Outcome

Primary outcomes

Progression-free Survival (Pfs)

Overall Survival (Os)

Secondary outcome

Survival Rate

Quality Of Life

Safety

Quality Control, Data Management And Monitoring

Sample Size Calculation

Statistical analysis

Discussion

Conclusion

Trial status

Abbreviations

Declarations

References

Supplementary Files

Status:

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