This trial is an open, Single-center, randomized trial, 180 patients with stage III and IV gastric cancer who met the inclusion criteria will be randomly assigned to three groups of ABC, receiving S-1, XSLJZD combined with S-1, Symptomatic treatment for 5 year. The flowchart of the trial is presented in Fig. 1.
This trial was to determine the efficacy and safety of S-1 combined with XSLJZD in the treatment of advanced gastric cancer, and the therapeutic advantages of this combination mode over single drug S-1. In addition, this trial also provides a scientific basis for exploring an ideal maintenance therapy for advanced gastric cancer.
The reporting of the protocol follows the Standard Protocol Items: Recommendations for Interventional Trials 2013(SPIRIT2013) guidelines[17,18]. Additional file 1 contains the SPIRIT 2013 checklist.
The trial procedures and informed consent form have been approved by the independent Ethics Committee of the Affiliated Hospital of Guangdong Medical University in Guangdong province, China (YJ2016-010KT-01). Information on any AEs will be reported to the Ethics Committee until to reach a stable situation. Moreover, the Ethics Committee has the duty to periodically evaluate the progress of this trial.
Recruitment and diagnostic criteria
The trial was carried out at the Cancer Center of the Affiliated Hospital of Guangdong Medical University. The Cancer Center has obtained the qualification of "National Clinical Drug Testing Institute". The participants were all inpatients of cancer center of Affiliated Hospital of Guangdong Medical University, mainly recruited through Internet advertisements and hospital posters. The patients interested in participating in the trial will be evaluated by clinicians to determine their qualifications. The clinician will inform the patient of the detailed trial objectives, process, and potential benefits and risks. All participants will sign the informed consent before participating. The diagnostic criteria are as follows:
- Diagnostic criteria: According to the diagnostic criteria in the “Specifications for the Diagnosis and Treatment of Common Malignancies” prepared by the Medical Department of China, TNM and clinical staging refer to NCCN guidelines, stage III or IV gastric cancer diagnosed by pathology or cytology.
- Diagnostic criteria for maintenance stage of advanced gastric cancer: After a certain course of treatment, patients with stage III and IV gastric cancer reaches the maximum tumor control effect (in CR/PR/SD status by the Response Evaluation Criteria In Solid Tumors, RECIST 1.1)and continue to receive drug treatment until the time of disease progression.
The inclusion criteria are as follows:
- There must be an informed consent form signed by the patient himself or by the witness;
- Stage III or IV gastric cancer diagnosed by pathology or cytology;
- Controlled by chemically treated diseases (CR/PR/SD);
- Age 18 to 75 years old (≥18 years old, ≤75 years old); expected survival period is more than 3 months;
- Karnofsky Performance Status (KPS) [20,21]≥60;
- According to the Response Evaluation Criteria In Solid Tumors (RECIST 1.1), at least one measurable lesion;
- Routine blood test: hemoglobin ≥ 90g/L; neutrophil count ≥ 1.5×109/L; platelet count ≥ 100×109/L;
- Biochemical examination: total bilirubin ≤ 1.5×upper limit of normal range (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2×ULN; if liver metastasis, ALT and AST ≤ 5×ULN Endogenous creatinine clearance rate ≥ 60ml/min;
- Cardiopulmonary function is basically normal.
The exclusion criteria are as follows:
- Patients with severe heart, liver or kidney damage or abnormal bone marrow function;
- Past or concurrent with other malignant tumors, except for cured skin basal cell carcinoma and cervical carcinoma in situ;
- The general situation is poor, and those who cannot eat Chinese medicine;
- According to the judgment of the investigator, serious accompanying diseases that endanger the safety of the patient or affect the patient's completion of the trial;
- Pregnant or lactating women;
- Those known to be allergic to the therapeutic drugs used in the trial.
Randomization and blinding
The cancer center examines the participants into groups. After passing the examination, according to the random number generated by the computer, according to the order of the participants into groups, the drugs corresponding to the randomly assigned drug number are given. Participants who meet the eligibility criteria will be randomly assigned to the S-1 group, S-1 combined with XSLJZD, and the observation group in a 1:1:1 ratio. Clinicians, patients, data collectors, and outcome assessors will be blinded to the group assignment. The allocation will be unblended if a SAE occurs and when the final data analysis is complete.
The participants were randomly divided into three groups of ABC in a 1:1:1 ratio, each group of 60 cases, the details of the intervention are as follows:
- Group A(S-1 group): 80mg/m2/d, divided into two orally, swallowed with water for half an hour after breakfast and dinner, used for two weeks, rest for one week, and 21 days for one cycle.
- Group B(S-1 combined with XSLJZD group): S-1 80mg/ m2/d, divided into two orally, swallowed with water for half an hour after breakfast and dinner, used for two weeks, rest for one week, 21 days for one cycle; According to the syndromes of the patients, XSLJZD was given combined treatment. Later physicians replaced ginseng with Codonopsis pilosula to give full play to its functions of warming and benefiting qi, invigorating the spleen and nourishing the stomach, the composition of XSLJZD: Codonopsis 15g, Atractylodes 20g, Poria cocos 15g, tangerine peel 15g, 10g of Pinellia, 10g of woody, 10g of Amomum vulgaris, 10g of ginger, and 6g of licorice.
- Group C(symptomatic treatment/observation group): clinical symptomatic treatment and supportive treatment, no Chinese medicine and anti-tumor drugs.
The primary endpoint is PFS at six months and one year, the time from randomization to disease progression(Evaluation of tumor progression about RECIST 1.1) or death. For participants who did not observe tumor progression or death, the PFS data were deleted on the last effective tumor evaluation day.
- OS, time from randomization to death for any reason. The last follow-up time is usually calculated as the time of death for the participants who have lost the visit before death. The total survival time of the participants who survived in the last follow-up was deleted on the last contact day.
- Quality of Life Assessment (QOLA), including symptom improvement, KPS and AEs assessment before and after treatment, performed 1-3 days before each cycle of treatment, details are as follows:
- Symptom improvement, mainly observe the changes of common symptoms of gastric cancer and colorectal cancer (pain, diarrhea, fatigue, poor acceptance, sleep), refer to the "Guiding Principles for Clinical Research of New Chinese Medicine"[22,23]in the relevant TCM symptom integral quantification table(MDASI-TCM, Additional file 2), compared to the scores accumulated for each symptom, analyzed the difference before and after treatment.
- KPS, comparative analysis before and after the difference.
- Assessment of AEs (safety outcomes). Assessment and grading of AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0, AEs include nausea and vomiting, granulocytopenia, thrombocytopenia, anemia, impairment of liver and kidney function, diarrhea, peripheral neuritis, stomatitis, hand-foot syndrome and any other new symptoms or diseases related to or unrelated to intervention. SAEs refer to the events that must be hospitalized or prolonged, permanently and seriously disabled, life-threatening or death in clinical trials. SAEs will be reported to the chief researcher and the hospital ethics committee, and the experiment will be stopped within 24 hours.
Baseline was defined as pre chemotherapy (-7 to 0 days). During baseline examination, the patient's gender, age, marital status, education level, comorbidities, pathological gastric cancer, gastric cancer staging, radiotherapy and chemotherapy regimen, and medication records for the past 3 months will be recorded.
A detailed schedule of the trial is presented in Fig. 2(SPIRIT Figure).
This trial is expected to last for 5 years. After discontinuation of treatment, each patient will be followed until death or withdrawal from the trial. Follow up frequency: follow up every 28 ± 3 days before the end point of trial, and record the PFS; after the end point of trial, follow up every 3 months, and record the OS of 3-year and 5-year.
Case Elimination and withdrawal criteria
The elimination criteria are as follows:
- Case selection does not meet the inclusion criteria;
- Did not use the test drug;
- After the randomization, no data or major indicators missing, and the data is obviously incomplete;
- The drug prohibited by the test protocol was used, and the efficacy could not be evaluated.
Withdrawal criteria and solution
The withdrawal criteria are as follows:
- Participants voluntarily request to withdraw from the test;
- Severe adverse events(SAE) closely related to drugs occur, and toxicity intolerance makes the test impossible to continue.
- No reason for delaying treatment for more than 2 weeks;
- Can not be treated according to the program, poor compliance;
- Considering the interests of the Participants, the researchers believe that the best choice is to terminate the trial treatment.
Participants have the right to withdraw from the test at any time without any reason. Different follow-up solutions due to different reasons for participant withdrawal:
- If the participant does not appear as planned during the follow-up period, the researcher shall know the reason as much as possible, record the reason on the case report form(CRF), contact the participant as much as possible to ask the participant to conduct a final visit, record the last medication time, try to complete the effectiveness and safety inspection when withdrawing from the trial as specified in the scheme, and complete the safety follow-up period. AEs and outcomes were fully recorded. According to the actual situation of the participants, researchers can suggest or provide new or alternative treatment methods to the participants.
- If the participant is asking for termination of the trial, researcher will retain the data and must follow up in the specific follow-up steps specified in the trial. If the participant refuses to visit further, he or she should continue to track his or her survival status unless the participant refuses to disclose further information or is contacted. In this case, no further research evaluations should be conducted and no further information should be collected. The trial sponsor may retain and continue to use all the information before the withdrawal of the participant's informed consent, unless the participant requests that the collected information be withdrawn.
During the trial period, the use of any other anti-tumor drugs was prohibited except for trial drugs. When an adverse reaction occurs, it should be closely observed and actively treated. All drugs used simultaneously should be recorded on the CRF and stated.
According to the original observation record of the trial, the researcher will fill in the CRF in time, complete, correct and clear and check it. After checking, the data manager will input the original case report form into the online database repeated, and the database is password protected. After importing the collected patient data into the database, the data administrator and the main researcher will perform a secondary check on the data, correct all the errors and save them properly. When the experimental data is collected, the person leading the data analysis will analyze the data.
Sample size estimate
The randomized controlled trial (RCT) is an advantage test that uses an appropriate formula to estimate the sample size. According to the small-sample trial completed in the previous trial group, the median PFS of the S-1 combined with XSLJZD Group, the S-1 Group and the observation group were 8.7 months, 8.1 months and 5.1 months, the Log-Rank test showed statistically significant differences between the two groups (P=0.0039<0.05), suggesting that S-1 maintenance treatment was significantly better than the observation group. The PFS of the S-1 combined with XSLJZD Group was longer than that of the S-1 group, but the Log-Rank test showed no significant difference between the two groups (P=0.3321>0.05), but a prolonged trend. It suggests that the combination of Chinese medicine may be more prolonged PFS, but need to the further clinical research. Previous capecitabine was reported as a maintenance therapy for 11 patients with advanced gastric cancer. The median PFS was 10.4 months and the median OS was 19.7 months. Based on the results of our preliminary observational trial and expert advice，we assuming a significant level of α = 0.05, test efficacy (1-β) = 80%, Considering 10% dropout rate, the sample size of each group was 60, totaling 180 Participants.
- Primary endpoint PFS and secondary endpoint OS: The median of PFS and OS in each group was counted. Survival curves were plotted using Log-Rank test and Kaplam-meier survival analysis.
- symptom improvement assessment: behavioral status scores before and after chemotherapy (KPS), repeated measures analysis of variance before and after treatment in the group; TCM symptom scores before and after chemotherapy (MDASI-TCM), paired t test before and after treatment in the group the t test was used for comparison between groups.
protocol contributors or relevant medical administrations have the right to inspect the clinical research to ensure the authenticity of the data recorded in the clinical research and to comply with the provisions of the clinical research program. In this trial, an Independent Response Evaluation Committee (IREC), which consists of two oncology imaging diagnostic and evaluation experts unrelated to this trial and one oncology clinical expert. Under the premise of blindness, the IREC carries out an independent third-party evaluation of the objective imaging data of all participants, with each participant the most successful. The final was based on the evaluation of IREC. The participants of the clinical trial will be informed that there will be relevant personnel to check during the trial, but the privacy and data of the patients will be strictly protected.
During the clinical trial, clinical inspectors will conduct regular on-site monitoring visits to ensure that all content of the research protocol is strictly observed and the original data is checked to ensure consistency with the CRF. The research team of this research group consists of a Interdisciplinary researcher with reasonable structure and different expertise (oncology, TCM, epidemiology). Most of the researchers have obtained the "GCP training certificate of the national drug clinical trial institution". Each participant has a designated work schedule to ensure the smooth implementation of the experiment.
All records relating to the identity of the participant are kept confidential and the information will not be disclosed to the public beyond the limits permitted by relevant laws and/or regulations. The name of the participant will not be provided to the sponsor. Only the abbreviation of participant number and name is recorded in the medical record report form. If the participant's name appears in any other document, it must be hidden before a copy of the document can be provided to the sponsor. Research reports stored by computer must comply with local laws on data protection. Patients will be informed in writing that representatives of the trial sponsor, ethics committee or drug administration may review their medical records to check the collected information, and all personal information involved in the review will be strictly confidential and comply with local data protection laws. If the results of the trial are published, the personal identity of the patient will remain confidential. The researchers will keep a list to check the patient's records.