Effect of Traditional Chinese Medicine Collaborative Model (TCMCM) combined Adjuvant Chemotherapy in IIIb and IIIc Gastric Cancer: Protocol for a Randomized Controlled Trial

Metastasis and/or recurrence are the primary cause in decreasing the survival time of gastric cancer patients who experienced radical operation. Among whom, patients with stage IIIb and IIIc are especially in high risk of metastasis and recurrence, result in a signicant poor survival time than patients with earlier stages. Herbal medicines are natural substances that have been used for centuries in China, auricular acupressure and acupoints has shown promise in reducing side effects of chemotherapy(cid:0)this traditional Chinese medicine collaborative model(cid:0)TCMCM(cid:0)has been studied in cancer, however, the specic effects have not been systematically evaluated. This study was designed to evaluate whether TCMCM can decrease adverse effects after chemotherapy and reduce the recurrence rate and metastasis in stage IIIb and IIIc gastric cancer. This prospective(cid:0)multicenter, randomized, open-label trail will recruit 260 patients with stage IIIb and IIIc gastric cancer who undergo radical surgery with D2 lymphadenectomy. Randomization to usual adjuvant chemotherapy or the intervention (TCMCM) with a 1:1 ratio will be used. Patients in the intervention group received an oral traditional Chinese formula, auricular acupressure and acupoints, all participants will be continuing to receive usual adjuvant chemotherapy. The primary outcome is 3-year disease free survival rate. Secondary outcomes include quality of life(cid:0)side effects caused by chemotherapy and safety outcome measures. Assessments will be performed at Screening period and 4(cid:0)8 cycles after adjuvant chemotherapy(cid:0)9, 12, 18, 24,30 and 36 months after randomization, and adverse events will be recorded.In addition,biological samples will be collected for mechanism exploration studies. quality of life of all participants. All results are recorded in the CRF table and the ecacy is assessed using scoring method. Assessments will be performed at Screening period and 4, 8 cycles after adjuvant chemotherapy, 9, 12, 18, 24, 30 and 36 months after randomization.


Abstract Background
Metastasis and/or recurrence are the primary cause in decreasing the survival time of gastric cancer patients who experienced radical operation. Among whom, patients with stage IIIb and IIIc are especially in high risk of metastasis and recurrence, result in a signi cant poor survival time than patients with earlier stages. Herbal medicines are natural substances that have been used for centuries in China, auricular acupressure and acupoints has shown promise in reducing side effects of chemotherapy this traditional Chinese medicine collaborative model TCMCM has been studied in cancer, however, the speci c effects have not been systematically evaluated. This study was designed to evaluate whether TCMCM can decrease adverse effects after chemotherapy and reduce the recurrence rate and metastasis in stage IIIb and IIIc gastric cancer.

Method/design
This prospective multicenter, randomized, open-label trail will recruit 260 patients with stage IIIb and IIIc gastric cancer who undergo radical surgery with D2 lymphadenectomy. Randomization to usual adjuvant chemotherapy or the intervention (TCMCM) with a 1:1 ratio will be used. Patients in the intervention group received an oral traditional Chinese formula, auricular acupressure and acupoints, all participants will be continuing to receive usual adjuvant chemotherapy. The primary outcome is 3year disease free survival rate. Secondary outcomes include quality of life side effects caused by chemotherapy and safety outcome measures. Assessments will be performed at Screening period and 4 8 cycles after adjuvant chemotherapy 9, 12, 18, 24,30 and 36 months after randomization, and adverse events will be recorded.In addition,biological samples will be collected for mechanism exploration studies.

Discussion
This will be the rst clinical trial to evaluate the disease-free survival (DFS) and improvements in quality of life in patients of stage IIIb and IIIc gastric cancer receiving TCMCM, which may be used to formulate a standardized TCMCM plan. We are also performing this trial to assess the feasibility of a larger-scale clinical trial in the future.

Background
Gastric cancer is one of the most common malignancy and the second leading cause of cancer-related death thought the world [1]. More than half of the world's gastric cancer cases occur in Asia, accounting for 42% of China [2,3]. Due to lack of effective diagnostic and therapeutic strategies, more than 80% gastric cancer patients in China are already in advanced stages at the time of diagnosis and the 5-year survival rate remains quite low [4]. Among whom, patients with stage IIIb and IIIc are especially in high risk of metastasis and recurrence, result in a signi cant poor survival time than patients with earlier stages.
With the continuous improvement of postoperative chemotherapy regimens, the DFS and overall survival (OS) of gastric cancer were prolonged [5,6], Several clinical trials have established the effects for adjuvant chemotherapy in the treatment of gastric cancer [7] [8] [9]. Chemotherapy has been the standard treatment for patients with advanced gastric cancer [10]. However, about 40%-60% of patients with gastric cancer after resection have recurrence or metastasis, the prognosis is still poor [11] ,and they are toxic and often cause side effects affecting the quality of life of patients [12]. Therefore, there is still an urgent need to explore new methods to improve the prognosis of patients after radical gastrectomy.
In China The effect of herbal medicines have been demonstrated material and bene cial effects in improving available cancer therapeutics [13,14], auricular acupressure and acupoints are the nonpharmacological and noninvasive therapy that can diminish the side effects of chemotherapy and improve the quality of life they are safe effective and easily accepted by patients [15,16]. Hence, many patients diagnosed with cancer always choose to resort to TCM therapy. However, due to the individual treatment model of TCM and the need for frequent adjustments, it is di cult to design rigorous modern controlled trials for TCMCM, large-scale, randomized-controlled trials evaluating the e cacy of TCMCM and especially high-quality designed clinical trials are lacking, and only a few studies have comprehensively evaluated the prognostic value of this treatment in patients of GC [17]. We will assess the clinical effectiveness, quality of life, and safety outcomes to evaluate the e cacy of TCMCM in IIIb and IIIc gastric Cancer, we designed this randomized, open-label study.

Methods/design Study design
This study protocol was registered in the ClinicalTrials Registry https://register.clinicaltrials.gov/ with the number NCT03607656 on 1 July 2018.The study will identify patients with stage IIIb and IIIc gastric cancer who undergo curative D2 gastrostomy beginning in June 2018 at three centers in China, including Longhua Hospital a liated to Shanghai University of TCM, Renji Hospital a liated to Shanghai Jiaotong University School of Medicine and Jiangsu Province Hospital of Chinese Medicine a liated to Nanjing University of Chinese Medicine. The present study is designed as a longitudinal randomized interventional study with two study arms. Patients in the intervention group received an oral traditional Chinese formula, auricular acupressure and acupoints, all participants will be continuing to receive usual adjuvant chemotherapy which according to the National Comprehensive Cancer Network (NCCN) gastric cancer Treatment Guidelines. The trial design and checklist for this study protocol are summarized in Fig. 1 and Additional le 1 respectively.

Sample size estimate
Our previous study described the 3-year disease-free survival rate was 49% who underwent the Chinese herbal medicines combined with chemotherapy and 28% in the chemotherapy group. With a power of 0.9, the total number of randomized controlled trials was 197. Considering the 20% of follow-up loss, the con nement factor in different hospitals increased by 10% of the sample size, we will recruit a total of 260 patients for this trial.

Recruitment
Before the research, investigators of three centers are responsible for the introduction the clinical research related matters and the records of the baseline data respectively, and prospective participants will be informed of the bene t and possible risk associated with this study. Participants will be told that they can withdraw from the trial at any time without specifying reasons. Eligible participants will be randomized into two groups with different treatments once informed consent has been obtained. The investigator must have the expertise, quali cation and ability of the clinical trial. After the quali cation examination, the personnel requirements are relatively xed. Every investigator will participate in training on the fully understand the speci c connotation of the clinical study programme.

Criteria:
Inclusion Criteria: • Histologically proven gastric carcinoma with radical operation, TNM (primary tumor, regional nodes, metastasis) stage IIIb or IIIc (The 8th edition of the tumor-node-metastasis (TNM) staging system from the American Joint Cancer Committee/Union Internationale Contre le Cancer (AJCC/UICC)); •The age of onset is 18 years old; • Karnofsky performance status higher than 70; • Adequate hepatic, renal, cardio and hematologic function; • With patients' consent and comply to long term follow-up.
Exclusion Criteria: • Gastrectomy beyond D2, or TNM stage beyond IIIb and IIIc; • Histological type beyond gastric carcinoma; • Conversion chemotherapy before surgery; • Concurrent cancer; • Women of gravid or lactating; patients with mental illness; • Uncontrolled signi cant comorbid conditions such as unstable angina or myocardial infarction.

Randomization
In order to minimize selection bias, all eligible patients will be randomly assigned in a 1:1 ratio to the treatment group or the control group. Randomization will be performed by a professional, independent statistician who is not involved in the recruitment process of the study. The central randomization software "Clinstat Group" APP version 1.2.0. will be used for group allocation according to a randomization list. Randomization has two strati cation factors, the rst one is disease stage of IIIb or IIIc, and the second one is center (Longhua hospital, Renji hospital or Jiangsu Province Hospital of Chinese Medicine). The software server side pre-establishes two independent random lists according to the strati cation factor (stage: IIIB period vs. IIIC period), and each center shares a random list. Concealed allocation is guaranteed by the randomization program. Once the inclusion criteria have been ful lled and informed consent has been received, clinical researcher of centers will tell the statistician the information of patients 'gender, age, and the stage and then the statistician will log on the Clinstat Group to enter this basic information. Then the result is immediately presented on the screen. Neither investigators nor patients were masked to treatment assignment in this open-label trial.

Intervention
Enrolled patients in the control group will be accepted the treatment of adjuvant chemotherapy The chemotherapy can choose intravenous oxaliplatin 130 mg/m(2) on day 1 plus oral capecitabine 1000 mg/m(2) twice daily on days 1-14, every 21 days. Two additional chemotherapy regimens added after 27 June 2019.intravenous oxaliplatin 100 mg/m(2) on day 1 plus oral S-1 40mg/m(2) twice daily on days 1-14, every 21 days; or intravenous docetaxel 40mg/m(2) on day 1 plus oral S-1 40mg/m (2) twice daily on days 1-14,every 21 days; or intravenous docetaxel 50mg/m(2) on day 1 plus intravenous oxaliplatin 85 mg/m(2) on day 1 plus 5-FU intravenously CIV24h on day 1, every 14 days; Each participant should take eight (8) cycles of chemotherapy. The choice of chemotherapy regimen, including adjustments, are directed by one of two Chief physicians.
In addition to the above-mentioned adjuvant chemotherapy treatment, participants in the treatment group will receive an oral traditional Chinese formula based on the Jianpi theory, The major herbal formula components were Radix Pseudostellariae (12g), Rhizoma Atractylodis Macrocephalae (12g), Poria(30g), Rhizome Pinelliae Preparata (9g), green tangerine peel (4.5g), Concha Ostreae (30g), and Prunella vulgaris (9g). The herbal components above were mainly provided by Sunbow Pharmaceutical (7600 Zhongchun Road, Shanghai 201100, China). This Chinese medicine factory has quality control (certi ed GMP ShanghaiG0172). The preparation of the formula water decoction and its quality control had been described in our previously published articles. The patient started taking the Chinese herbal within 8-12 weeks after enrollment. The administration method was mainly oral administration of the decoction, and one dose per day was taken in 2 to 4 times. The clinical interventions of oral traditional Chinese formula were designed and adjusted on by senior TCM physicians in every center, and the formula is based on syndrome differentiation by examination, listening, smelling, interrogation, pulse-taking and palpation, the dose of each ingredient in the prescription will be decided by the physician. According to the clinical syndrome differentiation, adjust the medication every 1~2 weeks, continuous treatment for 6 months and above or until disease progresses (relapse/metastasis/die), unacceptable toxicity, or withdrawal of consent.
On the rst day of every cycle adjuvant chemotherapy, participants received auricular acupressure and acupoints by the research nurse. Auricular acupressure and acupoints points were chosen by a panel of expert faculty from Shanghai university of TCM. The auricular acupressure selected for this study were shenmen jiaogan and stomach. Magnetic beads held in place by tape were used to stimulate the three auricular acupoints, one side of the ear was selected for each time, and both sides of the ear were used in turn. Three times per day for 3 min per time (9min total .The acupoint selected for this study were neiguan zusanli and fenglong, The acupoint remained on the skin points for 24 hours. Even if they did not experience uncomfortable.

Biological specimens
Next Generation Sequencing (NGS) technology is used to observe the mutations of tumorigenesis-related genes and potential treatment-related genes in some patients, and to assess the relationship between tumor mutation burden (TMB) and the prognosis of gastric cancer. Blood was collected 3 times before surgery, after chemotherapy, regeneration and metastasis.
Patients without recurrence/metastasis will be examined 24 months after enrollment or at the end of the study.

Primary endpoint
The primary endpoint is 3-year disease free survival rate DFS was de ned as the date of randomization until the date of progression(tumor metastasis or recurrence) or the date of death from any cause. If symptoms or signs of suspected recurrence or metastasis or abnormal tumor markers are found during follow-up, CT/MRI/gastroscopy should be performed promptly and PET-CT should be performed if necessary. All subjects Used the response evaluation criteria in solid tumors version 1.1(RECIST 1.1) to estimate the objective curative effect. If workup revealed relevant tumor markers persisted abnormally, However CT or MRI examinations failed to reveal any mass, it was evaluated by the research team's expert group. Kaplan Meier curves will be performed to evaluate Intention-To-Treat ITT and Per-Protocol PP , 2 years after the end of the study. Assessments will be performed at Screening period and 4, 8 cycles after adjuvant chemotherapy, 9, 12, 18, 24, 30 and 36 months after randomization.

Side effects of chemotherapy
Side effects that occur during chemotherapy should be documented. Using NCI-CTC standard to record adverse effects of chemotherapy and treatments. compare toxicity and adverse events according to the NCI-CTC anti-cancer drugs in acute and subacute toxicity criteria and the Levi special sensory nerve toxicity grading criteria for oxaliplatin. Clinical researchers adjust medications based on toxic side effects. After the completion of treatment, follow-up examination was conducted along with the imaging examination.When a potentially dangerous or life-threatening adverse reaction occurs, a reduction in the dose or interruption of the drug can be allowed.

Safety outcomes
Safety indicators included assessment of vital signs at each visit, weight, KPS score, blood, liver and kidney function, fecal routine, and electrocardiogram. Adverse events (AEs) were de ned as all unexpected or unintended symptoms, signs, or disorders that developed to patients who received adjuvant chemotherapy, and no regard was given to their causality with chemotherapy.
According to the NCI common adverse events evaluation standard (v4.02) to compare adverse events.If serious adverse events occur during the study period, participants can withdraw from the study and the patient needs to complete the examinations and evaluations as much as possible.

Follow-up
Follow-up appointments for all patients will take place at Screening period and 4,8 cycles after adjuvant chemotherapy 9, 12, 18, 24,30 and 36 months after randomization. Tumor marker examinations are checked every 3 months for the rst two years, then every six months. A full abdominal augmentation CT/MRI and chest CT examination were performed every 3 months in a year, and then every six months; the gastroscope was examined once a year. All patients are followed up for 3 years or until recurrence, metastasis or death.

Withdrawal of patients
Patients can discontinue their participation in the study at any time for any reason if they wish to do so without any consequences. further, study medication can be stopped prematurely in case of serious adverse reaction, or if, in the investigator's opinion, study medication should be stopped for any other reason. If the patients in the control group continued to take Chinese herbal medicine orally in other hospitals for 6 months, they were judged to be out of the group.

Data collection and management
The investigators and research coordinator will be required to study the researcher's manual carefully before the trail begins.
Medical records are original records and cannot be changed. The original record must not be altered when making any corrections, and can only be accompanied by an explanation and date, signed by the physician participating in the clinical trial. All patient data collected during this trial will be managed in using an electronic case report form (eCRF). The management team will review for quality and audit the eCRFs, and queries will be sent out to each participating center regularly. Data monitoring will also be conducted by way of site visits. The data will be managed and analyzed according to the study protocol. After each topic is tested and reviewed by the auditor, the data administrator locks the data until the last topic data is locked. Data Monitoring Committee DMC will be carried out by Xiyuan Hospital of China Academy of Chinese Medical Sciences. The data management are not involved in clinical observations. Statistical analysis SPSS Statistics version 22.0 will be the primary tool for data management and statistical analyses. All patients will be followed according to the protocol, and both intention-to-treat and per protocol analyses will be performed. Missing data will be adjusted for using the last observation information to obtain a complete database. Besides descriptive statistics and visualizations, Independent sample T test and Chi-square test (χ2test) will be used for numerical variables and categorical variables respectively in the comparison between the two groups. When the distribution of variables is abnormal, a non-parametric test will be selected.
Univariate analysis and survival rate calculations were performed using the Kaplan-Meier method, and the Log-rank test was used to compare the factors. The association of DFS with each clinical/demographic factor was compared between the two groups using the Kaplan-Meier analysis. Multivariate data are analyzed using COX regression analysis, trend testing, and so on. Statistical analysis of the research materials will be carried out by Fudan University Cancer Hospital. Statistical analysts are not involved in clinical observations.

Others
Random grouping √

Study case work after completion
Auditor review case The auditor regularly audits through the EDC and reviews the eCRF records locks the data The data manager locks the data after each subject completes the test and is audited by the auditor.

Research evaluation
Adverse event assessment methods are the same for patients in the intervention group.Furthermore,free acupuncture and acupoints treatment will becomes more acceptable and conducive to reducing the dropout rate. In addition, our team will provide one-to-one health guidance to each patient. Therefore, we believe that most patients should be able to cooperate with the treatment and ensure good adherence to the program during the 2-year follow-up period.
In our randomized clinical trial, we tried to assess not only disease-free survival but also quality of life, side effects and Safety indicators. Side effects of chemotherapy affect prognoses in patients with gastric cancer and therefore need to be assessed, treated, and prevented. However, neither preventive nor therapeutic methods have been established for these therapies.The present study is the rst multicenter, randomized, open-label study conducted to clarify the effects of TCMCM, for the prevention and treatment of survival prognosis and quality of life in patients with stage IIIB, IIIC gastric cancer after surgery. After the completion of this study, we expect our trial can not only preliminarily evidence about the e cacy of the Chinese medicine, but also provide a more standardized and humanized treatment plan for the postoperative patients with gastric cancer, which is bene cial to more and more patients.  Figure 1 The trial design and checklist for this study protocol

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