SOX regimen was used for adjuvant chemotherapy:
- Oxaliplatin 130 mg/m2 given intravenously on day 1
- S-1 given orally twice a day (half an hour after breakfast and dinner) for 14 consecutive days, and the dose of S-1 is shown in Table 1
- Repeated every 3 weeks
Patient's body surface area (m2)
S-1 single oral dose
Concurrent chemoradiotherapy regime
- Technique of irradiation: intensity-modulated radiation therapy
- Preparation prior to CT simulation: fast 4 hours and drink 100 ml of water (including 5 ml of contrast agent) 30 minutes prior to scan; patients with remnant stomach drink additional semiliquid diet (like congee) 10 minutes before scanning
- Technique of simulation: patients in the supine position with forearm on forehead, and use custom immobilization device (e.g. thermoplastic mask) to fix body from lower thorax to lower abdomen. The scanning range is from the apex of lung to the pelvic inlet, with 5 mm slice thickness. Intravenous contrast should be used whenever available unless allergic to contrast, old age, or with serious complications.
- Irradiation field: the clinical target volume (CTV) include anastomosis with a 3-cm margin in the cranio-caudal direction, and regional lymph node drainage area [No.110 (below carina), 20, 1–3, 7–9, 11 (proximal 1/3),16a1-2]. The planning target volume (PTV) will be obtained by expanding the CTV by 5–7 mm in radial direction, and by 10 mm in cranio-caudal direction.
- Dose prescription and fractionation: a total dose of 45 Gy at 1.8 Gy per day, 5 days per week, for 5 weeks. Dose prescription and recording should comply with the recommendations of the ICRU 83.
- Organ at risk (OAR) volume definition and dose constraints: the complete volumes of the remnant stomach, the liver, the kidneys, the lungs and the heart have to be delineated. Intestine and spinal cord must be outlined the volume between above and below 2 cm range of PTV. In this study, the normal tissue dose constraints is shown in Table 2.
- Concurrent chemotherapy: S-1 given orally twice a day (half an hour after breakfast and dinner), Monday to Friday, during radiotherapy, and the dose of S-1 is shown in Table 1
Normal Tissue Dose Constraints
V40 < 50% (no hot spot)
V30 < 40%
Dmean < 18 Gy
V20 < 30%
V20 < 20%
V30 < 30%
Dmax ≤ 50 Gy
Dmax < 40 Gy
The three-year DFS is the primary endpoint of this study. It is defined as the percentage of patients without locoregional recurrence, distant metastasis, or tumor-related death at 3 years measured from the date of randomization. Once a patient is lost after the last follow-up, his/her survival time will be censored at the last date the patient is known to be alive.
The secondary endpoints of this study included three-year OS, three-year LRFS, three-year DMFS, and QoL.
Three-year OS is defined as the percentage of patients in this study who are still alive at 3 years measured from the date of randomization. In this study, locoregional recurrence was defined as recurrence at the anastomotic site, tumor bed, remnant stomach or regional lymph nodes site, and distant metastasis is defined as non-regional lymph node recurrence, peritoneal seeding, metastasis to other organs. Three-year LRFS and DMFS are defined as the percentage of patients who are without locoregional recurrence or distant metastasis at 3 years measured from the date of randomization respectively. EORTC QLQ-C30 and QLQ-STO22 questionnaires will be used to evaluate QoL of patients at baseline, every 4-week during treatment and every visit after treatment.
Adverse events are defined as any adverse medical event that occurs between the inclusion in the study with the signing of the informed consent and the last visit, regardless of whether there is a causal relationship with the drugs or treatments being studied.
Adverse events include the following:
- All suspected adverse drug reactions (ADR)
- All reactions due to drug overdose, abuse, withdrawal, allergy or toxicity
- Obviously unrelated diseases, including the aggravation of pre-existing diseases
- Injury or accident
- Abnormalities found by physiological or physical examinations and requiring clinical treatment or further examination (unlike repeated validation examinations); abnormalities found in laboratory tests require clinical treatment or further investigation (unlike repeated validation tests); if these abnormalities are related to another reported event (e.g. elevated liver enzymes in jaundice patients), they should be described in the notes to the clinical event report and not listed as a separate adverse event.
Adverse Event Record
Research physicians should use concise medical terminology to report all adverse events directly observed by physicians or spontaneously reported by subjects. In addition, patients should be asked about adverse events every time they visit a doctor at the beginning of treatment, fill in the adverse event record table truthfully, record the occurrence time, severity, duration, measures taken and outcome of adverse events. Adverse events should be recorded in the Adverse Events Table of Case Report Form (CRF) .
Grading of adverse events
Adverse events were classified into grades 1–4 according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE v4.0) and the European Organization for Research and Treatment of Cancer (EORTC)/Radiation Therapy Oncology Group (RTOG) score:
- Grade 1: Mild, asymptomatic or mild symptoms, only clinical diagnosis or symptoms, can be tolerated
- Grade 2: Medium, has a certain impact on normal life
- Grade 3: Severe, unable to carry out normal daily activities; leading to hospitalization or prolonged hospitalization
- Grade 4: Life threatening, if emergency intervention is needed, otherwise there is a direct risk of death
- Grade 5: Death
Serious adverse events
When an adverse event meets one or more of the following criteria, it is classified as a serious adverse event (SAE):
- Causing death
- Need for hospitalization or extended hospitalization
- Causing persistent or severe disability or dysfunction
- Congenital deformity or birth defect
- Major medical events
Any serious adverse events in the course of clinical research must be reported by fax or telephone to the ethics committee and the principal investigator within 24 hours. The principal investigator will collect data and reports according to SFDA and Ministry of Health's reporting requirements on adverse reactions. Researchers must fill in a serious adverse event form to record the occurrence time, severity, duration, measures taken and outcome of serious adverse events.
Once SAE occurs, all antineoplastic therapy should be discontinued immediately, and the relationship between adverse events and research drugs or radiotherapy should be assessed, and appropriate symptomatic and supportive treatment should be given until the patient recovers or remains stable.
According to CTCAE v4.0, the toxicities during the study should be graded. When adverse drug reactions occur, the dose of drugs should be reduced according to the following principles, or even discontinue treatment. Details of each patient's dose reduction and withdrawal should be recorded in the CRF table.
Dose reduction/withdrawal principle for adverse drug reactions of concurrent chemotherapy and adjuvant chemotherapy
- No special treatment should be given when grade 1 adverse reactions occur
- S-1/oxaliplatin should be discontinued and given symptomatic treatment when grade 4 leucopenia, grade 3 gastrointestinal adverse reactions, grade 2 anemia and thrombocytopenia, and grade 2 liver and kidney dysfunction occur. If the grade of adverse reactions dropped to 0–1 within 5 days after treatment, the initial dose of S-1/oxaliplatin was restored; if not, consideration should be given to reducing dose of S-1/oxaliplatin to 80% of the initial dose. If the above adverse reactions persist for more than 3 days after symptomatic treatment and dose reduction, or other adverse reactions with new grade 2 or higher occur again, S-1/oxaliplatin should be terminated.
- When other grade 3 adverse reactions occur, the treatment principle is the same as that of corresponding grade 2 adverse reactions
- If any grade 4 adverse reactions occur, the concurrent chemotherapy or adjuvant chemotherapy should be stopped and not continued.
Principles of interruption or discontinuation of radiotherapy
- When the acute grade 3 radiation toxicities occurs, radiotherapy should not be interrupted and symptomatic treatment should be given. If it does not recover to grade 0–1 within 7 days, radiotherapy should be interrupted, and restarted after the grade of toxicity return to 0–1. If the same toxicities of above grade 2 reoccur, radiotherapy should be terminated. When radiotherapy is terminated, S-1 should be terminated at the same time.
- Any grade 4 adverse reactions except leukopenia occurred, radiotherapy should be discontinued. When the adverse reactions recover to grade 0–1, restart radiotherapy, but not chemotherapy.
- Dose of radiation should not be adjusted unless new adverse reactions occur or the original adverse reactions are aggravated.
Patients should be followed up once every 3 months within 2 years after operation and once every 6 months 2 years after operation until 5 years. Follow-up contents include physical examination, performance status monitoring, weight monitoring, routine blood test, blood chemistry, tumor markers (including CEA and CA19-9), adverse events and QoL assessment. Chest, abdominal, and pelvic CT should be performed every 6 months, and gastroscopy is recommended once a year. If new symptoms or symptoms worsen, patients should receive follow-up visit at any time. The recurrence and/or metastasis must have biopsy or clinical imaging evidence, and the time and location of recurrence and/or metastasis should be recorded in detail.
In this study, the sample size was estimated by statisticians. The 3-year DFS of the experimental group is expected to be increased from 47–60% (δ = 0.13), which provides strong evidence for adjuvant treatment of locally advanced EGJ adenocarcinoma. With a one-sided alpha = 0.05 and 1-β = 0.8, 172 per group would be necessary, and 206 endpoint events need to be observed. Given an estimated dropout rate of 10%, the required total sample size would be 378. Patients enrolled in this study would be randomly divided into experimental group and control group, stratified by whether the EGJ is invaded or not and by postoperative stage. The ratio of the two groups was 1:1.
The analysis was based on the intention-to-treat (ITT) population. The ITT population should include all patients receiving randomization. Per-protocol (PP) population should include all patients who received at least two cycles of chemotherapy and completed radiotherapy for experimental group and received at least four cycles of chemotherapy for control group.
Comparison of baseline data between the two groups: if the quantitative data is normal distribution, t test is used; if it is not, rank sum test is used; χ2 test is used for qualitative data. Survival analysis is carried out by SPSS software package. Log rank χ2 analysis is used for comparison between the two groups, and Cox regression model is used in multivariate analysis. χ2 test is used to compare the recurrence rate, metastasis rate and the incidence of side effects between the two groups. Two-tailed test is used, and p < 0.05 is considered statistically significant.
Randomization, data collection and monitoring
All potential participants will be initially screened by the designated pathologists, and then further screened according to the inclusion criteria and exclusion criteria by the designated clinicians. Those eligible subjects who signed the consent will be randomized to either experimental group (adjuvant chemotherapy plus chemoradiotherapy) or control group (adjuvant chemotherapy alone) in a ratio of 1:1. Randomization will be stratified by whether the EGJ is invaded or not and by postoperative stage. We use a mobile application software, developed by Fudan University Biostatistics Central Office (Shanghai, China), to perform randomization. Data management and storage will be carried out by an independent data collection group (yitu-med, https://edcs.yitu-med.com), and personal information will be encoded. The principal investigator and core investigators will review the enrollment progress and data entry.
This study was carried out according to the Declaration of Helsinki. The protocol, the informed consent form and the case report form have been reviewed and approved by to the medical ethics committee of our hospital (IRB-2019-196), and the main members who participated in the study have obtained the certificate of the Good Clinical Practice (GCP) course.
Participation in this study is completely voluntary. All patients will be informed of the study process, benefits, costs, potential adverse reactions and other alternative treatment options in detail before entering this study, and then sign the informed consent. All the signed informed consent will be kept by the principal investigator. After entering this study, patients could withdraw from the study at any time for any reason and receive other alternative treatment.