A multicentre, open, prospective, randomized controlled trial will be conducted that includes 3 regional hospitals in Henan, which is the area with the highest incidence of ESCC in the world, including the First Affiliated Hospital of Henan University of Science and Technology (HUST), Anyang Tumour Hospital of HUST, and Nanyang Centre Hospital. A total population of 216 x 105 is served by these three hospitals (Fig. 1).
This study protocol was approved by the Ethics Committees of all of The First Affiliated Hospital of HUST, Anyang Tumour Hospital of HUST, and Nanyang Centre Hospital. The study is performed in accordance with the Declaration of Helsinki, and written informed consent will be collected from each study participant prior to enrolment.
The First Affiliated Hospital of Henan University of Science and Technology (HUST), Anyang Tumour Hospital of HUST, and Nanyang Centre Hospital.
A total of 196 ESCC patients with T1bN+M0, T2-4aN0-2M0 will be randomized to the CRT group or the surgery group.
1. Age: 18-75 years;
2. Mainland Chinese;
3. Oesophageal squamous cell cancer is confirmed by histology;
4. Tumour is resectable;
5. Clinical stage: cT1bN+Mo, or cT2-4aN0-2M0
6. Performance status score: 0-2
1. Patient had distant metastasis to solid visceral organs or local invasion into the trachea, descending aorta, or recurrent laryngeal nerve.
2. Patient had a serious premorbid condition or a poor physical status that compromised the thoracotomy.
3. Compromised cardiac function or creatinine clearance less than 50 ml/min.
4. MVV of pulmonary function test is less than 30%.
Patients will be withdrawn from the study if they withdraw informed consent and decline to continue treatment or follow-up.
Recruitment will be from cancer centres of The First Affiliated Hospital of Henan University of Science and Technology (HUST), Anyang Tumour Hospital of HUST, and Nanyang Centre Hospital, Henan province, China. Research staff will regularly check the inpatient registry Information System and identify any potentially eligible patients. They will liaise with an oncologist to ensure the patient’s history and screening results are clear for study commencement. Eligible participants who present at cancer center when research staff are present will complete informed consent documentation after discussion with the oncologist, fill out baseline measures, then be randomly allocated to DCRT or NCRT plus surgery group.
The randomisation codes will be generated by the study statistician using computer-generated random numbers. Participants will be randomly allocated to DCRT or NCRT plus surgery group in 1:1 order. Then in each group, participants will be secondary randomly allocated to subgroups with one of three different chemotherapy regimens in 1:1:1 order.
Patients will receive further staging workup, including oesophagoscopy, endoscopic ultrasonography (EUS), computer tomography (CT) of the thorax and abdomen with contrast, and ultrasonography of the cervical region with fine needle aspiration cytology for any suspicious nodes. PET-CT will be used when the disease stage is difficult to confirm by general imaging examination, but it is not compulsory.
Standard oesophagectomy surgery will be performed for patients by specialists. The surgical approach to the mid or lower thoracic oesophagus will bewas standardized to two-stage oesophagectomy to achieve a 5-cm minimum proximal margin. For tumours located over the proximal mid thoracic oesophagus where a 5-cm proximal margin could not be achieved, a three-stage oesophagectomy will bewas performed. We will performed a two-field lymphadenectomy in situations of either cervical or thoracic anastomosis. All the oesophagectomies will bewere performed through the thoracoscopy operation or an open approach. A radical surgical resection iswas defined as macroscopic clearance of the oesophageal tumour with no residual disease left (R0). Patients in the standard oesophagectomy group will received postoperative adjuvant chemotherapy if the resection iswas considered to be R1 as if microscopic disease is left behind.
IMRT radiotherapy will bewas performed for patient in the DCRT group with 50 Gy/25 F and in the surgery group with 42 Gy/21 F for NCRT, at 2 Gy/day, 5 times/week, until disease progression or unacceptable toxicity iswas found. The dosage for the individual patients will bewas governed by the dose constraints of the normal organs. Target volume length included 5 cm on each side of the imaged visible tumour and malignant nodes. Radiotherapy will bewas delivered in two consecutive phases. Phase I started with anterior-posterior opposing portals to 30 Gy, while phase II will bewas given with three fields to another 20 Gy (or 12 Gy in surgery group for NCRT), which is subject to the limiting radiation dose of the heart, lung, and spinal cord.
Patients will be randomized given one of three regimens below:
Xelox: oxaliplatin 65 mg/m2, d1, 8, 22, 29, plus capecitabine, 625 mg/m2, bid, d1-5; 6 weeks in total.
Single capecitabine: capecitabine, 625 mg/m2, bid, d1-5; q1w, 6 weeks in total.
PF: cisplatin, 75 mg/m2, d1, 29, 5-Fu, 750 mg/m2, CIV 24 h, d1-4, d29-32.
The primary outcome measures are 2-year/5-year overall survival (OS).
The secondary outcomes are 2-year/5-year disease-free survival (DFS), treatment-related adverse events (AEs) and QoL. The recurrence of the disease is defined as either endoscopic recurrence confirmed with biopsy or distant metastasis. The operative mortality is defined as an in-hospital death within 30 days of perioperative period.
All patients will be followed in the hospital where they received treatment at the 16th week after random allocation, then, at 3-month intervals in the first 2 years, and 6-month intervals for the next 3 years thereafter. Local or systemic recurrences and any AEs will be recorded. For the DCRT group, patients could be treated with salvage oesophagectomy if the disease doesn’t reach complete remission at the 16th week follow-up. As well as for the surgery group, patients could be treated with radiation or chemotherapy if R0 is impossible to take or there is local recurrence at the 16th week of follow-up.
QoL will bewas evaluated in all patients using the quality of life-core 30 questionnaire (QLQ-C30; ver. 3.0, in Chinese) and the supplemental quality of life-oesophageal module 18 questionnaire (QLQ-ES18, in Chinese) for patients with oesophageal cancer, both of which were developed by the European Organization for Research and Treatment of cancer (EORTC). For this evaluation, each patient will bewas visited in person during hospitalization 1 week before and 1 week after surgery, and contacted by telephone at 12 and 24 weeks postoperatively (Fig. 2) .
This trial will be conducted in accordance with ICH Guidelines for Good Clinical Research Practice and relevant local ethical regulations. Study data will be collected and managed using a regulatory approved electronic data capture system.
Data quality will be assured through range checks for data values. Integrity of trial data will be monitored by regularly scrutinising data for omissions and errors. In order to protect confidentiality before, during and after the trial, personal information about potential and enrolled participants will remain secure in a locked research office at The First Affiliated Hospital of Henan University of Science and Technology. Study data will be retained, securely password protected, for a minimum of 15 years from completion. Details of data management procedures can be found in the protocol.
The primary method of analysis will be provision of descriptive statistics characterizing key features, such as Because of participant numbers and the aims of the study, we will report descriptive analyses. Recruitment rate (number of patients approached, number consenting to participate and number eligible to be randomised), will be reported, as will frequencies and proportions of missing data and participant attrition, both during intervention and follow-up periods every three months.
Sample Size Estimation and Statistical Analysis
Sample size calculation is based on the 5-year OS in patients treated with oesophagectomy of 29.4% and 50% in DCRT group . We used the log-rank test to compare the survival rate difference between the surgery and DCRT group. We defined the α as 0.05, and β as 0.2. We supposed that the rate of loss to follow-up per year is 2.5% and 12.5% in 5 years. A sample size of 96 patients was determined to be required for each group.
The baseline data of the patient characteristics and the primary and secondary outcome measures will be compared using the Student’s t-test for the normally distributed parametric data and the Mann-Whitney U test for the nonparametric data. For the data in proportions, a X2 test or the Fisher’s exact test (if one of the expected values is less than 5) will be used. The provision of a 95% confidence interval will be calculated with the relative risk for cancer recurrence, morbidities and mortalities related to each therapy. We will use the Kaplan-Meier curve to represent the probability of survival within 2 years and 5 years after the initial diagnosis, and compare the two groups using the log-rank test. A value of P < 0.05 is considered to be statistically significant. The statistical analysis will be performed with the SPSS software (version 13.0; SPSS Inc., Chicago, IL, United States).
Collecting, assesing, reporting and managing adverse events
The most common side effects of CRT are myelosuppression, oral mucositis, hand-foot syndrome and peripheral neuritis. More severe side effects are rare. Information about solicited and spontaneously reported adverse events will be sought from all participants during telephone reviews by the trial GP. If a participant reports an adverse event, the trial GP will determine appropriate action, which may include dose alteration or withdrawal. If an adverse event is identified more serious than grade 4, the trial GP will forward this information immediately to the Principal Investigator and Data Safety Monitoring Board. All of the serious AEs (SAEs), suspected adverse reactions and serious unexpected suspected adverse reactions will be recorded immediately in the source documents, and on the adverse event case report form. Each event will be followed until resolution, stabilisation or until it has been determined that the study treatment is not causal. SAEs still on going at the end of the study will be followed up to determine final outcome. Any SAE will be recorded and reported immediately that occurring after the study considered to be possibly related to study treatment. Economic compensation will be provided by the trial sponsor that to who suffer harm from trial participation.
For the data monitoring of the QoL outcome, some measures will be taken firstly to prevent and reduce the missing data through enhancing the investigator training, communication, patient education and data monitoring. Secondly, we will confirm the causes of missing data case by case and record in detail. Then the suitable missing data handling methods such as last observation carried forward (LOCF) or multiple imputation (MI) will be chosen at last.
Authorship eligibility guidelines will follow ICMJE guidelines. The final trial dataset will be available to the investigative team and on reasonable request.