Study design (Fig. 1)
HCHTOG1903 is a single-centre phase III two-arm open-labelled RCT. Eligible patients are randomly assigned to nCT or nCRT (CROSS protocol) and surgery with a 1:1 allocation ratio (Fig. 1). The purpose of this study is to confirm the superiority of a standard nCRT regimen in terms of OS over nCT as preoperative therapy for resectable locally advanced ESCC.
Primary endpoint
The primary endpoint was OS in all randomized patients. OS is defined as the number of months from randomization to death from any cause, and patients are censored on the last day they are known to be alive.
Secondary endpoints
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Disease-free survival (DFS) time: The time from the date of randomization to the date of first recurrence (local, regional or distant) or death.
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pCR rate: The degree of tumour regression is classified into four categories according to the modified Ryan scheme: grade 0, no viable cancer cells, including lymph nodes; grade 1, single cells or rare small groups of cancer cells; grade 2, residual cancer with evident tumour regression but more than single cells or rare small groups of cancer cells; and grade 3, extensive residual cancer with no evident tumour regression [8].
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Postoperative complications: The definition of each complication is listed in supplemental file 1. All postoperative complications will be captured for up to 90 days after surgery and graded according to the Clavien–Dindo classification [9].
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Postoperative mortality: 30-day and 90-day postoperative mortality.
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Adverse events (AE): Chemoradiation/chemotherapy-related adverse events are collected according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 5.0. All non-serious and serious AEs occurring in each patient will be reported up to 3 weeks after the last dose of chemotherapy or radiation therapy has been received.
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Quality of life (QOL) assessment and nutritional risk screening (NRS): The European Organization for Research and Treatment of Cancer (EORTC) questionnaires C30 and OES18 were used to assess QOL. The nutritional risk score is calculated according to the data collected on the NRS 2002 form. QOL and NRS were assessed at randomization, in the middle of neoadjuvant therapy, 1 week before surgery and 2 weeks, 1 month, 3 months, 6 months, 9 months, and 12 months after surgery.
Patient selection
Patients in the Affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital) with histologically proven resectable thoracic ESCC after preoperative staging will be considered for enrolment in the trial. All patients undergo pre-treatment staging according to the 8th UICC TNM system [10]. This included a history taking; physical examination; pulmonary-function tests; electrocardiogram (ECG); routine haematologic and biochemical tests; endoscopic ultrasonography with biopsies; upper gastrointestinal contrast; cardiac and cervical ultrasonography; computed tomography (CT) scans of the brain, thorax, and abdomen; and bone scintigraphy. Positron emission tomography (PET) with fluorodeoxyglucose is used when distant metastasis is suspected. All oesophageal cancer patients will be discussed by a multidisciplinary team (MDT) before any treatment. Written informed consent is obtained from all patients by the doctors in charge prior to participation in the trial.
Inclusion criteria
Eligible patients must meet all of the following criteria:
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Histologically proven squamous cell carcinoma.
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Tumours are located in the thoracic oesophagus.
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Age is between 18 years and 70 years.
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ECOG performance status of 0 or 1.
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Clinical stages cT2-T4aN + M0 and cT3-4aN0M0 based on the 8th UICC TNM system (10).
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No metastatic cervical lymph nodes.
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R0 resection is expected by the McKeown minimally invasive oesophagectomy (MIE), open right thoracotomy oesophagectomy or hybrid approaches after MDT discussion.
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No prior chemotherapy, radiotherapy or hormonal therapy was administered against any cancers.
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Adequate cardiac function: ejection fraction ≥50%.
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Adequate respiratory function: FEV1% ≥ 50% and DLCO ≥50%.
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Adequate bone marrow function: white blood cell count ≥4 × 109/L; absolute neutrophil count (ANC) ≥ 1.5 × 109/l; platelets ≥100 × 109/L; haemoglobin ≥9 g/dl.
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Adequate liver function: serum bilirubin ≤1.5 × upper limit of normal (ULN); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.0 × ULN (ULN as per institutional standard).
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Adequate renal function: glomerular filtration rate ≥ 60 ml/min calculated using the Cockcroft-Gault formula.
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Written consent is obtained.
Exclusion criteria
Patients meeting any of the following criteria are not eligible for this trial:
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Synchronous or metachronous (within 5 years) double cancers.
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Active infection requiring systemic therapy.
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Tumour width > 5 cm.
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Patients requiring systemic steroid medication.
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Patients with contraindications for oesophagectomy.
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Psychiatric disease.
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Patients in whom gastric tubes cannot be used for reconstruction after oesophagectomy.
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Pregnant or lactating women or women of childbearing potential.
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Hypersensitivity for paclitaxel, cisplatin or carboplatin drugs.
Randomization
A clinical research coordinator is responsible for randomization. Computerized randomization lists are created, and the results are placed in sealed opaque envelopes. After confirmation of the eligibility criteria, the patients are randomly allocated (1:1) to the nCT group or nCRT group. The intervention in this study is not blinded.
Treatment regimens (Fig. 2)
Arm A - neoadjuvant chemotherapy
Patients in arm A receive 2 cycles of chemotherapy prior to surgery. The detailed regimen runs are as follows: paclitaxel 175 mg per square metre of body-surface area on day 1 and cisplatin 75 mg per square metre of body-surface area on day 1 (cisplatin can be divided into 3 days). Chemotherapy was repeated every 3 weeks (Fig. 2). The doses of paclitaxel and cisplatin will be reduced to 75% of the planned dose if any grade 4 toxicity appears during chemotherapy.
Arm B - neoadjuvant chemoradiotherapy
Patients in arm B receive chemotherapy and concurrent radiotherapy prior to surgery. On days 1, 8, 15, 22, and 29, the patient will receive 5 cycles of chemotherapy, carboplatin (area under the curve (AUC) = 2 (calculated using the Calvert formula)) and paclitaxel at a dose of 50 mg per square metre of body-surface area are administered intravenously (Fig. 2). If the white blood cell (WBC) count is < 1.0 × 109/L and/or platelets are < 50 × 109/L, chemotherapy is delayed by 1 week until recovery to above these values. The doses of paclitaxel and carboplatin will be reduced to 75% of the planned dose if any grade 4 toxicity appears during chemoradiotherapy. Concurrent radiotherapy with 41.4 Gy is given in 23 fractions of 1.8 Gy each, with 5 fractions administered per week, starting on the first day of the first chemotherapy cycle. The gross tumour volume is defined as the volume of the primary tumour and the regional metastatic lymph nodes. The clinical target volume (CTV) includes the primary tumour with a 3-cm cranio-caudal margin, metastatic lymph nodes and regional lymph nodes. The planning target volume is defined as the CTV plus a 0.5–0.8 cm isotropic margin. All patients are treated by means of external-beam radiation using the 3-D conformal radiation technique.
Surgery
After neoadjuvant therapy, patients will receive the same examinations as pre-treatment. Endoscopy evaluation is not necessary after neoadjuvant therapy. In the nCT group, the operation will be performed between 3 and 8 weeks following completion of nCT, and in the nCRT group, the operation will be performed between 4 and 8 weeks following completion of nCRT (Fig. 2). MIE, open right thoracotomy oesophagectomy or hybrid approaches with a total 2-field lymphadenectomy will be performed. A gastric tube will be used to reconstruct the digestive tract after oesophagectomy. Oesophagectomy with a transhiatal or left thoracotomy approach is not acceptable because of the limited capacity for lymph node dissection, especially for the lymph nodes along the bilateral recurrent laryngeal nerve, with the two approaches. All postoperative complications will be recorded on the case report form for up to 90 days after surgery.
Follow-up
All randomized patients will be followed up for at least 5 years after patient accrual is completed. The first follow-up visit will occur 1 month after surgery. From then on, follow-up visits will occur at 3 months, 6 months, 9 months and 12 months for the first year; QOL and NRS will also be evaluated. In the second year, follow-up visits will occur every 3 months and every 6 months from the third year until the end of follow-up. The detailed examination items include a CT scan of the thorax and upper abdomen, and ultrasonography of the neck. PET/CT is used when distant metastasis is suspected. Recurrence of disease should be documented by appropriate imaging and biopsies where appropriate.
Translational research
The clinical trial includes tissue and blood sample collection for translational research. Trial participants will be asked to provide additional optional written consent for sample collection. The standard tissue sample consists of a pre-treatment biopsy tumour tissue and normal mucosa and a postoperative biopsy of tumour tissue and normal mucosa. Fasting blood samples are obtained at the time of the pre-treatment evaluations, in the middle of neoadjuvant therapy, pre-surgery, and 1 week after surgery. The blood samples are centrifuged at 1300×g for 10 min to remove cells and debris. All samples will be stored at the Henan Cancer Hospital Tissue Bank at − 80 °C for future translational research.
Statistical analysis
We assumed 5-year OS with preoperative chemotherapy to be 30% and expected a 12% increase in 5-year OS with preoperative chemoradiotherapy. We set a two-sided type I error of 5%, a power of 80% and a 5% drop out each year for an estimated 3 years of enrolment. A total of 456 patients (228 patients in each group) will be enrolled in this study according to the estimate calculated with PASS 11 statistical software (NCSS, LLC. Kaysville, Utah, USA).
An interim analysis is planned after recruitment of approximately 230 patients. Data will be analysed according to the intention-to-treat (ITT) principle with all randomized patients. A per-protocol analysis, excluding patients who did not sufficiently comply with the protocol, will supplement the ITT analysis as a secondary analysis. Comparisons between the groups will be made with the chi-square test and Fisher exact test for categorical parameters, while with Student’s t tests or Mann–Whitney U tests will be used for comparisons of continuous variables. Survival rates in the two treatment arms will be estimated by the Kaplan-Meier method. Then, the Cox proportional hazard model and the log rank test will be used to evaluate the independent survival factors. All tests will be two-sided. The significance level is set at 0.05.
Funding, registration, ethical considerations and current status
This study was funded by the Province-Ministry Co-construction Project of Health Committee of Henan Province (SB201901108). The study protocol (version 2.0) has also undergone peer-review by this government funding body. The protocol (version 2.0) was reviewed and approved by the Affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital) Ethics Committee (No. 2019082223) in September 30, 2019. The study will be conducted in accordance with ethical principles founded in the Declaration of Helsinki [11]. Data are collected using the individual trial case number on case report forms and personal information will not be individually identifiable. The Department of Clinical Trial Management of the Affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital) will be responsible for reviewing the trial data approximately every 6 months. The corresponding author (Dr. WQX) will be responsible for design and conduct of HCHTOG1903.The final trial dataset will be available to principle investigators.
This study was registered before the start of recruiting at ClinicalTrials.gov in October, 2019 (registration number: NCT 04138212). Our study began to recruit in October, 2019 and it is still at the stage of recruiting.