Design
The ESO-Shanghai 12 trial is a prospective, multicenter, randomized phase 3 study, in which patients are randomized to receive radiation at a dose of 61.2 Gy or 50.4 Gy based on the 18F-FDG PET/CT response (stratified by SUVmax > 4 and SUVmax ≤ 4). Both arms will undergo concurrent chemoradiotherapy with a paclitaxel/cisplatin (TP) regimen for two cycles followed by consolidation chemotherapy for two cycles (Fig. 1).
Objectives
Primary endpoints
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1.
Overall survival in PET/CT non-responders (time frame: 2 years)
The time between the start of the study treatment (day 1) and death from any cause or the last follow-up (for patients who are alive at the end of the study) in patients who have an SUVmax > 4 on PET/CT at 28 radiotherapy fractions.
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2.
Overall survival in the intention-to-treat (ITT) population (time frame: 2 years)
The time between the start of the study treatment (day 1) and death from any cause or the last follow-up (for patients who are alive at the end of the study) in the ITT population.
Secondary endpoints
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1.
Local control in PET/CT non-responders, the ITT population, and PET/CT responders (time frame: 2 years)
The time between the start of the study treatment (day 1) and local recurrence (including primary tumor recurrence and regional lymph node failure).
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2.
Progression-free survival in PET/CT non-responders, the ITT population, and PET/CT responders (time frame: 2 years)
The time between day 1 and the first event of local failure, metastatic recurrence, progression, or death.
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3.
Overall survival in PET/CT responders (time frame: 2 years)
Overall survival in patients who have an SUVmax ≤ 4 on PET/CT at 28 radiotherapy fractions.
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4.
Questionnaire: European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ)-C30 (time frame: 2 years)
A quality-of-life score will be obtained based on the answers to the questionnaire.
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5.
Questionnaire: EORTC-QLQ-OES18 (time frame: 2 years)
A quality-of-life score will be obtained according to the answers to the questionnaire.
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6.
Exploration of predictive and prognostic biomarkers.
Patient selection
Inclusion criteria
To be eligible for inclusion in this study, patients must fulfill all the following criteria:
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1.
Participating in the study voluntarily and able to sign the informed consent form.
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2.
Aged between 18 and 75 years, and of either sex.
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3.
Pathologically confirmed with ESCC [T1N1-3M0, T2-4NxM0, TxNxM1 (supraclavicular lymph node metastasis only), (American Joint Committee on Cancer Staging Manual, 8th Edition)].
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4.
No receipt of radiotherapy, chemotherapy, or other treatments prior to enrollment.
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5.
Using an effective contraceptive to prevent pregnancy.
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6.
No severely abnormal hematopoietic, cardiac, pulmonary, renal, or hepatic function, or immunodeficiency.
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7.
White blood cells (WBC) ≥ 3.5*109/L, hemoglobin ≥ 9 g/dL, neutrophils ≥ 1·5*109/L, platelet count ≥ 100*109/L, alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) < 2·5 * upper limit of normal (ULN), total bilirubin (TBIL) < 1·5 * ULN, and creatinine < 1·5 *ULN.
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8.
An Eastern Cooperative Oncology Group (ECOG) score of 0–2.
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9.
Life expectancy of more than 3 months.
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10.
Agrees to undergo 18F-FDG PET/CT assessment at 28 radiotherapy fractions.
Exclusion criteria
The following patients will be ineligible for this study.
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1.
Patients whose total radiotherapy dose reaches 61.2 Gy/34 Fx if the normal tissue dose complies with the standard criteria.
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2.
Patients with esophageal perforation or hematemesis.
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3.
Patients with a history of radiotherapy or chemotherapy for EC.
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4.
Patients with a history of surgery within 28 days before Day 1.
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5.
Patients with a history of prior malignancies (other than skin basal cell carcinoma or cervical carcinoma in situ with disease-free survival of at least 3 years).
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6.
Patients who are participating in another interventional clinical trial less than 30 days.
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7.
Pregnant or breastfeeding women or fertile patients who refuse to use contraceptives.
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8.
Patients with drug addiction, alcoholism, or acquired immunodeficiency (AIDS).
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9.
Patients experiencing uncontrolled seizures or psychiatric disorders.
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10.
Patients with any other condition which, in the investigator's opinion, would make them an unsuitable candidate for the clinical trial.
Study treatment
The treatment plan is shown in Fig. 1. Patients will receive radiotherapy combined with concurrent chemotherapy. Radiotherapy will begin on day 1, concurrent with the beginning of cycle 1 of chemotherapy. Radiotherapy will be delivered with photons (≥ 6 MV) to a total dose of 50.4 Gy in 28 fractions or 61.2 Gy in 34 fractions. 18F-FDG PET/CT will be performed for all patients at baseline and at 28 radiotherapy fractions (± 3 days), and then patients will be randomized after assessment. Patients will be stratified according to the SUVmax (≤ 4 or > 4), GTV (≤ 40 cm2 or > 40 cm2) and tumor location [cervical/upper thoracic location with heart dose ≤ 10 Gy or (middle/lower thoracic location or heart dose > 10 Gy)] (Fig. 2).
18F-FDG PET/CT assessment
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1.
Pre-PET/CT patient preparation
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Patients will not undergo a barium meal examination at least 1 week before the PET/CT scan.
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Prior to injection, the patient must fast for at least 6 h.
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Blood glucose measurement will be performed before the injection of 18F-FDG, and blood glucose levels should be less than 140 mg/dL.
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The height and weight of patients will be measured using calibrated and medically approved devices.
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2.
Injection of 18F-FDG
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Patients will receive an 18F-FDG dose of 3.7 MBq/Kg of body weight in accordance with the manufacturer’s recommendations. Patients will be kept in a quiet and dimly lit room before and after the injection.
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A saline flush of 1 mL will follow the 18F-FDG injection.
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The exact time of dose calibration will be recorded using a global time recording device, which will be consistently used throughout the study for time recording. The exact time of injection will be noted and recorded to permit the correction of the administered dose for radioactive decay. Furthermore, any of the dose remaining in the tube or syringe, or any 18F-FDG that is spilled during the injection will be recorded. The 18F-FDG injection will be performed using an intravenous catheter and three-way stopcock.
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3.
PET/CT imaging
All PET exams will include three trans-axial, whole-body series, attenuated and non-attenuated, corrected PET and CT images.
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The scan will be conducted 60 ± 10 min after the injection of 18F-FDG.
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The patient will be instructed to empty their bladder immediately before the image acquisition.
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A spiral CT scan using the low-dose technique (120 kV, 140 mA, 5-mm slice thickness) will be conducted first, followed by a PET emission scan from the distal femur to the top of the skull.
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A PET emission scan covering the same transverse field of view will be obtained immediately after the CT scan. The PET data will be reconstructed using a Gaussian filter iterative (iterations 4; subsets 8; image size 168) for the reconstruction of emission images. The CT data will be used for attenuation correction of the PET images, and fused images will be displayed on a workstation.
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4.
Reporting of PET findings and SUV calculations
SUVs are commonly used in clinical practice in addition to visual assessments. The SUV is a measurement of the uptake in a tumor normalized on the basis of a distribution volume. It is calculated as follows:
$${\text{SUV}} = \frac{{{\text{Act}}_{{{\text{voi}}}} \left( {\text{kBq/ml}} \right)}}{{{\text{Act}}_{{{\text{administered}}}} {{\left( {{\text{MBq}}} \right)} \mathord{\left/ {\vphantom {{\left( {{\text{MBq}}} \right)} {{\text{BW}}\left( {{\text{kg}}} \right)}}} \right. \kern-\nulldelimiterspace} {{\text{BW}}\left( {{\text{kg}}} \right)}}}}$$
In this calculation, Actvoi is the activity measured in the volume of interest (see “Definitions for volumes of interest (VOI) and regions of interest (ROI)”), Actadministered is the administered activity corrected for the physical decay of 18F-FDG at the start of acquisition, and BW is body weight. The patient’s height, weight, and sex will be reported to allow for other SUV normalizations (lean body mass, body surface area).
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PET/CT images will be analyzed independently by two senior nuclear medicine physicians using a multimodality computer platform (Syngo, Siemens, Knoxville, TN, USA). For any inconsistent or equivocal interpretations, another experienced radiologist will be invited to the discussion to reach a consensus.
Radiotherapy
IMRT will be required. The radiation plan for all patients will involve 61.2 Gy/ 34 Fx, at 1.8 Gy/ day for 5 days per week. The standardized-dose group will receive a radiation dose of 50.4 Gy/28 Fx, while the high-dose group will receive 61.2 Gy of radiation. The patients will be immobilized in the supine position and receive a contrast-enhanced planning CT scan 0.5 cm under the cricothyroid membrane (for thoracic tumors) or basis cranii (for cervical tumors) below the kidney. IMRT will be delivered to all patients using 6 MV photons. The radiation target volume will be delineated by the field involved.
GTV
The GTV will be defined as any visible primary tumor and metastatic lymph nodes. The primary tumor will be delineated using esophagography, esophagoscopy, contrast-enhanced thoracic CT, and 18F-FDG PET/CT). Metastatic lymph nodes will be identified using biopsy, increased uptake of FDG on PET/CT, or based on the following radiographic criteria: nodes of ≥ 1 cm in the shortest axis in the intrathoracic and intra-abdominal region or nodes of ≥ 0.5 cm in the shortest axis along the recurrent nerve.
CTV
The CTV will be defined as the GTV plus 3 cm of the proximal and distal normal esophagus without lateral margins.
PTV
The PTV will be generated by applying a 1-cm margin to the CTV.
Tissue inhomogeneity correction will be adopted for planning purposes. The criteria for dose distribution will be as follows: 95% of the PTV to receive ≥ 99% of the prescribed dose; 99% of the PTV to receive ≥ 95% of the prescribed dose; < 2 cm3 of the PTV to receive ≥ 120% of the prescribed dose; and < 1 cm3 of the PTV to receive ≥ 110% of the prescribed dose. The highest and lowest dose points inside the PTV will be recorded.
Normal organ contouring and dose restrictions
Normal organs, including the spinal cord, heart, and right and left lungs, will be contoured on each slice of the planning CT with no planning margin. The spinal cord dose constraint must not be exceeded for any reason. The heart contours will extend from the beginning of the right atrium and right ventricle (the pulmonary artery trunk, ascending main aorta, and superior vena cava will be excluded) down to the apex of the heart. The lung volume will be defined as the total lung minus the PTV.
The priority order of consideration for normal organ dose restrictions will be as follows:
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1.
Spinal cord: the highest dose point must be of less than 45 Gy.
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2.
Lung: the volume of the lung (PTV excluded) receiving 20 Gy must be equal to or less than 30% of the total lung volume, and the mean lung dose must be equal to or less than 15 Gy at the same time.
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3.
Heart: the mean dose must be less than 40 Gy.
Dose modifications
It is strongly recommended that the normal organ dose constraints are not exceeded. If any dose constraint needs to be exceeded to achieve adequate coverage of the PTV, the physician will decide whether the dose should be modified, or whether the patient should be excluded from the trial. The acceptable violations of dose modification will be as follows: 92–95% of the PTV to receive ≥ 99% of the prescribed dose and normal organ dose restrictions (except the spinal cord) exceeding 5–10%.
Radiotherapy interruption
If the any of the following toxicities are observed, radiotherapy will be delayed until the toxicity improves to grade 2 or lower.
If the following toxicity is observed, radiotherapy will be delayed until complete recovery.
The suspension of radiotherapy will be permitted for 2 weeks at most; if the patient does not recover within 2 weeks, radiotherapy will be terminated.
Radiotherapy quality assurance
The IMRT planning CT of the first three patients from each participating institution will be sent to Fudan University Shanghai Cancer Center for central quality assurance to ensure that the center complies with the specific study requirements for delineation, planning, and dose distribution.
Chemotherapy
Patients in both groups will receive two cycles of concurrent chemotherapy with radiotherapy followed by two cycles of consolidation chemotherapy after CRT. Each cycle of chemotherapy will last for 28 days (4 weeks). The drugs to be used include: paclitaxel 135 mg/m2/day, intravenously guttae (IVGTT) over 3 h, day 1; and cisplatin 25 mg/m2/day, IVGTT, days 1–3.
Chemotherapy interruption and dose modification
If the following toxicities are observed on day 1, chemotherapy will be delayed until toxicity improves to grade 1 or lower.
A delay to chemotherapy of 2 weeks at most will be allowed; if the patient does not show sufficient improvement within this time, chemotherapy will be terminated.
Chemotherapy dose modifications will be based on the greatest toxicity during the last cycle. Any patients for whom chemotherapy dose modifications are required will receive the modified dose during subsequent cycles. If modifications are needed, the doses of paclitaxel and cisplatin will be decreased by 25% from the planned dose for the first cycle and by 50% for the second cycle. Dose modifications will be permitted twice at most; for patients who still require dose modification after this point, chemotherapy will be terminated.
The criteria for dose modification are as follows:
Dose modification of paclitaxel
Dose modification of cisplatin
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Febrile neutropenia (ANC < 0.5 × 109/L and fever over 38.3° C or over 38.0° C for 1 h).
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Peripheral neuropathy of grade 2 or higher.
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Serum creatinine > 3 times the upper limit of normal.
Adverse events will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE V.4.0). All adverse events that occur during the course of the trial (from the start of treatment until 28 days after the end of treatment), regardless of their relatedness to the study medication, will be recorded. Adverse events that occur more than 28 days after the end of treatment will only be recorded if they are relevant.
Quality of life
Quality of life (QOL) is measured as secondary endpoints in this trial and will be assessed using hard-copy versions of the EORTC core questionnaire, the EORTC QLQ-C30 (version 3.0) [30], the disease-specific module for EC, and the QLQ-OES18 [31]. The following assessment points have been chosen to describe QOL changes across time: before the start of treatment (baseline), at the end of radiotherapy (28 or 34 fractions), before two consolidative chemotherapy cycles, and at each follow-up. The EORTC-QLQ-C30 and EORTC-QLQ-OES18 questionnaires will be completed by patients and checked by physicians at clinic visits to minimize the number of missing items and assessments. Time windows of ± 3 weeks will be applied for follow-up assessment.
Adverse events
Adverse events will be accessed according to National Cancer Institute Common terminology for adverse events (NCI-CTCAE) (version 4.0) [32] and will be monitored throughout the study.
Translational research
The clinical trial will involve the collection of tissue samples and blood samples for future translational research and the development and/or validation of biomarkers. Trial participants will be asked for additional optional consent to participate in this aspect of the study. The standard tissue sample will consist of pretreatment biopsy of tumor tissue. The blood samples will include 2 × 5 ml ethylenediamine tetraacetic acid (EDTA) blood samples, one of which will be collected at the time of pretreatment, postconcurrent and preconsolidation chemotherapy, and the other after recurrence. All samples will be stored at the FUSCC BioBank for future translational research.
Statistical analysis
For patients with residual tumors of esophagus, it is estimated that the 2-year survival rate of low-dose radiotherapy group and high-dose radiotherapy group is 11% and 27%, according to literature [33, 34]. The expected enrollment time is 7 years, and the last enrolled patients were followed up for 2 years. According to the ratio of 1:1, bilateral α = 0.05, power = 0.80. When 5% of the patients are expected to fall off, 66 cases in each group and 132 cases in total were included in the PET/CT non-responder group. For non-selected population, the 2-year survival rate is estimated to be 40% of the standard-dose radiotherapy group and 49% of the high-dose radiotherapy group, based on literature data [6, 35]. According to the same enrollment and follow-up time conditions, 323 cases are included in each group, and the total number of samples is determined to be 646. The double end-point fixed sequence method was used to test the PET/CT non-responder group first, and then the overall intention-to-treat population. When the number of PET/CT non-responder reached 132 and the total population reached 646, the enrollment could be ended. Fixed sequence is applied in statistics of primary endpoint.