Patient Selection
To be eligible for this study, patient must fulfill all of the inclusion criteria (Table 2), and be excluded if matching any of the exclusion criteria (Table 3).
Patients would be asked to withdraw from the trial when they have (1) ≥ grade 4 allergic or severe adverse reactions, (2) progress in disease during treatment, (3) pregnancy; (4) shown reluctance of continuation, (4) any conditions for which investigators may prematurely terminate the trial.
Sample Size and Statistical analysis
A total sample size of 105 will be required for this phase 2 study. The Kaplan-Meier method and log-rank tests will be used to estimate the local control rate and OS. Cox regression will be used to estimate the hazard ratios. Data will be analyzed with SPSS version 19.0 (SPSS Inc., Chicago, IL, USA).
Treatment
The treatment schedule is outlined in Figure 1. Patients will receive S-1 combined with concurrent radiotherapy. S-1 is orally taken and begins on day 1, with the beginning of cycle 1 of radiotherapy.
According to the current clinical practice in China, radiotherapy is delivered with photons to a total dose of 61.2 Gy in 34 fractions, which is distributed in 5 days per week at 1.8 Gy/d[17]. In detail, S-1 will be orally taken half an hour after the breakfast and dinner, then radiotherapy will be delivered within 30-60 minutes after oral administration.
Radiotherapy
The intensity modulated radiation therapy (IMRT) based on a CT simulation planning system with 5 to 8-mm-thick scan slice throughout the cricoid cartilage and diaphragm (available in enlargement of scan range if necessary), which is delivered with photons at least 6 MV, is applied for this trial.
The gross tumor volume (GTV) is defined as all known involved field, consisting of visible esophageal tumor and metastatic lymph nodes based on the imaging of endoscopic ultrasound, esophageal radiography or CT scan (whichever is larger). The metastatic lymph nodes shall meet at least one of the following conditions: pathologic confirmation or short axis of ≥10 mm in the mediastinum or cervix, short axis of ≥5 mm at tracheoesophageal groove, or histologically proven metastatic via puncture.
The clinical target volume (CTV) includes the GTV as well as the superior-inferior regions 3cmbeyondthe primary tumor along the esophagus. The lateral, anterior and posterior borders of CTV are the same as GTV.
The planning target volume (PTV) is defined as a further 1 cm expansion added to the superior, inferior, anterior, posterior and lateral borders of CTV. The field next to the spinal cord can be slightly modified for less radiation exposure to the spinal cord.
Tissue inhomogeneity correction is adopted and suggests that 95% of the PTV receive ≥99% of the prescribed dose; 99% of the PTV receive ≥95% of the prescribed dose; <2 cm3 of the PTV receive ≥120% of the prescribed dose; <1 cm3 of the PTV receive ≥110% of the prescribed dose. The highest and lowest dose points inside the PTV need to be recorded.
Doses for critical organs delineated on all slices of the planning CT should be restricted to some degree. In the treatment plan, the spinal cord will be contoured on every CT slice and the margin of vertebra tube can be regarded as risk volume. The heart contours should begin at the level of the right atrium and right ventricle (pulmonary artery trunk, ascending main aorta and superior vena cava are excluded) and extend to the apex of the heart. The margin of both lungs can be contoured by automatic tools built in the system, but trachea and bronchia must be contoured manually and be excluded. The priority order of critical organ dose restrictions in details is as follows:
- Spinal cord: The max dose point must be less than 45 Gy, and cannot be exceeded for any reason.
- Lungs: The lung volume (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.
- Heart: The mean dose must be less than 40Gy.
Dose Modifications
By principle, all participants should receive the required dose as enough as possible during the trial. Though, in some conditions, modifications of treatment dose can be taken into consideration.
Chemotherapy Dose modifications and interruption
First of all, chemotherapy dose modifications are strictly limited to twice at most and chemotherapy delay 2 weeks at most, otherwise, chemotherapy will be terminated.
If any following situation is observed during the trial, chemotherapy modification should be based on the details in adherence to the minimum dose administration in co-occurrence of several toxicities.
Hematological toxicity
Chemotherapy should be stopped and delayed when participants suffer from either ANC <1.5×109 /L or PLT <80×109 /L. If necessary, the chemotherapy dose should be modified according to the lowest counts of blood cells in the previous cycle (Table 4).
Non-hematological toxicity
The patient will continue to get chemotherapy after recovery from ≥ grade 3 non-hematological toxicities (except neurotoxicity and nephrotoxicity) and satisfaction to ≤ grade 2 CTCAE. S-1 dose should be modified as follows: daily dose reduces from 100 mg to 80 mg or 80 mg to 60 mg when ≥ grade 3 non-hematological toxicities (except neurotoxicity and nephrotoxicity) occurred.
Radiotherapy Dose modifications and interruption
Logically, the normal organ dose constraints should not be exceeded. If the dose has to exceed the constraint value in order to achieve adequate coverage of PTV, some modifications are taken into consideration by investigators, or the patient has to be excluded from the trial. The acceptable violations are as follows: 92–95% of the PTV is able to receive ≥99% of the prescribed dose; the critical organ dose restrictions can exceed 5%–10%, except the spinal cord where dose should be strictly controlled under 45Gy.
If following toxicity is observed, radiotherapy has to be delayed until toxicity is no more than grade 2. Besides, it is allowed to suspend at most 2 weeks or radiotherapy will be terminated.
- WBC <2.0 ×109 /L or ANC <1.0 ×109 /L
- PLT <50 ×109 /L
- Grade 4 or higher non-hematological toxicity
Observed adverse events during the study are evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) V4.0[18]. When adverse reactions such as leukopenia, vomiting occur, symptomatic drugs can be given concomitantly to relieve discomfort. All concomitant medications should be recorded. No other drugs related to tumor treatment (including other chemotherapy drugs, thymosin et al.) can be used during the trial.
Assessment of the endpoints
The primary endpoint is 3-yr local control rate and the number and grade of participants with adverse events according to the CTCAE V4.0. It’s necessary to take esophagoscopy or fine-needle aspiration of superficial lymph node for pathological diagnosis to prove relapse. The local control time is from the start of treatment (day 1) to the date when the measurable new local recurrence, including the primary tumor and regional lymph node, is first observed. For patients who die of any other cause before the failure of local control are recorded, the local control time will be defined as the time from day 1 to death. Patients who do not experience local control failure or death in the end will use the time of the last tumor assessment as the endpoint. Death is the second endpoint in this study and can be quantified by OS, which refers to the time from day 1 to death for any reason. When a patient is lost to follow-up, OS is up to the last recorded time of the contact with the patient. For patients who are still alive at the time of the last collection, the last contact time is used as the survival time. All patients will be followed up every 3 months for first 2 years and every 6 months after 2 years until death, loss of follow-up, or study termination for survival analysis and subsequent treatment.