ESOPEC: prospective randomized controlled multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (NCT02509286)
Design
The ESOPEC trial is a two-arm randomized phase III study in which patients are randomized
to either perioperative chemotherapy according to the FLOT regimen (4 preoperative
and 4 postoperative cycles of FLOT) or to neoadjuvant chemoradiation according to
the CROSS regimen (41.1Gy plus carboplatin/paclitaxel) (Fig. 1). The primary objective of this phase III trial is to investigate whether perioperative
chemotherapy improves overall survival compared to neoadjuvant chemoradiation. To
achieve this objective, 438 patients will be recruited for the trial. Randomization
is performed in blocks concealed from the investigator in a ratio of 1:1 with N stage
(cN0/cN+) and recruitment site as stratification factors. Written informed consent
is obtained from all patients prior to participation in the trial. Patient recruitment
is taking place at 16 trial centers in Germany. All participating centers are highly
experienced in gastrointestinal oncology and esophageal surgery and are performing
at least 20 combined modality treatments of patients with localized esophageal adenocarcinoma
per year in their center.
Fig. 1. Trial diagram of the ESOPEC trial
Target population
Patients of both genders with histologically-proven adenocarcinoma of the esophagus
(according to Union internationale contre le cancer (UICC) TNM7) 15] are enrolled in this trial; eligible patients must have non-metastatic disease. Patients
are only allowed to enter the trial if they provide their written informed consent
and if the responsible investigator has verified that all selection criteria are met.
Inclusion criteria
Eligible patients must meet all of the following criteria:
1. Histologically-proven adenocarcinoma of the esophagus according to the Un UICC
TNM7 definition 15]. Tumors of the esophagus and tumors of which the epicenter is within 5 cm of the
esophagogastric junction and also extend into the esophagus are both eligible for
inclusion in the trial in the case of adenocarcinomatous histology. Translated to
Siewerts classification of esophagogastric adenocarcinoma (AEG), all Type AEG 1 are
eligible. Type AEG 2 and Type AEG 3 are eligible in case of esophageal infiltration.
2. Pre-treatment stage cT1N+ M0 or cT2-4a N0/N+, M0 (In case of stage cT4a, curative
resectability has to be explicitly verified by the local surgical investigator prior
to randomization).
3. Age???18 years
4. No prior abdominal or thoracic radiotherapy
5. Eastern Cooperative Oncology Group (ECOG) performance status 0–2
6. Adequate cardiac function. Patients with a cardiac history should have a cardiology
consultation and should have a left ventricular ejection fraction??50 % (determined
by echocardiography)
7. Adequate respiratory function (pulmonary function tests only necessary in symptomatic
patients)
8. Adequate bone marrow function (White Blood Cells 3×10^9/l; Hemoglobin??9 g/dl;
platelets 100×10^9/l)
9. Adequate renal function (Glomerular filtration rate 60 ml/min) and
10. Adequate liver function (Total bilirubin 1.5x Upper Level of Normal (ULN); Aspartate
transaminase (AST) 2.5x ULN and Alanine transaminase (ALT) 3x ULN
11. Written informed consent and ability to understand the nature of the study and
the study-related procedures and to comply with them
12. Women of child-bearing potential must have a negative serum pregnancy test during
screening period.
Exclusion criteria
Patients meeting any of the following criteria are not eligible for this trial:
1. Patients with tumors of squamous, adenosquamous or other non-adenocarcinoma histology
2. Patients with advanced inoperable or metastatic esophageal adenocarcinoma
3. Esophageal adenocarcinoma staged cT1N0 and cT4b
4. Esophageal adenocarcinoma cT4a evaluated as not curatively-resectable by the local
surgical investigator.
5. Gastric carcinoma (according to UICC TNM7 15])
6. Prior chemotherapy for gastrointestinal cancer
7. Clinically-significant (active) cardiac disease (e.g. symptomatic coronary artery
disease or myocardial infarction within last 12 months)
8. Clinically-significant lung disease (Forced expiratory volume in one second (FEV1)
1.5 l)
9. Peripheral neuropathy grade 1
10. Pregnant and lactating women, or patients of reproductive potential who are not
using effective birth control methods. If barrier contraceptives are used, they must
be continued by both sexes throughout the study.
11. Participation in another intervention trial with interference to the chemotherapeutic
or chemoradiotherapeutic intervention during this study or during the last 30 days
prior to informed consent.
12. Expected lack of compliance with the protocol
Study treatment
Perioperative chemotherapy (Arm A)
The perioperative chemotherapy arm consists of 4 cycles of chemotherapy prior to surgery
and a further 4 cycles of chemotherapy post-surgery. Each cycle of chemotherapy lasts
14 days (2 weeks). The drugs used in the FLOT regimen include 5-FU, leucovorine, oxaliplatin
and docetaxel. They are applied intravenously according to the following scheme: 5-FU
2600 mg/m
2
(24 h) day 1 and leucovorin 200 mg/m
2
(2 h), day 1 and oxaliplatin 85 mg/m
2
(2 h) day 1, and docetaxel 50 mg/m2 (1 h), every 2 weeks. Four neoadjuvant cycles
are given over 8 weeks prior to surgery and 4 adjuvant cycles are given over 8 weeks
post-surgery.
Neoadjuvant chemoradiation (Arm B)
The neoadjuvant chemoradiation arm consists of the CROSS regimen, which includes a
combination of chemotherapy and radiotherapy prior to surgery. The patient receives
5 weeks of radiation therapy and 5 concurrent weekly cycles of chemotherapy. Patients
are irradiated by external beam radiation, using 3D conformal radiation technique.
In detail, radiotherapy with concurrent intravenous chemotherapy is given according
to the following scheme: radiotherapy with 41.4Gy given in 23 fractions of 1.8Gy:
days 1–5, days 8–12, days 15–19, days 22–26 and days 29–31. Chemotherapy: paclitaxel
50 mg/m2 (1 h) day 1, 8, 15, 22, 29 and carboplatin (2 mg/ml/min AUC) (1 h) day 1,
8, 15, 22 and 29.
Surgery (both arms)
In both arms, surgery is carried out preferably 4 to 6 weeks after the end of neoadjuvant
treatment. Open, minimally-invasive or hybrid resection techniques are allowed in
the trial.
Esophageal resection
1. Esophageal adenocarcinoma with its epicenter located at the thoracic esophagus
and AEG type 1 tumors are treated by subtotal esophagectomy with transthoracic resection.
2. Esophageal adenocarcinoma with its epicenter located at the cardia (AEG Type 2)
are treated either by subtotal esophagectomy with transthoracic resection, transabdominal
distal esophageal resection plus gastrectomy or by esophagogastrectomy, depending
on both patient characteristics and local center expertise.
3. Esophageal adenocarcinoma with its epicenter located 2 cm aboral to the cardia
(AEG Type 3) which are substantially infiltrating the esophagus above the Z-line are
surgically treated by transabdominal distal esophageal resection plus gastrectomy.
Extent of lymphadenectomy
In case of subtotal esophagectomy and esophagogastrectomy, a mediastinal and abdominal
2-field lymphadenectomy is carried out. In case of transhiatal resection of the distal
esophagus plus gastrectomy, lower mediastinal and abdominal modified D2-lymphadenectomy
is performed.
Surgical reconstruction
After transthoracic esophagectomy, the continuity of the digestive tract is restored
by a gastric tube reconstruction or colonic interposition procedure with an intrathoracic
or cervical anastomosis. Reconstruction for transabdominal lower esophageal resection
plus gastrectomy is carried out by esophagojejunostomy.
Study objectives and endpoints
Primary endpoint
The primary endpoint is the overall survival time in the intent-to-treat population.
This will be calculated as time from start of study treatment to death due to any
cause. After randomization, patients will be followed up for a minimum duration of
36 months or until death. For patients alive at study closure, the survival time will
be censored at time of last known survival status.
Secondary endpoints
– Progression-free survival (PFS) time: defined in the intent-to-treat population
as the time interval from randomization to the first event of locoregional failure,
metastatic recurrence/progression or death. Progression is examined by computed tomography
(CT) and/or upper endoscopy.
– Recurrence-free survival (RFS) time: defined in resected patients who achieved
an R0 or R1 resection as the time interval from surgery to the date of first recurrence
(local, regional or distant) or death, whichever comes first. Recurrence is examined
by CT and/or upper endoscopy.
– Site of failure (recurrence):
Local failure: Patients are followed for local and regional failure irrespective
of metastatic recurrence. Local failure is defined as local anastomotic or esophageal
recurrence or progression, a tumor that cannot be resected or R2 resection at surgery.
Local recurrence is examined by esophago-gastro-duodenoscopy.
Regional failure: Regional failure is defined as regional mediastinal and or celiac
lymphatic recurrence or progression. Regional recurrence is examined by CT.
Distant failure: Distant failure is defined as the appearance of distant metastases.
Subclassification of distant recurrence includes hematogenous, distant lymphatic and
peritoneal/pleural recurrence. Distant recurrence is examined by CT.
Hematogenous recurrence comprises liver, lung, bone metastases and all other distant
organ metastases. Distant lymphatic recurrence comprises all lymphatic metastases
other than in the D1,D2 and mediastinal compartment.
– Postoperative pathologic stage:
Resectional status (R0/R1/R2)
Histo-pathological regression after neoadjuvant treatment according to Becker et
al. 16]
Postoperative pathology according to the UICC TNM7 system 15]
– Surgical site complications:
Frequency of anastomotic leakage. The diagnosis of anastomotic leakage is made considering
the following definition: Defect of the esophagogastric wall integrity at the anastomotic
site leading to a communication between the intra- and extraluminal compartments (detection
by radiographic imaging, endoscopy, on re-laparotomy or on re-thoracotomy).
Frequency of intrathoracic fluid collection or abscess requiring invasive treatment
Frequency of intraabdominal fluid collection or abscess requiring invasive treatment
Frequency of surgical site infection according to the Center of disease control (CDC)-definition
17]
– Non-surgical site complications:
Frequency of postoperative pneumonia with at least 3 of 4 of the following criteria:
Purulent tracheal secretion, temperature??37.5 °C, white blood count 12 000 or??4500
/ml, elevated C-reactive protein level AND radiological evidence of pulmonary infection
AND a positive sputum culture
Frequency of postoperative Acute Respiratory Distress Syndrome (ARDS), defined as
severe hypoxia (PaO2/ FiO2??200), diffuse bilateral pulmonary infiltration and pulmonary
wedge pressure less than 18 mmHg. Acute lung injury, defined as PaO2/FiO2 between
200 and 300, is considered as ARDS.
Frequency of postoperative major bronchial sputum with atelectasis, defined as bronchial
sputum with radiographic or bronchoscopically-proven atelectasis requiring bronchoscopy
and lack of fever or hyperleukocytosis
Frequency of postoperative respiratory failure, defined as the inability of a patient
to maintain a PaO2??60 mmHg or a PaCO2??55 mmHg, requiring oro-tracheal intubation
and assisted ventilation.
Frequency of postoperative deep venous thrombosis.
Frequency of postoperative lung embolism.
Frequency of postoperative myocardial infarction.
Frequency of postoperative stroke.
Postoperative hospital stay after surgery until discharge, in days.
Overall complications (Grade 2 and higher) according to the modified Clavien-Dindo
classification (MCDC)
– Postoperative mortality: 30-day postoperative mortality.
– Days of hospitalization: for neoadjuvant, surgical and adjuvant treatment, in days.
– Quality of Life: measured by European Organization of Research and Treatment of
Cancer (EORTC) QLQ-C30, OES18, CIPN20 questionnaire scores.
Data collection and follow-up
Pre-therapeutic work-up and screening assessment
Screening evaluations have to be performed within 21 days prior to randomization.
For this evaluation, inclusion and exclusion criteria are checked and validated. The
complete pre-therapeutic work-up includes a physical examination, medical history,
demography, vital signs, body weight, electrocardiogram, standard laboratory tests,
upper endoscopy with biopsies, endoscopic ultrasound and a CT scan of the thorax and
abdomen. In patients with a history or symptoms of cardiac and/or pulmonary disease,
additional cardiology review/echocardiography (ejection fraction 50 %) and/or pulmonary
function tests (FEV1??1.5 l) are mandatory. Clinical tumor staging (cTNM) is based
on the data obtained from endoscopic ultrasound and CT scan. When baseline assessments
are completed, check and validation of inclusion and exclusion criteria for the study
is performed. Detailed information on all screening evaluations is given in Additional
file 1: Table S1 and Additional file 2: Table S2.
Assessments during the treatment phase
Treatment visits are performed biweekly during perioperative chemotherapy (Arm A)
and weekly during neoadjuvant chemoradiation (Arm B) and contain measurements of patients’
vital signs, body weight, electrocardiogram and standard and hematologic laboratory
tests (Fig. 2). Preoperatively, within 1–3 weeks after end of neoadjuvant treatment, clinical re-staging
of the tumor is carried out by upper endoscopy and a CT scan of the thorax and abdomen.
On the day of discharge from hospital after surgery, standard laboratory tests, body
weight, histo-pathology report, treatment and postoperative data as well as quality
of life questionnaires are assessed.
Fig. 2. Treatment and visit week scheme of the ESOPEC trial
Assessments during the follow-up phase
The first follow-up visit is performed 6 months after start of treatment, even if
postoperative chemotherapy is still ongoing at that date. From then on, follow-up
visits are carried out every 3 months in the first year of follow-up and every 6 months
from the second year after treatment until the end of follow-up (min. 3 years) (Fig. 2). Evaluation for disease recurrence is performed by clinical visitation including
physical examination, body weight and CT scan of the thorax and abdomen.
For all patients, follow-up assessment is performed until the end of the trial or
death. The end the trial (end of trial follow-up) will be 3 years after the study
treatment of the last patient started.
Information on the sequence of enrolment, therapeutic interventions and outcome assessments
is given in Fig. 3. Detailed information on all assessments during the pre-therapeutic phase, treatment
phase and follow-up phase are given in Additional file 1: Table S1 and Additional file 2: Table S2.
Fig. 3. Schedule of enrolment, interventions and assessments of the ESOPEC trial
Statistical planning
The sample size of the ESOPEC trial has been planned to ensure sufficient power to
demonstrate an overall survival advantage of perioperative chemotherapy compared to
neoadjuvant chemoradiation. The sample size calculation is based on the primary endpoint
overall survival. It is assumed that the overall survival rate for esophageal adenocarcinoma
patients treated with neoadjuvant chemoradiation according to the CROSS regimen is
55 % at 3 years after randomization, as observed in a comparable setting 3]. For patients with perioperative (neoadjuvant and adjuvant) chemotherapy according
to the FLOT regimen, a conservative assumption of an overall survival rate of 68 %
is made. This assumption is based on survival rates of about 72 % reported for the
treatment based on FLOT (i.e. FLOT?+?surgery?+?FLOT) in a different patient population
8] as well as our own experience of 68 % 10] and 70 % 3-year overall survival (retrospective analysis; esophageal adenocarcinoma;
all patients treated with FLOT?+?surgery?+?FLOT; unpublished data). This corresponds
to a hazard ratio of 0.645 of treatment arm A compared to treatment arm B. The treatment
effect will be assessed by estimation of the hazard ratio with corresponding asymptotic
two-sided 95 % confidence interval. To test superiority of arm A (based on FLOT) over
arm B (based on CROSS) at one-sided significance level of 2.5 %, the null hypothesis
is rejected if the asymptotic two-sided 95 % confidence interval lies completely below
one. Under the above assumptions, the study is planned to detect superiority of arm
A over arm B with a power of 80 %, which requires a total number of 163 events (deaths)
to be observed. Yet, only 88-97 % of randomized patients are expected to be resectable
at the time of surgery due to deterioration of tumor staging or the patient’s overall
condition 3], 7]. To account for a possibly diminished observed hazard ratio, the sample size is calculated
to achieve a power of 90 %. Therefore, 218 events (deaths) have to be observed. The
required number of patients to be randomized to observe this number of events depends
on the length of follow-up. With a recruitment period of 3 years and an additional
follow-up period after the end of recruitment of 3 years, it can safely be assumed
that a sufficient number of events will have been observed by the end of the trial
if a total of 438 patients are available for analysis.
The effect of treatment with respect to the primary endpoint overall survival will
be estimated and tested by Cox regression. The regression model will include treatment
(Arm A: FLOT vs. ArmB: CROSS), N stage (N0, N+), age and trial center as independent
variables. As estimate of the effect size, the hazard ratio between the two treatment
arms will be given with the corresponding asymptotic two-sided 95 % confidence interval.
The two-sided test on the difference between the two treatment arms at two-sided significance
level 5 % will be based on the corresponding asymptotic two-sided 95 % confidence
interval from the Cox regression model. Overall survival rates in the two treatment
arms will be estimated by the Kaplan-Meier method.
Translational substudies
In the setting of the ESOPEC trial, correlative substudies are included addressing
the value of circulating tumor cells, circulating tumor DNA, circulating miRNA, adipokines,
inflammatory markers and possible proteomic determinants of malignancy as biomarkers
for prognosis and treatment outcomes. Therefore, patient blood samples are drawn and
analyzed pretherapeutically and during the course of treatment. Formalin-fixed paraffin-embedded
(FFPE) tumor specimens are centrally biobanked and analyzed. Tumor specimens include
material from pre-treatment biopsies and operative specimens. A tissue bank of esophageal
adenocarcinoma treated in well- standardized protocols with highly-controlled prospective
clinical follow-up data will be created. The biological substudies of the trial are
designed for validation of existing hypotheses and for discovery and generation of
new hypotheses addressing important questions in chemotherapeutic and radiotherapeutic
research of esophageal adenocarcinoma. Specifically, focus is on questions concerning
biological determinants of chemotherapeutic and radiotherapeutic response and resistance.
Comparison of pretherapeutic and intra- and posttherapeutic samples and specimens
by the methods mentioned above may disclose biological differences in the tumors which
could be used as criteria for choice of a specific therapeutic protocol in the future.