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JOURNAL ONKOLOGIE – STUDIE
ROBOT-2

RAMIE Versus MIE for Resectable Esophageal Cancer, a Randomized Controlled Trial (ROBOT-2 Trial).

Rekrutierend

NCT-Nummer:
NCT04306458

Studienbeginn:
Januar 2021

Letztes Update:
03.02.2021

Wirkstoff:
-

Indikation (Clinical Trials):
Esophageal Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
-

Sponsor:
University Medical Center Mainz

Collaborator:
-

Studienleiter

Peter Grimminger, MD,PhD
Principal Investigator
JGU Medizin Mainz, dept. AVTC

Kontakt

Pieter Christiaan van der Sluis, MD,PhD
Kontakt:
Phone: +31628880709
E-Mail: p.c.vandersluis-2@umcutrecht.nl
» Kontaktdaten anzeigen

Studienlocations
(1 von 1)

University Medical Center Mainz
55131 Mainz
(Rheinland-Pfalz)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Peter P Grimminger, MD
Phone: +496131177291
E-Mail: peter.grimminger@unimedizin-mainz.de

Evangelos Tagkalos, MD,MHBA
Phone: +496131177291
E-Mail: evangelos.tagkalos@unimedizin-mainz.de
» Ansprechpartner anzeigen

Studien-Informationen

Detailed Description:

Aim of the study This is a randomized controlled parallel-group, superiority trial comparing

RAMIE to MIE with intrathoracic anastomosis (Ivor-Lewis) in patients with resectable

esophageal adenocarcinoma or adenocarcinoma of the gastroesophageal junction in the Western

World.

Methods Objectives Patients with resectable esophageal adenocarcinoma or adenocarcinoma of

the gastroesophageal junction are randomized at the outpatient department to either (a)

robot-assisted minimally invasive esophagectomy (RAMIE) or (b) conventional minimally

invasive esophagectomy (MIE). The objective is to evaluate the extent of lymph node

dissection, efficacy, risks, survival and cost-effectiveness of RAMIE as an alternative to

MIE as treatment for esophageal adenocarcinoma or adenocarcinoma of the gastroesophageal

junction. We hypothesize that RAMIE leads to an improved lymph node dissection compared to

MIE.

Study design This is a multicenter investigator-initiated and investigator-driven randomized

controlled parallel-group, superiority trial comparing RAMIE to MIE. This study is conducted

in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice

Guidelines. The independent ethics committee of the University Medical Center of the Johannes

Gutenberg University, Mainz, Germany has approved the study. Written informed consent will be

obtained from all participating patients. All centers participating in the ROBOT-2 trial have

extensive experience in minimally invasive esophageal surgery and have an experience with at

least 50 MIE an 50 RAMIE procedures performed.

Clinical trial monitoring will be conducted by an independent data monitor from the Johannes

Gutenberg University, Mainz, Germany. A Data safety monitoring board (DSMB) will evaluate

safety for patients included within this trial. All outcomes will be evaluated by a (blinded)

external independent data committee board for the Upper GI International Robotic association

(UGIRA).

Study protocol Patients are informed about the trial by one of our surgeons at the outpatient

department. After receiving the information, all patients get one week time to consider their

consent. After obtaining informed consent, randomization, with concealment of allocation, is

done centrally by an online randomization program. There is no blinding for the patient,

surgeon and coordinating researcher because this is difficult in daily practice. However the

UGIRA committee and DSMB are blinded to the allocated intervention. This study is funded by

Intuitive surgical Inc., Sunnyvale, CA, USA. Neoadjuvant (radio)chemotherapy will be

administered according to current international policy. Multiple esophageal cancer biopsies

for pathological analysis will be obtained through esophagogastroscopy of which 4 biopsies

will be snap frozen and stored for translational research. All resection specimens will be

preserved and stored (biobank) for translational research. The study will start on April 1st

2020. Inclusion will take approximately 2 years. Follow up for each patient will be 5 years.

Total duration of the study will be 7 years.

Surgery All procedures (RAMIE or MIE) will be carried out by experienced surgeons with

experience of at least 50 MIE and 50 RAMIE procedures. All patients will receive an epidural

catheter to provide adequate postoperative analgesia. Patients will be intubated with a

left-sided double-lumen tube to enable selective desufflation of the right lung during the

thoracic phase in both procedures.

Antibiotic prophylaxis (Ampicillin 2000 mg and Sulbactam 1000mg) will be administered 30

minutes prior to incision. A thoracic drain will be positioned in the right hemithorax at the

end of the procedure. Extubating will take place in the operating theater directly

postoperatively and hereafter all patients will be admitted to the intensive care unit (ICU)

for hemodynamic and respiratory monitoring. Hemodynamical and respiratory stable patients

were discharged towards the surgical ward. All patients were placed on a nil-by-mouth routine

for the first 3 days postoperatively. In absence of clinical signs of anastomotic

insufficiency, patients started with sips of water and the oral intake was gradually

increased to solid food. There was no enhanced recovery program.

Surgical procedure: RAMIE The RAMIE technique using the 4 arm daVinci Xi system was described

previously (daVinci Xi system, Intuitive Surgical Inc., Sunnyvale, CA, USA).20 For the

abdominal phase, the patient is placed in supine position. Robotic trocars positions are

shown in figure 2a. The lesser omentum is opened and transected closely to the liver, until

the left crus of the diaphragm is reached. Hereafter, the greater gastric curvature is

dissected. An abdominal lymphadenectomy is performed including lymph nodes surrounding the

hepatoduodenal ligament, the celiac trunk, along the left gastric and splenic artery and the

lesser omental lymph nodes. The left gastric artery and vein are ligated with robotic

Hem-o-lok and transected at their origin. The gastric conduit is created at the level of the

crow's foot using a (robotic) endostapler .

For the thoracic phase, the patient is positioned in the left lateral decubitus position,

tilted 45° towards the prone position (semi-prone). Trocars positions are shown in figure 3a.

The robotic system is brought into the field at the dorsocranial side of the patient. After

incision and installation of the operation robot and selective desufflation of the right

lung, the pulmonary ligament is divided. Hereafter, the parietal pleura is dissected at the

anterior side of the esophagus from the diaphragm up to the azygos arch. The azygos vein is

ligated with robotic Hem-o-lok and divided. Dissection of the parietal pleura is continued

above the azygos arch to establish dissection of the right paratracheal lymph nodes. At the

posterior side of the esophagus, the parietal pleura is dissected cranially to caudally along

the azygos vein, including the thoracic duct. The thoracic duct is clipped with robotic

Hem-o-lok to prevent chylous leakage. The esophagus is resected en bloc with the surrounding

mediastinal lymph nodes. The gastric conduit is pulled up and the specimen is removed through

a small incision (mini-thoracotomy) at the location of the trocar in the 6th intercostal

space. Continuity is created with a circular stapled esophago-gastrostomy, which is routinely

oversewn with a V-Lock (Medtronic). An omental wrap around the anastomosis is created in all

patients.

Surgical procedure: MIE For the abdominal phase, the patient is placed in supine French

position. The lesser omentum is opened and transected closely to the liver, until the left

crus of the diaphragm is reached. Hereafter, the greater gastric curvature is dissected. An

abdominal lymphadenectomy is performed including lymph nodes surrounding the hepatoduodenal

ligament, the celiac trunk, along the left gastric and splenic artery and the lesser omental

lymph nodes. The left gastric artery and vein are ligated with clips and transected at their

origin. The gastric conduit is created at the level of the crow's foot using an endostapler

For the thoracic phase, the patient is positioned in the left lateral decubitus position,

tilted 45° towards the prone position (semi-prone). After selective desufflation of the right

lung, the pulmonary ligament is divided. Hereafter, the parietal pleura is dissected at the

anterior side of the esophagus from the diaphragm up to the azygos arch. The azygos vein is

ligated with an Endostapler or clips. Dissection of the parietal pleura is continued above

the azygos arch to establish dissection of the right paratracheal lymph nodes. At the

posterior side of the esophagus, the parietal pleura is dissected cranially to caudally along

the azygos vein, including the thoracic duct. The thoracic duct is clipped with a clips to

prevent chylous leakage. The esophagus is resected en bloc with the surrounding mediastinal

lymph nodes.

The gastric conduit is pulled up and the resection specimen is removed through a small

incision (mini-thoracotomy) at the location of the trocar in the 6th intercostal space.

Continuity is created using stapled esophago-gastrostomy, which is routinely oversewn with a

V-Lock (Medtronic). An omental wrap around the anastomosis is created in all patients.

Statistical analysis All prospective data will be statistically analyzed by the use of the

statistical software SPSS. All analyses were performed according to the intention-to-treat

(ITT) principle. Results are presented as risk ratios with corresponding 95% confidence

intervals (CI). To evaluate significance of differences between groups, the chi-squared test

was used as appropriate for categorical variables and the student's T-test and non-parametric

Mann-Whitney U-test for continuous variables.

Differences over time in quality of life and pain scores between and within treatment groups

were assessed using linear mixed-effects models adjusted for the baseline value. Overall and

progression-free survival curves were estimated with the Kaplan-Meier method and compared

with the log-rank test. All reported P-values were two-sided. Significance level was set at

0.05.

The cost-effectiveness analysis will compare the mean costs and effects for both strategies

and result in an incremental cost-effectiveness ratio. Uncertainty in the balance between

costs and effects will be assessed with bootstrapping. A time horizon of 5 years will be

applied, and costs and effects will be discounted according to Dutch guidelines.

If the baseline characteristics differ after randomization, i.e. there is a lack of balance

in the confounding factors; this will be corrected using the multivariate analysis or by

using a net benefit regression approach.

Interim-analysis There will be one interim-analysis. The stopping rule used for efficacy

(i.e. better outcome for minimally invasive for the primary endpoint) is the Peto-approach,

meaning a p-value <0.001. The trial will not be stopped for futility (i.e. no difference) and

there is no there is no formal stopping rule for harm.

After every 50 patients, individualized patient description charts including safety

parameters will be presented to the UGIRA Data Safety Monitoring Board (DSMB). The DSMB will

discuss these in a plenary, telephone or online conference with the study coordinator and

principal investigator present. The trial research group will discuss in a plenary session

together with the DSMB the potential harm per patient and determine whether a relationship

can be drawn between the surgical procedure and the adverse events. Consensus will be reached

and the Institutional ethical board will be informed.

Ein-/Ausschlusskriterien

Inclusion Criteria:

- Histologically proven adenocarcinoma of the intrathoracic esophagus and

gastroesophageal junction (including Siewert I and II)

- Surgically resectable (T1-4a, N0-3, M0)

- Age ≥ 18 and ≤ 90 years

- European Clinical Oncology Group (ECOG) performance status 0,1 or 2

- Written informed consent

Exclusion Criteria:

- Esophageal squamous cell carcinoma

- Carcinoma of the cervical esophagus

- Carcinoma of the gastro-esophageal junction (GEJ) with the main part of the tumor in

the gastric cardia (Siewert type III)

- Prior thoracic surgery at the right hemithorax or thoracic trauma

Studien-Rationale

Primary outcome:

1. Total number of dissected lymph nodes (Time Frame - Up to 2 weeks postoperatively):
Total number of dissected lymph nodes in the resection specimen according to the TIGER classification



Secondary outcome:

1. Postoperative complications (Time Frame - Operation date till date of discharge until 52 weeks postoperatively):
Postoperative complications and specific complications

2. Length of intensive care unit (ICU) and hospital stay (Time Frame - Operation date till date of discharge until 52 weeks postoperatively):
Days in the ICU and hospital

3. In hospital mortality (IHM) (Time Frame - Hospital admission period up to 90 days postoperatively):
30, 60 and 90 day mortality

4. Pathology results (Time Frame - Up to 2 weeks postoperatively):
Radical resection (R0 and R1)

5. Survival (Time Frame - 5 years postoperatively):
Overall and disease free survival (2,3 and 5 year)

6. Operation statistics (Time Frame - day of operation):
Operating time (thoracic, abdominal and total), blood loss, intraoperative complications

7. Postoperative pain (Time Frame - Before operation (baseline), daily during admission in the first 14 days, postoperatively: 6 weeks, 6 months and yearly post-operatively up to 5 years):
Postoperative pain scores on a visual analogue scale (VAS)

8. Cost analysis (Time Frame - date of operation until 1 year postoperatively):
Cost analysis

9. Surgeons fatigue (Time Frame - Day of operation):
Surgeons fatigue directly after Operation assessed by Psychomotor Vigilance tests (PVT) before and after esophagectomy

10. Quality of life after esophagectomy (Time Frame - Before operation (baseline), at discharge, postoperatively: 6 weeks, 6 months and yearly up to 5 years post-operatively):
Quality of life assessed by questionnaire European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30

11. Postoperative Recovery (Time Frame - 14 days postoperatively):
Dutch discharge criteria (removal of thoracic tubes, no requirement of intravenous fluid resuscitation, tolerance for solid oral intake, the ability to mobilize independently and adequate pain control with oral analgesics)

12. Quality of life after esophagectomy (Time Frame - Before operation (baseline), at discharge, postoperatively: 6 weeks, 6 months and yearly up to 5 years post-operatively):
Quality of life assessed by questionnaire European Organisation for Research and Treatment of Cancer (EORTC OES18)

13. Quality of life after esophagectomy (Time Frame - Before operation (baseline), at discharge, postoperatively: 6 weeks, 6 months and yearly up to 5 years post-operatively):
Quality of life assessed by questionnaire Short Form (SF)-36

14. Quality of life after esophagectomy (Time Frame - Before operation (baseline), at discharge, postoperatively: 6 weeks, 6 months and yearly up to 5 years post-operatively):
Quality of life assessed by questionnaire EuroQol (EQ)-5D

Studien-Arme

  • Experimental: Robot assisted minimally invasive esophagectomy
    Robot assisted minimally invasive esophagectomy
  • Active Comparator: Minimally invasive esophagectomy
    Conventional minimally invasive esophagectomy

Geprüfte Regime

  • Minimally invasive esophagectomy:
    Conventional minimally invasive esophagectomy
  • daVinci Xi system:
    robot assisted minimally invasive esophagectomy

Quelle: ClinicalTrials.gov


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