Background
Objective
Methods
Study design
Study population
Study algorithm (Table 1, Fig. 1, Fig. 3)
Pretreatment | CRE-I (4–6 weeks after nCRT) | CRE-II (10–14 weeks after nCRT) | Standard surgery arm (6, 9, 12, 16, 20, 24, 30, 36, 48 and 60 months after nCRT) | Active surveillance arm (6, 9, 12, 16, 20, 24, 30, 36, 48 and 60 months after nCRT) | |
---|---|---|---|---|---|
Informed consent | X | ||||
Inclusion | X | ||||
Treatment allocationh | X | ||||
ECOG performance status | X | X | X | X | X |
Endoscopy with bite-on-bite biopsies | X | X | X | X | |
Radial EUS | X | X | X | ||
Linear EUS with FNA of suspected lymph nodes | X | X | X | ||
18F–FDG PET-CT (whole-body) | X | Xa | Xb | Xc | Xb |
Quality of Life (EQ-5D, QLQ-C30, QLC-OG25 en Cancer Worry Scale) | X | X | Xd | Xd | |
Oesophagectomy | Xe | Xf | All | At indicationg |
CREs
Active surveillance
Surgery
Pathology
Centralised multidisciplinary tumour board
Follow-up
Study parameters/endpoints
-
The percentage of patients in the active surveillance arm who do not undergo surgery (i.e. patients who are cured by nCRT or who have occult distant metastases during initial staging, which become manifest during active surveillance);
-
Clinical irresectability (cT4b) rate; R0-resection rate defined as percentage of patients within the entire randomised population who undergo resection, defined as a tumour-free resection margin;
-
Postoperative morbidity/complications for all randomised patients with cCR who undergo resection, as defined by the Esophageal Complications Consensus Group [23];
-
Postoperative mortality for all patients with cCR who undergo resection, defined as 90 day- and/or in-hospital mortality;
-
Progression-free survival, defined as the interval between randomisation and the earliest occurrence of disease progression resulting in primary (or peroperative) irresectability of disease, locoregional regrowth (after completion of therapy);
-
Distant dissemination rate;
-
Cost-effectiveness.
Safety and stopping rules
-
Proportion of all patients in the active surveillance arm that present with an irresectable or incurable (T4b or R2) regrowth, in the absence of distant metastases;
-
Proportion of all patients in the active surveillance arm that undergo a microscopically non-radical (R1) resection;
-
Postoperative morbidity; postoperative in-hospital mortality in all patients in the active surveillance arm, proportion of all patients in the active surveillance arm with hospital stay > 60 days or who develop postoperative trachea-neo-oesophageal fistula;
-
Proportion of all patients in the active surveillance arm that develop distant dissemination after 1 and 2 years of follow-up.
Statistical analysis
Sample size calculation
Data analysis
Ethical and regulatory considerations
Discussion
Acknowledgements
Coordinating Investigator | ||
Drs. B.J. Noordman | Surgery | Erasmus MC |
Project Leader | ||
Prof. dr. J.J.B. van Lanschot | Surgery | Erasmus MC |
Principal Investigators | ||
Dr. S.M. Lagarde | Surgery | Erasmus MC |
Dr. B.P.L. Wijnhoven | Surgery | Erasmus MC |
Erasmus MC, Rotterdam | ||
Dr. K. Biermann | Pathology | Erasmus MC |
Dr. A. van der Gaast | Medical Oncology | Erasmus MC |
Dr. E. Ista | Implementation Fellow | Erasmus MC |
Dr. N.C. Krak | Radiology | Erasmus MC |
Dr. J.J.M.E. Nuyttens | Radiotherapy | Erasmus MC |
Dr. S. Polinder | Health Economics | Erasmus MC |
Dr. M.C.W. Spaander | Gastroenterology | Erasmus MC |
Prof. dr. E.W. Steyerberg | Public Health | Erasmus MC |
Dr. R. Valkema | Nuclear Medicine | Erasmus MC |
Almelo | ||
Dr. A. Agool | Nuclear Medicine | Zorggroep Twente |
Drs. J. van Baarlen | Pathology | Lab PON |
Drs. E.M. Hendriksen | Radiotherapy | Medisch Spectrum Twente |
Dr. R. Hoekstra | Medical Oncology Zorggroep Twente | |
Dr. E.A. Kouwenhoven | Surgery | Zorggroep Twente |
Drs. A. van der Linde | Gastroenterology | Zorggroep Twente |
Amsterdam | ||
Dr. A. Bartels-Rutten | Radiology | AVL-NKI |
Dr. J. van Dieren | Medical Oncology/Gastroenterology | AVL-NKI |
Dr. J. van Sandick | Surgery | AVL-NKI |
Dr. P. Snaebjornsson | Pathology | AVL-NKI |
Dr. E. Vegt | Nuclear Medicine | AVL-NKI |
Drs. F.E.M. Voncken | Radiotherapy | AVL-NKI |
Apeldoorn | ||
Dr. H. Doornewaard | Pathology | Gelre Ziekenhuis |
Drs. G.W. Erkelens | Gastroenterology | Gelre Ziekenhuis |
Dr. G.S. Madretsma | Medical Oncology Gelre Ziekenhuis | |
Dr. E.S van der Zaag | Surgery | Gelre Ziekenhuis |
To be determined | Nuclear Medicine | |
To be determined | Radiotherapy | |
Delft | ||
Drs. M.R.J. ten Broek | Nuclear Medicine | Reinier de Graaf Group |
Drs. R.J. Dallinga | Radiology | Reinier de Graaf Group |
Dr. J.W.T. Dekker | Surgery | Reinier de Graaf Group |
Dr. V.O. Dezentjé | Medical Oncology Reinier de Graaf Group | |
Dr. R.R. de Krijger | Pathology | Reinier de Graaf Group |
Dr. K.J. Neelis | Radiotherapy | Reinier de Graaf Group |
Drs. R. Quispel | Gastroenterology | Reinier de Graaf Group |
Eindhoven | ||
Dr. G.J. Creemers | Medical Oncology | Catharina Cancer Center, Eindhoven |
Dr. G.A.P. Nieuwenhuijzen | Surgery | Catharina Cancer Center, Eindhoven |
Dr. M.C. van der Sangen | Radiotherapy | Catharina Cancer Center, Eindhoven |
Dr. E.J. Schoon | Gastroenterology | Catharina Cancer Center, Eindhoven |
Dr. D.N.J. Wyndaele | Nuclear Medicine | Catharina Cancer Center, Eindhoven |
Heerlen | ||
Dr. J. Buijsen | Radiotherapy | Maastro Clinic |
Dr. R.G. Riedl | Pathology | Zuyderland MC |
Drs. W.M.J. Schreurs | Nuclear Medicine | Zuyderland MC |
Dr. M.N. Sosef | Surgery | Zuyderland MC |
Dr. L.E. Oostenbrug | Gastroenterology | Zuyderland MC |
Drs. F.A.R.M. Warmerdam | Medical Oncology | Zuyderland MC |
Leiden | ||
Dr. J.J. Boonstra | Gastroenterology | LUMC |
Dr. M. Slingerland | Medical Oncology | LUMC |
Dr. W.O. de Steur | Surgery | LUMC |
Dr. I.M. Lips | Radiotherapy | LUMC |
To be determined | Nuclear Medicine | |
To be determined | Radiology | |
To be determined | Pathology | |
Leeuwarden | ||
Dr. H. Balink | Nuclear Medicine | Medisch Centrum Leeuwarden |
Dr. W.E. Fiets | Medical Oncology | Medisch Centrum Leeuwarden |
Dr. K. van der Linde | Gastroenterology | Medisch Centrum Leeuwarden |
Dr. J. Nieken | Pathology | Medisch Centrum Leeuwarden |
Drs. V. Oppedijk | Radiotherapy | Radiotherapeutisch Instituut Friesland |
Prof. dr. J.P.E.N. Pierie | Surgery | Medisch Centrum Leeuwarden |
Drs. R. Wolf | Radiology | Medisch Centrum Leeuwarden |
Maasstad Ziekenhuis, Rotterdam | ||
Dr. P.P.L.O. Coene | Surgery | Maasstad Ziekenhuis |
Dr. I. Al Butaihi | Nuclear Medicine | Maasstad Ziekenhuis |
Dr. M. Kliffen | Pathology | Maasstad Ziekenhuis |
Dr. E.M.M. Kuiper | Gastroenterology | Maasstad Ziekenhuis |
Dr. E.F. Courrech Staal | Radiology | Maasstad Ziekenhuis |
Nijmegen | ||
Dr. M.J.R. Janssen | Nuclear Medicine | Radboudumc |
Drs. M.H. Liedenbaum | Radiology | Radboudumc |
Drs. C. van der Post | Pathology | Radboudumc |
Dr. S.A. Radema | Medical Oncology | Radboudumc |
Prof. dr. C. Rosman | Surgery | Radboudumc |
Drs. H. Rütten | Radiotherapy | Radboudumc |
Prof. dr. P.D. Siersema | Gastroenterology | Radboudumc |
Tilburg | ||
Dr. L.V. Beerepoot | Medical Oncology | Elisabeth Tweesteden Ziekenhuis |
Dr. W.L. Hazen | Gastroenterology | Elisabeth Tweesteden Ziekenhuis |
Dr. J. Heisterkamp | Surgery | Elisabeth Tweesteden Ziekenhuis |
Drs. J.C. van Oord | Radiology | Elisabeth Tweesteden Ziekenhuis |
Drs. T. Rozema | Radiotherapy | Instituut Verbeeten |
Dr. I.A.C. Vermeltfoort | Nuclear Medicine | Instituut Verbeeten |
Dr. A.A.M. van der Wurff | Pathology | Elisabeth Tweesteden, Ziekenhuis |