Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03222895 |
| Other study ID # |
W17_069 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
March 1, 2019 |
| Est. completion date |
June 1, 2028 |
Study information
| Verified date |
February 2024 |
| Source |
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) |
| Contact |
Suzanne S Gisbertz, MD, PhD |
| Phone |
+31205669111 |
| Email |
s.s.gisbertz[@]amc.nl |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial Summary
Background: Lymph node status is an important prognostic parameter in esophageal carcinoma
and an independent predictor of survival. Distribution of metastatic lymph nodes may vary
with tumor location, tumor histology, tumor invasion depth and neoadjuvant therapy. Surgical
strategy depends on the distribution pattern of nodal metastases but consensus on the extent
of lymphadenectomy differs worldwide. Especially for adenocarcinoma the distribution of lymph
node metastases has not yet been described in large series. Aim of the present study is to
evaluate the distribution of lymph node metastases in esophageal carcinoma specimens
following transthoracic esophagectomy with at least a 2-field lymphadenectomy.
Methods: The TIGER-study is a multinational observational cohort study. All patients with a
resectable esophageal or gastro-esophageal junction carcinoma in whom a transthoracic
esophagectomy with a 2- or 3-field lymphadenectomy is performed in participating centers will
be included. All lymph node stations will be excised and separately sent for pathological
examination. Cluster analysis will be performed to identify patterns of metastases in
relation to tumor location, tumor histology, tumor invasion depth and neoadjuvant therapy.
Conclusion: TIGER will provide a roadmap of the location of lymph node metastases in relation
to tumor histology, tumor location, invasion depth, number of lymph nodes and lymph node
metastases, pre-operative diagnostics, neo-adjuvant therapy and survival. Patient-tailored
treatment can be developed on the basis of these results, such as the the optimal radiation
field and extent of lymphadenectomy based on the primary tumor characteristics.
Description:
Primary Objective:
Aim of the TIGER study is to evaluate the distribution of lymph node metastases in esophageal
carcinoma specimens following transthoracic esophagectomy with at least 2-field
lymphadenectomy.
Secondary Objective(s):
- Accuracy of preoperative diagnostics (especially EUS and PET-CT) and added value of EBUS
(endobronchial ultrasonography) to existing staging with EUS (endoscopic
ultrasonography)/PET-CT
- Prognostic value of different lymph node stations
- Three- and 5-year overall and disease free survival
- Distribution pattern of recurrence or metastases
- Number of harvested lymph nodes in patients who are treated with and without
neo-adjuvant chemoradiotherapy
- Frequency of skip nodal metastases
- Ratio of nodal metastases inside and outside the radiation field o Lymph node metastases
will be defined as inside or outside the radiation field nodes.
Study design:
TIGER is a multinational observational cohort study. The duration of the study will
approximately be 7 years (2 years inclusion, 5 years follow-up). The participating centers
are distributed over 18 countries.
Sample size calculation:
In 2012, the incidence of esophageal cancer was 456,000 new cases worldwide. Only a small
percentage of patients with esophageal cancer present with curable disease at time of
diagnosis. We aim to include all patients with resectable disease in participating centers in
a 2 year time period. We aim to include 5000 patients. This number suffices for (i)
descriptive purposes and (ii) clustering of metastases diffusion profiles into meaningful
subgroups within predefined strata (patients with adenocarcinoma or squamous cell carcinoma,
with and without neoadjuvant therapy, different tumor heights and invasion depths, and
following a 2- or 3-field lymphadenectomy).
Study procedures:
Patients will not undergo any additional procedures for the study. This is an observational
study only. Patients will be treated according to national guidelines.
Follow-up:
Patients will be followed up for 5 years after the operation according to national
guidelines. Follow-up will be scheduled every three months the first year, every six months
the second until the fourth year and once yearly until the fifth year. Investigations are
performed according to national guidelines. In the Netherlands, these are performed on
indication of patients' complaints.
Statistical analysis:
Primary study parameter(s):
Numbers and percentages of resected lymph nodes and lymph node metastases will be given per
lymph node station. Tumor location and invasion depth will be categorized. Patients with
adenocarcinoma and squamous cell carcinoma and patients with and without neoadjuvant therapy
will be analyzed separately. Also patients following a 2- or 3-field lymphadenectomy will be
analyzed separately.
Secondary study parameter(s) :
The sensitivity, specificity, and positive and negative predictive values of EUS and PET-CT
will be reported. Perioperative morbidity and mortality will be summarized descriptively. For
each patient group mentioned in 5.4, explorative cluster analyses will be done to identify
subgroups of patients with different patterns of lymph nodes metastases, tumor locations and
invasion depths. Potentially relevant other characteristics at the time of surgery like age,
gender, tumor differentiation, vaso-invasive growth will be included in the analysis. No
restrictions will be applied to the number of clusters in each analysis, but the ratio of the
largest cluster size to the smallest cluster size should preferably not exceed the value of 3
and/or the smallest cluster size should be minimally 30 patients. Characteristics introducing
patient outliers will be excluded and one should further be able to attribute meaning to the
resulting cluster profiles. Clusters that show the phenomenon of skip metastases will be
noted. The resulting clusters will be evaluated for the diffusion pattern of future
metastases during follow-up (descriptive analysis), the number of future metastases during
follow-up (Poisson regression or generalized estimation equation, whichever appropriate), for
3- and 5-year overall and disease free survival (Kaplan-Meier survival analysis).
Multivariate analysis will be performed using the Cox hazard regression method. The
univariate analysis, including all baseline parameters, will serve as the basis for the
multivariate Cox hazard regression model. Variables showing association (p < 0.10) with
survival in univariate analysis will be included in the multivariate analysis. Age and sex
will be included in all multivariate analyses. Results are presented as hazard ratio with
exact 95% confidence interval (95% CI). After 5-years of follow-up the efficacy index will be
determined (incidence of metastases to an area (%) x 5-year overall survival rate (%)). A
log-rank test, Mann-Whitney U test, or χ2-test will be used as indicated to compare groups. A
value of p < 0.05 will be considered statistically significant. Statistical analysis will be
performed with SPSS 21.0 software (SPSS, Inc., Chicago, IL, USA). No formal power analysis or
sample size calculation will be performed, but the 5,000 inclusions will suffice for an
exploratory study.
Other study parameters:
Baseline characteristics will be presented in a baseline table. Clinical and pathology data
will be presented in separate tables.
Study population:
Central data management is organized via the secured TIGER database that can be found on
TIGERstudy.net. Patient inclusion and data registration of these patients will be done by the
participating local PI, surgeon or fellow for the center they are representing on the TIGER
website. The local PI is responsible for the inclusion and data registration of all eligible
patients in his or her center.
All patients with resectable esophageal carcinoma undergoing transthoracic esophageal
resection are eligible for inclusion.
Patients will be treated according to national guidelines and may be neo-adjuvantly treated
with chemotherapy or chemoradiation. An esophagectomy with a 2- or 3-stage lymphadenectomy
will be performed followed by a gastric tube or colonic interposition for reconstruction. All
lymph node stations will be excised and separately sent for pathological examination. Initial
microscopic evaluation will be performed by standard H&E staining. In case of suspicion of
micro-metastasis or isolated tumor cells in the lymph node, or in case of suspicion of
residual tumor cells in patients with extensive response to neoadjuvant therapy, additional
keratin stains will be performed. For the TIGER-study a new lymph node classification is
designed, and lymph nodes will be recorded according to that classification system. Patients
will be followed-up for 5 years after the operation.
