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.
