Tailored lymphadenectomy using Sentinel node Navigation surgery in high-risk (sub)mucosal esophageal Adenocarcinoma Patients: SNAP-III study

Esophageal adenocarcinoma (EAC) is the most rapidly rising cancer in the
Western World. Barrett*s esophagus (BE) is a premalignant condition
predisposing to EAC. Therefore endoscopic surveillance has become standard care
for patients with BE in order to evaluate malignant degeneration. Surveillance
with biopsy protocols and additional advancements in optics of endoscopes lead
to early detection of dysplasia and neoplastic lesions in the esophagus.
Patients with early EAC may be considered for surgical treatment depending on
the risk for LN metastases. The risk of LN metastasis in early EAC depends on
various histopathological characteristics, such as tumor infiltration depth,
presence of lymphovascular invasion, and tumor differentiation grade. Based on
these histopathological characteristics, early EACs can be divided into several
risk groups. In case of a low-risk mucosal EAC and low-risk T1b EAC (i.e.
superficial submucosal infiltration <500µm, not poorly differentiated, and
absence of lymphovascular invasion), an ER is considered to be a curative
treatment, since in these lesions spread of tumor cells to the adjacent LNs is
highly exceptional (<2%). The long-term outcome for endoscopically treated
patients with low-risk T1 EAC is excellent with reported disease-free survival
and overall survival rates of respectively 84% and 84% after 5 year of
follow-up. In case of high-risk T1b EAC (i.e. deep submucosal invasion >500µm,
and/or poor differentiation, and/or lymphovascular invasion) the risk of
concomitant LN metastases is considered to be high, and current guidelines
recommend esophagectomy in case of acceptable clinical condition. In patients
with high-risk T1b EAC treated with surgery the 5-year disease-free survival
and overall survival are respectively 78-89% and 68-70%. The third risk group
involves high-risk T1a EAC (i.e. mucosal invasion with poor differentiation
and/or lymphovascular invasion), in which the risk of LN metastasis is recently
reported to be higher than previously assumed. Although no clear consensus
exists on the best treatment option for this last risk group, some patients
with high-risk T1a EAC are referred for surgery. However, esophagectomy is a
major surgical procedure associated with significant morbidity (up to 45%),
mortality (2-4%) and reduced quality of life post-operative.
Our study group therefore stepwise investigated a less invasive, esophageal
preserving treatment algorithm for patients with high-risk T1 EAC, consisting
of radical (R0) ER of the tumor followed by SN guided selective lymphadenectomy
without concomitant esophagectomy. This new treatment algorithm might be of
great value since it is less invasive compared to standard of care, and more
importantly, upper-GI anatomy remains intact. It might well be associated with
lower morbidity and mortality, and therefore might lead to a better quality of
life post-operative.
SNNS is a concept which is already extensively used in the treatment of breast
cancer and melanoma. During SNNS, a day before surgery a radioactive tracer is
injected peritumoral or around the resection scar in case of ER of the tumor.
Macrophages in the SN absorb the radioactive particles and visualization and
detection is possible through planar images or SPECT/CT images. These images
serve as a guide to the surgeon, who identifies the SNs using a gamma probe and
subsequently resects them.
Pathological status of SNs is assumed to predict the status of locoregional
LNs. The extent of the lymphadenectomy can be tailored according to the
pathological status of the SN(s). In case of a tumor-positive SN in patients
with an early EAC, two- or even three-field lymphadenectomy is required, while
in case of a tumor-negative SN lymphadenectomy might be minimized. Several
studies showed that SNNS is feasible in EAC and associated with high detection
and accuracy rates (88-100% and 78-100%, respectively) and a high sensitivity
(78-100%). Early EAC, clinically staged as T1, is associated with the best
results, while patients with advanced carcinoma are being considered
non-suitable candidates because of the destruction of lymph vessels by the
tumor and neoadjuvant therapy, and the formation of fibrosis after neoadjuvant
therapy.
The current study is expected to be last step before the whole treatment
algorithm can be implemented into clinical practice and logically follows our
previously performed research. Preclinical studies showed that
thoracolaparoscopic lymphadenectomy is feasible in human cadavers and safe in a
porcine survival study. A clinical pilot-study in patients planned for
esophagectomy showed that - while leaving the esophagus in situ - a sufficient
number of LNs could be removed (median of 30) during radical lymphadenectomy.
However, during this extensive lymphadenectomy discoloration of the esophagus
was observed. This could possibly indicate significant damage to the
vascularization of the esophagus, an observation not seen in the porcine model.
To prevent ischemia of the esophagus, an esophageal sparing radical
lymphadenectomy was abandoned and replaced by a more restricted approach using
SNNS.
A recent study of our study group investigated the feasibility and accuracy of
SNNS using CT-lymphoscintigraphy combined with per-operative gamma probing in 5
patients with a high-risk T1b EAC and planned esophagectomy. In these patients,
during endoscopy a radioactive tracer was injected in the submucosa, around the
endoscopic resection scar. We could identify and resect SNs in all
participating patients (median of 4 SNs) and no AEs occurred. However, upon
histological evaluation one LN in the peritumoral region, not identified as SN,
contained tumor cells. Because of a high amount of radioactive tracer at the
tumor site (or at the ER scar site), peritumoral SNs are hard to visualize;
also known as the shine-through effect. We therefore adapted the protocol
incorporating submucosal injection of Indocyanine Green (ICG) combined with a
radioactive tracer in four quadrants around the endoscopic resection scar. ICG
is a tricarbocyanine dye that has been used clinically for hepatic clearance,
cardiovascular function testing and retinal angiography on the basis of its
dark green color. It is a non-specific contrast agent, it does associate with
albumin, making it an excellent vascular agent for evaluating both the blood
and lymphatic system. ICG binds to plasma proteins and protein-bound ICG emits
light with a peak wavelength of 830nm when illuminated by NIR light. The
excitated ICG can be visualized during surgery with a NIR camera and this
technique enhances visualization of peritumoral LNs. Combining scintigraphy
with ICG NIR has shown promising results in SN mapping in gastric cancer. In
our recently finished study the feasibility of the above mentioned combination
of radioactive tracer and ICG was investigated for SN mapping in high-risk EAC.
In all five included patients SNs could be detected on lymphoscintigraphy and
SPECT/CT (median of 2 SNs). During SNNS procedure a median of 5 SNs were
identified and resected of which none were tumor positive on histopathologic
evaluation (Overwater et al., unpublished data, NL61467.100.17). Please note
that so in all studies so far the SNNS procedure was immediately followed by an
esophagectomy with radical lymphadenectomy in the same session.
The current study investigates the feasibility and safety of a new treatment
algorithm for patients with high-risk T1a or T1b EAC consisting of radical ER
of the tumor, followed by a SN procedure with selective lymphadenectomy by
means of scintigraphy with a radioactive tracer (technetium) combined with NIR
technology with ICG. In the current protocol, the esophagus is only resected in
case of proven tumor positive sentinel node(s).

The aim of this study is to evaluate the feasibility and safety of new
esophageal preserving treatment algorithm for patients with high-risk T1a or
T1b EAC consisting of radical ER of the tumor, followed by a SNNS procedure
with selective lymphadenectomy.

In this multicenter, prospective pilot study we will include a total of 10
patients with a high-risk T1a or T1b EAC.

Patients will be subjected to a SN procedure. One day before sentinel node
procedure patients will undergo an upper endoscopy for submucosal injection of
the radioactive tracer (technetium) and indocyanine green in four quadrants
around the endoscopic resection scar. After injection of the radioactive tracer
and dye a lymphoscintigraphy and SPECT/CT will be constructed, which will show
the location of the SNs and thus serves as a guide for the surgeons during the
SN procedure. During surgery the SNs will be detected using a laparoscopic
gamma probe and a laparoscopic NIR camera, followed by SN guided selective
lymphadenectomy without concomitant esophagectomy.
After SNNS the follow-up phase starts during the following 24 months. In case
of tumor-negative sentinel nodes (most likely the case), patients will enter a
strict endoscopic surveillance program by high-definition endoscopy and
endoscopic ultrasound. In order to assess the effect of the surgical SNNS
procedure on esophageal and gastric motility, assessment of GI tract
functioning using high-resolution manometry (HRM) and gastric emptying testing
will be done before, and three months after the SNNS procedure. Finally,
quality of life will be assessed by means of questionnaires.

In patients with a high-risk submucosal EAC, lymph node metastases in earlier
surgical series is reported to occur in up to 40% of patients. These series
probably overestimate the risk, and have understaged the esophageal tumor. In
recent series, in which patients with a high-risk submucosal EAC were treated
surgically or endoscopically, we found an incidence of 16%. Moreover, the
number of tumor-related deaths in both groups (surgical vs. endoscopic
treatment) was equal (12%) and invasive surgical treatment did not cure all
patients: still some patients developed metastatic disease.
Recently, we analyzed a cohort (n=18) of patients with a high-risk submucosal
EAC which were treated endoscopically, and underwent endoscopic follow-up.
After a median of 23 months of follow-up, none of these patients has developed
lymph node metastasis. We therefore hypothesize that the risk for lymph node
metastasis in these tumors is much lower than reported in earlier surgical
series, and that selective lymphadenectomy using SNNS is justified.
In patients with high-risk mucosal EAC, a recent retrospective analysis from
our research group has showed that the risk of LN metastasis is comparable to
the risk in patients with high-risk submucosal EAC. During a median follow-up
of 31 months, 6 of 27 patients (22%) with high-risk T1a EAC were diagnosed with
LN metastasis. Although the risk of LN metastasis in this specific patient
category is higher than previously assumed, the majority of patients with
high-risk mucosal EAC will not develop LN metastasis. Therefore we believe that
these patients may also benefit from a selective lymphadenectomy using SNNS.
We are unsure however, about the risk of developing lymph node metastasis after
resection of tumor-negative sentinel nodes. We think this risk is very low (in
line with literature on SNNS in breast cancer and melanoma). In either way, we
will keep patients under strict endoscopic follow-up with EUS to be able to
detect lymph node metastasis as soon as they develop. When lymph node
metastasis will occur, patients will be discussed in a multidisciplinary
meeting and most optimal treatment will be determined.
The SN procedure is extensively being used in the treatment of breast cancer
and melanomas. Possible risks include an allergic reaction to the radioactive
tracer or associated substances, which is extremely rare, and exposure to
radioactive beams, of which the amount stays below the maximum threshold. The
risks of upper endoscopy, upper gastrointestinal functioning tests and PET-CT
are negligible. They are mainly associated with the introduction of the
endoscope and include sore throat and sedation related side effects such as
local bruising or pain at the I.V. site, allergic reaction to the medications
or I.V. CT contrast medium and over sedation requiring sedation reversal
medications and longer post-procedure observation. Medications used for
conscious sedation are carefully titrated and monitored based on the patients'
arousal levels and vital signs.