Sentinel node Navigation surgery in early esophageal Adenocarcinoma Patients with lymph node involvement: SNAP-IV 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 a submucosal EAC are treated surgically in most centers
worldwide, since the risk for lymph node (LN) metastases in these tumors is
considered to be high. The risk of LN metastasis in submucosal EAC depends on
various histopathological characteristics, such as tumor infiltration depth,
presence of lymphovascular invasion, and tumor differentiation grade. Based on
these histopathological characteristics, submucosal EACs can be divided into
two risk groups. In case of a low-risk T1b EAC (i.e., superficial submucosal
infiltration <500µm, not poorly differentiated, and absence of lymphovascular
invasion), an endoscopic resection (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 T1b 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%. 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 T1b EAC,
consisting of radical (R0) ER of the tumor followed by sentinel node (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-gastrointestinal 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.
Sentinel node navigation surgery (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 a submucosal 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 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 (unpublished data, NL61467.100.17) 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). In
two patients an additional SN was detected per-operative in the peritumoral
region with ICG and NIR, resulting in a median of 3 SNs identified and
resected. Thus, combining ICG with scintigraphy enhances the visualization of
peritumoral SNs in high-risk EAC.
Currently we are investigating the feasibility and safety of the
adapted SNNS procedure in patients with high-risk T1b EAC which have been
radically removed by endoscopic resection (NL71361.041.019). As the prevalence
of lymph node metastasis in this specific patient category is believed to be
low, there is a reasonable chance that none of the included patients in this
study will have tumor-positive lymph nodes. Moreover, in all our previous
feasibility studies none of the resected SNs were tumor-positive on
histopathologic evaluation. However, the therapeutic value of the SNNS
procedure is determined by the accurate identification of tumor-positive LNs as
SNs. Therefore, we want to perform the SNNS procedure in patients with early
EAC and clinical suspicion on LN metastasis in order to obtain evidence that
the SNNS procedure can accurately detect tumor-positive LNs as SNs. These
patients a

The aim of this study is to validate the accuracy of SNNS for the detection of
tumor-positive LNs using lymphoscintigraphy with radioactive tracer and NIR
with ICG in patients with early EAC with regional LN involvement (clinically
staged as T1N1).

In this multicenter, prospective pilot study we will include up to 5 patients
with an early EAC and suspicion of regional LN metastasis, clinically staged as
T1N1.

Patients will be subjected to a SN procedure. One day before SN procedure
patients will undergo an upper endoscopy for submucosal injection of the
radioactive tracer (technetium) and indocyanine green in four quadrants around
the tumor or 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. The SN procedure will be followed by lymph node
dissection and esophagectomy with gastric tube reconstruction (standard care).

Included patients will not have any benefit, apart from the fact that they will
contribute to developing a new, less invasive, esophageal preserving treatment
for early esophageal cancer and thus possible benefit for patients with
esophageal cancer in the future.
The SN procedure is extensively being used in the treatment of breast
cancer and melanomas. An allergic reaction to the radioactive tracer,
indocyanine green or associated substances might develop. However, in the
previous feasibility studies none of the in total 10 included patients
developed any signs of an allergic reaction. Patients will be exposed to
radiation because they will undergo the lymphoscintigraphy and SPECT/CT.
Additional exposure might lead to a slightly increased risk for cancer.
However, the amount of extra ionizing radiation in this study is low and
therefore the associated risk acceptable. The risks of upper endoscopy are
negligible.
The result of the surgical procedure will not differ from daily
practice: no additional incisions will be made and oncological result will be
the same as standard of care. Procedure time of surgery will be extend to a
minimum. We estimate that surgery will take up to 60 minutes longer compared to
surgery without SNNS.
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