Sentinel node Navigation surgery in early esophageal Adenocarcinoma Patients: the SNAP study

The incidence of esophageal adenocarcinoma (EAC) is increasing in the West (1).
EAC arises from Barrett*s esophagus (BE). In BE, esophageal squamous epithelium
progresses to adenocarcinoma through a multi-step transition consisting of
intestinal metaplasia, low grade dysplasia (LGD), high grade dysplasia (HGD),
and finally invasive cancer. Patients with known BE are offered endoscopic
surveillance. Recent developments, such as the spread of high definition
endoscopes through the community, combined with a higher awareness and improved
recognition of early lesions in Barrett*s esophagus have led to an increase in
detection of early EAC. Early EAC can be treated with endoscopic resection
techniques, such as endoscopic mucosal resection (EMR) or endoscopic submucosal
dissection (ESD) (2). In case of low-risk early EAC (i.e., negative resection
margins, histology showing a tumour confined to the mucosa, not poorly
differentiated, and absence of vascular or lymphatic invasion), an endoscopic
resection is considered to be a curative treatment, since in these lesions
spread of tumour cells to the adjacent lymph nodes is highly exceptional
(<2%)(3). In case of deep (> 500 micrometers) submucosal invasion, poor
differentiation grade, or lymphovascular invasion, the risk of concomitant
lymph node metastasis is considered to be too higher, and surgical
esophagectomy is recommended in case of acceptable clinical condition (4, 5).
However, esophagectomy is a major surgical procedure associated with
significant morbidity (up to 40%), mortality (2-4.5%) and reduced quality of
life postoperative(2, 6). Our study group investigated a new treatment
algorithm for high-risk early EAC, consisting of endoscopic radical (R0)
resection of the tumor, in combination with thoracolaparoscopic lymph node
dissection without concomitant esophagectomy. Preclinical studies show that
thoracolaparoscopic LN dissection is feasible in human cadavers and safe in a
porcine survival study (Künzli et al, unpublished data7). This new treatment
algorithm might be of great value in the treatment of early esophageal
carcinoma, since this may lead to a tailored treatment and might be associated
with less morbidity and mortality and a less impaired quality of life compared
to esophagectomy because of the less invasive character of the procedure and
intact upper-GI functioning. The concept of thoracolaparoscopic lymph node
dissection was recently investigated in a human pilot-study (Kunzli et al,
unpublished data), in which patients underwent a thoracolaparoscopic
lymphadenectomy, directly followed by esophagectomy and gastric tube
reconstruction. Results show that a median of 30 lymph nodes was removed, which
is comparable with the average number of lymph nodes removed during the
standard procedure (esophagectomy with LN dissection). Moreover, the esophagus
showed ischemic signs at the end of the lymphadenectomy, implying that such an
extensive lymphadenectomy without concomitant esophagectomy might not be as
safe as was presumed from the animal data, probably because of too extensive
devascularisation of the esophagus. Ideal would be to adjust the
lymphadenectomy to the individual patient status, thereby combining a limited
dissection of all relevant lymph nodes with preservation of the vascularisation
as much as possible. Sentinel node navigation surgery (SNNS) is a concept which
is already extensively being used in the treatment of breast cancer and
melanoma. A sentinel node is defined as the first lymph node(s) receiving
drainage from the primary tumor (8, 9,10). Pathological status of sentinel
nodes is assumed to predict the status of locoregional lymph nodes. The extent
of the lymphadenectomy can be tailored according to the pathological status of
the sentinel node(s) of the individual patient. In case of a tumor-positive
sentinel node, two- or even three-field lymphadenectomy is required, while in
case of a tumor-negative sentinel node further lymphadenectomy can be
abandoned. During sentinel node navigation surgery, a radioactive tracer is
injected peritumoral (or around the resection scar in case of endoscopic
resection of the tumor) a day before surgery. Macrophages in the sentinel node
absorb the radioactive particles and visualisation and detection is possible
through planar images or SPECT/CT images. These images serve as a guide to the
surgeon, who identifies the sentinel nodes using a gamma probe and subsequently
resects them. Pathological examination reveals if there is evidence of
(micro-)metastasis and the extent of lymphadenectomy can be tailored according
to the pathological status of the sentinel node(s). Because of a high amount of
radioactive tracer at the tumor site (or at the endoscopic resection scar
site), peritumoral lymph nodes are hard to visualize with this technique; also
known as the shine-through effect. Therefore, peroperative indocyanin green
(ICG) is injected peritumoral (or around the resection scar in case of
endoscopic resection of the tumor). 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 colour. 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 near-infrared (NIR) light (11,12). The excitated ICG can be
visualized during surgery with a near-infraredNIR camera and this technique
enhances visualization of peritumoral lymph nodes. Combining these two sentinel
node techniques has shown promising results in sentinel node mapping in gastric
cancer, but has not been evaluated in esophageal cancer (13). Several studies
already showed that SNNS is feasible in esophageal cancer and associated with
high detection and accuracy rates (88-100% and 78-100%, respectively) and a
high sensitivity (78-100%). Early esophageal cancer (T1-tumors) are 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 neo-adjuvant therapy and the formation of fibrosis after
chemoradiation therapy (10, 11, 12, 13, 14-19). and Takeuchi et al, abstract
ISDE 2014). However, none of the available studies investigated the value of
SNNS in patients who have undergone an endoscopic resection of an early EAC.
Furthermore, studies using an endoscopic gamma probe and subsequently
performing a minimally invasive esophagectomy, are scarce. We hypothesize that
SNNS might be of great value in early esophageal cancer, especially in the
treatment of high-risk early EAC (T1b-tumors). A treatment algorithm consisting
of endoscopic resection of the tumor, followed by SNNS and (adjusted) LN
dissection may preclude patients with a tumor-negative sentinel node from
esophagectomy and associated morbidity and mortality. Before applying this
technique in this treatment algorithm however, SNNS needs to be validated in
this specific patient group and the surgical team will have to be trained in
performing the procedure.

To evaluate the feasibility and accuracy of sentinel node navigation surgery in
patients with early esophageal carcinoma.

In this single-center pilot-study we will include a total of 10 patients with
an early esophageal adenocarcinoma (T1).

Sentinel node navigation surgery followed by lymph node dissection and
esophagectomy (standard care)

Overview sentinel node navigation surgery:

Day before surgery
1. Endoscopic submucosal injection of 0.5cc technetium-99m nanocolloid (total
of 100 MBq) 1 day before surgery (maximum of 24 hours) per quadrant in four
quadrants in the submucosal layer around the tumor or resection scar in case of
performed endoscopic resection.
2. Construction of planar images using a gamma camera, 15-30 minutes and 2
hours after injection of the radioactive tracer.
3. SPECT/CT of chest and abdomen will be performed 2 hours after injection of
the tracer. The imaging (SPECT/CT and lymphoscintigraphy) will show the
location of the sentinel nodes and thus serves as a guide for the surgeons.

Day of surgery
1. Endoscopic submucosal injection of 0.5ml of indocyanine green (ICG) each
injected in four regions in the submucosal layer around the tumor or resection
scar.
2. Intra-operative detection of the sentinel nodes (node with the highest
radioactivity) using an endoscopic laparoscopic gamma probe (Europrobe 3
system, PI medical) and laparoscopic near-infrared camera. Start with
identification in one compartment (thorax or abdomen, depending on the type of
anastomosis after esophagectomy)
4. Thoraco- or laparoscopic resection of the sentinel nodes in the first
compartment (either thorax or abdomen).
5. Ex-vivo identification of resected sentinel nodes using the gamma probe and
near-infrared camera.
6. Rest of lymph node dissection in the first compartment
7. Repositioning of the patient
8. Detection of the sentinel nodes using an endoscopic laparoscopic gamma probe
and near-infrared camera in the second compartment (thorax or abdomen)
9. Thoraco- or laparoscopic resection of the sentinel nodes in the second
compartment
10. Ex-vivo identification of resected sentinel nodes using the gamma probe and
near-infrared camera.
11. Rest of lymph node dissection in the second compartment and finalisation of
esophagectomy with gastric tube reconstruction.
12. Ex-vivo confirmation of absence of sentinel nodes in the esophagectomy
specimen using the gamma probe and near-infrared camera.
13. Investigation of the thorax and abdominal cavity with the endoscopic gamma
probe to confirm absence of sentinel nodes
14. Finalize esophagectomy and gastric tube reconstruction with cervical or
intra-thoracic anastomosis

Patients will undergo two extra endoscopies. The first endoscopy is for
injection of the radioactive tracer. The second endoscopy (on the day of
surgery, when the patient is anesthetized) is for injection of indocyanin
green. Upper endoscopy is an investigation which is performed many times a day
in the participating hospital. The participating endoscopists are skilled and
have vast experience in performing an upper endoscopy.The risks of upper
endoscopy are neglectable, and 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 IV site, allergic reaction to the medications and
over sedation requiring sedation reversal medications and longer post-procedure
observation.
The sentinel node procedure is a procedure which is extensively being used in
the treatment of breast cancer and melanomas. Since this is a feasibility
study, we do not tailor the lymphadenectomy: all lymph nodes will be removed,
regardless of the status of the sentinel node. Oncological result with thus be
the same as standard of care. An allergic reaction to the radioactive tracer,
dye (indocyanin green) or associated substances might develop, but is rare.
Procedure time of surgery will extend to a minimum: we think it will take up to
90 minutes longer compared to surgery without sentinel node navigation surgery.