Endoscopic management of patients with high risk T1a and T1b N0M0 esophageal adenocarcinoma:
a prospective multicenter registry

Over the last decades, the treatment of early adenocarcinoma has shiftes from
surgical treatment to endoscopic treatment. Endoscopic treatment has been
established as first choice treatment for low risk mucosal EAC, with excellent
efficacy and safety, also in long-term analyses. Endoscopic resection (ER)
offers local treatment and does not include lymph node dissection as is still
standard of care during esophagectomy. Therefore, the choice to perform
endoscopic follow-up after a radical ER of an early EAC, or to refer a patient
for additional surgery, is guided by the assumed risk of lymph node metastasis.
This risk is assessed by taking into consideration histopathological risk
factors such as tumor infiltration depth, differentiation grade, presence of
lymphovascular invasion, and the radicality of the endoscopic resection at the
deep vertical resection margin. Indications for endoscopic management are EAC*s
limited to the mucosa (T1m1-3), with good to moderate differentiation (G1, G2),
without lymphovascular invasion, which were radically resected (R0). Relative
indications for endoscopic resection are high risk mucosal EAC*s with
lymphovascular invasion and/or poor differentiation, and low-risk submucosal
EAC*s. No data exists on the risk of lymph node metastasis in high risk T1a
EAC, however, recent retrospective analysis shows that this risk may be higher
than previously assumed. Low risk submucosal EACs are defined as cancer limited
to the upper 500 microns of the submucosa, good to moderately differentiated
(G1-G2), and no lymphovascular invasion, which are radically resected. Based on
s studies the risk of lymph node metastasis in these submucosal cancers is
<2%., which is lower than the mortality risk of esophagectomy. Patients with a
high-risk submucosal EAC (deep submucosal infiltration >500nm, and/or poor
differentiation (G3), and/or presence of lymphovascular invasion are considered
surgical candidates. Traditionally, the risk of lymph node metastasis
associated with submucosal EAC was considered too high to offer these patients
endoscopic follow-up. Only in elderly patients with comorbidity, more often an
endoscopic protocol is selected. However, the risk of lymph node metastasis
associated with submucosal EAC*s is mainly based on surgical series. Recently a
number of studies, which included patients treated endoscopically, were
published indicating that the risk of lymph node metastasis may however be
lower than generally assumed.Therefore, a less invasive and organ preserving
approach may not only be an option in the frail and elderly, but for all
patients with submucosal EAC*s.

To evaluate the safety of an endoscopic follow-up strategy in patients with HR
T1a and T1b N0M0 esophageal adenocarcinoma (EAC).

Prospective international multicenter cohort study.

After endoscopisc treatment: endoscopic follow-up with frequent endoscopies and
EUS.
Intervals:

year 1 en 2: 3-4-monthly gastroscopy + EUS.
1 year after baseline endoscopy single CT-thorax/abdomen.
year 3 en 4: 6-monthly gastroscopy + EUS
year 5: 1x per year gastroscopy + EUS

Potential benefits: Included patients will not undergo esophagectomy with
lymphadenectomy as an additional treatment directly after ER. Esophagectomy is
associated with significant morbidity of up to 50%, mortality of 2-4% (even in
expert centers) and a temporary reduced quality of life. Moreover, the
digestive system is significantly affected, leading to a whole different life
(eat) style. Included patients will be followed endoscopically, which is far
less invasive than undergoing major surgery. We therefore hypothesize that
their quality of life will be less affected compared to patients undergoing
esophagectomy. Potential risks: The field for endoscopic therapy in submucosal
EAC is expanding. Currently, endoscopic therapy for so called *low-risk*
submucosal EAC is justified. These are superficial submucosal tumors (<500nm),
which are good to moderately differentiated (G1-2), without presence of
lymphovascular invasion, which are radically resected. The risk of lymph node
metastasis in these tumors is close to zero (<2%), and does not exceed the
mortality risk of esophagectomy. Therefore, endoscopic therapy is considered to
be curative. For patients with high-risk mucosal EAC no evidence on the risk of
LNM exists, except for our recent retrospective analysis performed in 9 Dutch
Barrett Expert Center which showed higher risk of LNM in the high risk T1a
group than in both T1b (LR and HR) groups. For patients with high risk T1a EAC,
endoscopic treatment and FU already is a relative indication. Including them in
our prospective analysis will not bring any potential risks. For patients with
a high-risk submucosal EAC, standard of care is to undergo esophagectomy with
lymphadenectomy. In this study, patients will not undergo surgical treatment,
but undergo upper endoscopies and EUS at regular time intervals. It might be
the case that the cancer will return. Majority of these local recurrences can
be treated endoscopically. In some cases the lesion cannot be treated
endoscopically. In that case, patients will be discussed in a multidisciplinary
meeting to determine which treatment is indicated regarding patient*s age,
comorbidities and preferences. In patients with a high-risk submucosal EAC, the
associated risk of lymph node metastasis is estimated to be about 16%. Far
majority of patients with a submucosal EAC therefore undergoes major surgical
treatment without finding any cancer cells in the esophagus or lymph nodes.
Moreover, esophagectomy is a procedure associated with significant morbidity
(up to 50%) and mortality (2-4%). If patients do develop lymph node metastasis
during follow-up, patients will be discussed in a multidisciplinary meeting to
determine optimal treatment. Standard of care in case of N+ disease is to
administer neoadjuvant chemoradiation therapy followed by surgery. Depending on
age, comorbidities and patient*s preference, the treating physician will
determine which treatment is indicated. Upper endoscopy is an investigation,
which is performed many times a day in all participating hospitals. The
participating endoscopists are skilled and have vast experience in performing
an upper endoscopy. The risks of upper endoscopy and endoscopic ultrasound are
negligible, 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. All patients undergoing endoscopy are monitored with continuous
pulse oximetry and vital signs assessment (blood pressure) during the
procedure. Medications used for conscious sedation are carefully titrated and
monitored based on the patients' arousal levels and vital signs.