Sentinel node and organ sparing surgery in stage I colon carcinoma (SENTRY trial)

Since the introduction of a Dutch nation-wide population screening programme
for colorectal cancer in 2014, an increase in incidence of T1-T2 tumours was
observed, with a subsequent increase in local excisions (e.g. transanal
endoscopic microsurgery and full-thickness resection) and polypectomies. The
risk of lymph node metastasis is relatively small in cT1-2 colon carcinoma.
Diagnostic accuracy of CT abdomen is very limited, for which reason a formal
oncological colonic resection has to be performed for definitive nodal staging
based on pathological examination of the draining mesocolon. However, segmental
resections after radical local excision of early cancers will overtreat 80 to
90% of patients depending on the histological risk profile since they do not
have lymph node metastases. Colonic resections are associated with substantial
morbidity and mortality.
To reduce the number needed to treat for colonic resection in early colon
cancer, risk stratification is applied based on histopathological examination
of locally excised lesions. In low-risk T1 lesions, colonic resections are
already omitted. We hypothesise that sentinel lymph node (SLN) biopsy can
identify patients with lymph node metastases in high-risk T1 and low-risk T2
tumours. In our experience, during a pilot study (n = 10), the SLN procedure
was a successful, fast and safe procedure.
The SLN procedure would be combined with an endoscopy-assisted limited
wedge-resection to further reduce local recurrence risk. The wedge resection is
a safe procedure to remove polyps and small tumours and has been performed in
multiple Dutch hospitals. Wedge resection can efficiently be performed since
the SLN already requires an intraoperative colonoscopy. The (local) recurrence
risk of node-negative pT1-2 patients after SLN biopsy and wedge resection after
endoscopic polypectomy should outweigh the risk of segmental colonic resection.
Thereby, patients can be offered a watchful waiting strategy after a negative
SLN procedure.
This sequential phase II and III study compares the combined SLN procedure and
wedge resection with segmental colectomy for patients with early-stage colon
carcinoma (high-risk T1 and low-risk T2) after endoscopic polypectomy. This
would be an innovating step towards organ preserving colon cancer treatment.

The aim of this study is to reduce the need for colectomy and its* associated
morbidity and mortality in patients with high-risk pT1 or low-risk pT2 colon
carcinoma after endoscopic polypectomy by performing a (robot-assisted)
laparoscopic wedge resection and SLN biopsy sentinel node biopsy and wedge
resection of the scar.

The SENTRY trial is designed to determine the oncological safety of an
organ-preserving approach with local excision combined with SLN procedure and
watchful waiting in case of a tumour negative sentinel node. Based on
experiences in organ preserving approaches in rectal cancer, it was decided
that a classical RCT design will likely result in slow accrual because of clear
patient preferences and lack of equipoise. These issues can be overcome by a
randomised patients* preference trial (RPPT) design. Oncological safety will be
determined using a non-inferiority design.
Therefore, we will conduct a prospective multicentre, non-inferiority,
randomised patients* preference trial. Eligible patients will be assigned to
either segmental colectomy (standard of care) or an experimental treatment with
wedge resection and sentinel node procedure including watchful waiting in case
of negative sentinel node, according to patients* preference or 1:1
randomisation in case the patient has no clear preference.
Patients* preference does lead to a substantial proportion of patients refusing
randomisation. However, patients* preference does not affect the primary
outcome of an RPPT, but increased participation (ranging 48-100%) which
improves external validity compared to a classic RCT since specific patient
groups might me more likely to not participate in a RCT. Furthermore,
participants of the patients* preference cohort have fewer crossovers and loss
to follow-up compared to participants in the randomised cohort. Therefore,
internal validity is improved and results can be better interpreted.
The study is designed as a sequential phase II-III study, in which the
feasibility of sentinel node biopsy and allocation according to patients*
preferences will be evaluated in phase II, the first 80 patients. The
feasibility is fulfilled if a SLN is detected in >=80% of patients. We will
subsequently proceed with the phase III trial to determine the non-inferiority
on the primary endpoint. Based on the preliminary data of the phase II trial,
we might adapt our power calculation. If <80% of SLNs are detected during phase
II, the study will be stopped. The study will not be paused to evaluate the
stopping rule since temporarily halting the study could result in confusion in
the including centres. More importantly, the DSMB can quickly evaluate the
stopping rule after the inclusion of the 40th patient (in experimental group)
since it is an intraoperative outcome.

1. Patients are identified at the outpatient clinic after multidisciplinary
consultation and asked for participation in the study.
2. Patients will be planned for endoscopic-assisted wedge resection.
3. Mechanical bowel preparation (MBP) will take place one day prior to surgery.

Sentinel lymph node identification
4. After achieving abdominal access and inspection of the abdomen, a
colonoscopy will be performed. Subsequently the gastroenterologist will create
four blebs around the tumour with 0.9% NaCl. Thereafter, the gastroenterologist
will inject ICG in the four blebs in order to minimise spill of ICG.
5. The available near-infrared camera system is used to visualise the SLN,
which will be harvested. If multiple SLNs appear, the first four SLNs will be
harvested.

Wedge resection
6. A suture is placed with intraluminal endoscopic visualisation at the base of
scar of the tumour.
7. Traction is given on the suture to enable positioning of a linear stapler.
8. The patency of the colonic lumen and total inclusion of the scar is checked
by the gastroenterologist before stapling.
9. After stapling, the resected specimen is removed in an endobag after which
the gastroenterologist and surgeon check the colon for signs of bleeding or
perforation before ending the procedure.
An instructional video of wedge resection is available at www.limeric.nl

Postoperative procedures
10. Postoperative care on the ward will be according to SOC.
11. Pathological examination will be done using haematoxylin & eosin (H&E). If
the SLN is negative, the SLN will be examined using serial slicing and
subsequent IHC.
12. If all SLNs are negative, an adjusted watchful waiting follow-up schedule
is followed.
13. If a SLN contains (micro)metastases (metastases >= 0.2 mm), a complementary
segmental resection and adjuvant chemotherapy will be advised by
multidisciplinary team if performance status allows. Treatment will always be a
shared decision between physician and patients.

Potential benefits associated with participation:
The wedge resection and SLN biopsy would result in less invasive surgery as no
segmental colectomy will be performed. One of the most important complications
of segmental colectomy is anastomotic leakage which is associated with
substantial morbidity, ICU admittance and longer length of stay. In case of a
wedge resection, there is also a staple line but no anastomosis between two
bowel segments after vascular ligation of mesenteric vessels. Therefore, the
risk of leakage is expected to be neglegible. Fewer complications would also
lead to reduced mortality.
Furthermore, a limited resection will be performed compared to segmental
resection which should improve postoperative bowel function due to the
organ-sparing nature of the surgery. Short-term this would reduce postoperative
ileus. Long-term might improve defaecation as patients undergoing segmental
colectomy often experience altered defaecation patterns.
The length of stay will be shorter due to the afore mentioned benefits. The
hospital stay of patients in the LIMERIC-I was most often one day, or two days
in the other cases. This is shorter than segmental colectomy. Due to more
experience with wedge resections, we expect that patients might even be treated
in day care.
The reduced hospital stay and fewer complications likely benefits both patients
and society since it improves quality-of-life and reduces costs.

Potential risk associated with participation:
One of the considerations of the wedge resection and SLN identification is the
risk of missed lymph node metastases. We estimate that the SLN procedure using
submucosal injection and improved near-infrared camera systems has a
sensitivity of 80% for the detection of lymph node metastases in the study
population (stage I), thereby accepting that we will miss 20% of metastasis in
a population with an overall absolute risk of 10%, accounting for 2% absolute
risk that a lymph node metastasis remains undetected. Furthermore, tumour
deposits (TDs) could potentially be missed when patients are treated with the
SLN procedure and wedge resection. However, in a large cohort of 103.755
patients, only 111 of 24,927 patients (0.45%) with stage I disease were
TD-positive.

Furthermore, subjects in the intervention arm of this study will be
administered ICG. ICG has a well-established safety profile and the risk of
anaphylaxis for ICG is reported to be about 1 per 42,000. In case an
anaphylactic reaction does take place, we will have the medication, necessary
for counteracting an anaphylactic reaction, present in the operation room.