Increasing the accuracy for endoscopic detection of early Barrett neoplasia, by adding probe-based confocal laser endomicroscopy to endoscopic tri-modal imaging: A feasibility study on Endoscopic Quad-Modal Imaging (EQMI)

Endoscopic surveillance of Barrett oesophagus (BO) patients is recommended to
detect high-grade intraepithelial neoplasia (HGIN) or early cancer (EC) at a
curable stage. With standard endoscopy, however, it is difficult to distinguish
areas with HGIN/EC. In the absence of visible lesions, random biopsies are
obtained for histological assessment of neosplasia, but these random biopsies
may miss dysplastic lesions (sampling error). The endoscopic detection of early
neoplasia may be improved by the use of endoscopic tri-modal imaging (ETMI); a
system that incorporates white light endoscopy (WLE) and autofluorescence
imaging (AFI) for primary detection of early neoplasia and allows for targeted
imaging of suspicious areas with narrow-band imaging (NBI). In a recent
international multicenter study, AFI increased the sensitivity for detecting
early neoplasia from 53% to 90% compared to WLE. Subsequent inspection with NBI
of AFI-positive areas reduced the false-positive rate of AFI from 81% to 26%.
Preliminary results of an international multicenter randomized cross-over trial
also show that AFI increases the detection of early neoplasia with 40%, but
again with a high false positive rate (i.e. do not contain neoplasia). The
false positive rate was reduced from 72% to 47% with NBI, but at the expense of
misclassifying 8 neoplastic lesions as unsuspicious.

For endoscopic quad-modal imaging (EQMI) a fourth imaging technique is added to
ETMI: probe-based confocal laser endomicroscopy (pCLE), a new endoscopic
imaging technique that allows for real-time histological evaluation of the
mucosa. pCLE evaluation of AFI+ areas may be a better approach to reduce the
high AFI false positive rate compared to NBI inspection. Furthermore, since it
provides images equivalent with histology, pCLE may allow real-time decision
making, e.g. by immediately removing lesions suspicious for early neoplasia by
endoscopic resection instead of obtaining biopsies and waiting for the outcome
of the histological evaluation before making a decision.

In patients with BO undergoing surveillance or work-up endoscopy for early
neoplasia, we aim to evaluate if EQMI, consisting of ETMI combined with pCLE,
increases the accurary of detecting early neoplasia (study phase 1).
In addition, we aim to determine if real-time pCLE inspection followed by
immediate endoscopic resection of lesions suspicious for early neoplasia, may
be a valid and safe alternative to the current standard of obtaining biopsies
and awaiting histological evaluation before scheduling an endoscopic resection
(study phase 2).

For this prospective international multicenter study (Amsterdam, Nottingham,
München, Jacksonville), a total of 60 patients will be included.

During endoscopy the BO is examined with WLE to detect suspicious lesions, all
findings are recorded. Then, the BO is inspected with AFI and the location,
size and macroscopic appearance for additionally detected lesions are recorded.
AFI-positive lesions are marked with argon plasma coagulation and further
inspected with NBI and, after intravenous administration of 2.5ml fluorescein
(10%), with pCLE. During NBI and pCLE areas are classified as 'suspicious for
neoplasia', 'normal', or 'indefinite'.
During phase 1 of this study, all marked areas are sampled by two biopsies for
histological correlation.
During phase 2 of this study, all areas that are graded as neoplastic with pCLE
will be immediately removed by endoscopic resection whereas areas graded as
normal or indefinite will be sampled by 2 biopsies, for histological
correlation.

All biopsy and endoscopic resection specimens will be evaluated by the same
expert gastro-intestinal pathologist to assess the presence of neoplasia.

Next to the general risks associated with upper endoscopy such as irritation of
the throat by introduction of the endoscope, difficult swallowing and
retrosternal pain, the use of ETMI for neoplasia detection and pCLE for optical
histopathology do not increase endoscopy risk.
During endoscopic resection, delayed bleeding may occur in 3.3% of cases,
usually easily manageable with endoscopic hemostatic techniques. Also, a
perforation may occur in 2.4% of cases, usually manageable with endoscopic and
conservative management.