Early detection of Barrett's esophagus and esophageal cancer: accuracy and acceptability of a novel screening strategy in primary care.

The ongoing increasing incidence of esophageal adenocarcinoma (EAC) in the
Netherlands during the last few decades and the still dismal prognosis has
stimulated interest in screening for Barrett*s esophagus (BE). Although BE is a
known precursor of EAC, a minority of patients with EAC (<10%) are known with a
previous diagnosis of BE, and hence, most cases of BE are undiagnosed.
Screening programs to detect BE followed by endoscopic surveillance and
treatment of dysplasia or early neoplasia seem able to reduce the incidence of
EAC and improve survival. A non-invasive screening tool, such as breath
testing, could select patients at risk for BE, after which unsedated transnasal
endoscopy (uTNE) can confirm or exclude the diagnosis. uTNE offers the
possibility of a more acceptable and accurate endoscopic assessment of the
esophagus with almost neglectable risks and lower costs compared to
conventional endoscopy.

To determine the accuracy and acceptability of a minimal-invasive screening
strategy (breath testing (eNose) followed by unsedated transnasal endoscopy
(uTNE)) for Barrett*s esophagus (BE) and esophageal adenocarcinoma (EAC).

The current study will be a mono-site cohort study in the Netherlands to assess
the accuracy of exhaled VOCs analysis using an electronic nose device for the
detection of BE the and acceptability of an invitation for the eNose breath
test followed by uTNE with biopsy sampling. Eligible patients will be invited
to undergo a breath test followed by unsedated transnasal endoscopy.

Baseline visit and breath test in general practice:
After completing these questionnaires, patients will be asked to deliver a
breath sample by in- and exhaling through the eNose (a handheld device of 650
gram) for 5 minutes. A nose clip will be used to prevent the entry of
non-filtered air and patients will be instructed to enclose the mouthpiece with
their mouth at all times.

Within 30 minutes after the breath test, patients will fill out a Numeric Pain
Rating Scale (NPRS) to measure the degree of pain, anxiety and discomfort (0
being *none* and 10 being *severe*). A Numeric Pain Rating Scale (NPRS) is also
used to measure the acceptability of the breath test (0 being *the worst
experience*, 5 being *neither pleasant nor unpleasant* and 10 being *the best
experience*). Additionally, the willingness to undergo a future repeat breath
test will be asked.

uTNE in hospital (follow-up visit):
Subsequently 3 weeks after the breath test, patients will be invited to undergo
an uTNE performed by an experienced endoscopist in the hospital. It is a safe
and well tolerated procedure that can be performed under local anesthesia.
Prior to the uTNE, possible adverse events will be assessed by direct
observation and patient interviews. Also, concomitant therapies will be
reviewed. Within 30 minutes after the uTNE, patients will fill out a Numeric
Pain Rating Scale (NPRS) to measure the degree of pain, anxiety and discomfort
(0 being *none* and 10 being *severe*). A Numeric Pain Rating Scale (NPRS) is
also used to measure the acceptability of the uTNE (0 being *the worst
experience*, 5 being *neither pleasant nor unpleasant* and 10 being *the best
experience*). Additionally, the willingness to undergo a future repeat uTNE
will be asked.

Follow-up questionnaires after breath test and uTNE:
7 days after the breath test and 7 and 30 days after the uTNE, patients will be
sent an email with a link to additional questionnaires. These questionnaires
are the Spielberger State-Trait Anxiety Inventory (STAI-6), the Cancer Worry
Scale (CWS-8) and the Impact of Event Scale (IES-15).26-31 Also, 7 days after
the uTNE, possible (severe) adverse events will be assessed and concomitant
therapies will be reviewed via a telephone call. A patient is considered lost
to follow-up if at least two attempts to contact the patient have been done.

Participants who provide informed consent will undergo a 5-minute breath
measurement followed by unsedated transnasal endoscopy. No health care risks
are associated with performing the breath test. Transnasal endoscopy is a safe
and well tolerated procedure that can be performed under local anesthesia.
Complications (epistaxis (1-2%) and vasovagal reaction (0.3%)) are infrequent
and mostly self-limiting. Upper endoscopy is commonly performed and carries a
low risk of adverse events. Several studies have shown that the risk of
complications during endoscopy is indeed extremely low. In addition to the
health-related burden, participating in this study could have a psychological
impact in terms of overdiagnosis and overtreatment. All data will be
anonymized, refusal to participate in the study or desire to withdraw from this
research will not lead to any difference for the participant in question. The
expected benefits of this study are possibly high as this novel non-invasive
screening device proves to be applicable in daily clinical practice.
Furthermore, screening could identify a significant number of abnormalities
that might have otherwise gone undetected until further progression of disease.