Trial Information

Detect InSpect ChAracterise Resect and Discard 2

Colorectal cancer (CRC) continues to be a major problem in the UK and is the second most
common cause of cancer death. The annual incidence is approximately 30,000 cases with an
annual mortality rate of in the region of 16,000 (1). Most sporadic non-hereditary CRCs
arise from benign colorectal adenomas (2). The detection and resection of colorectal
adenomas at colonoscopy has been shown to reduce the subsequent risk of CRC by as much as
80% (3).

The NHS Bowel Cancer Screening Programme (BCSP) began roll-out in 2006 in England and as of
April 2010, was established across 99.4% of the country. The BCSP is based on a strategy of
biennial faecal occult blood test (FOBt) screening for men and women aged 60-75, followed by
colonoscopy for those who test positive. Among its aims is the detection and resection of
potentially pre-malignant colorectal adenomas thereby potentially reducing the incidence of
CRC. The introduction of the BCSP has resulted in a dramatically increased demand for
colonoscopy. To date approximately 80,000 colonoscopies have been performed within the BCSP
and at least one adenoma found in just under half of the procedures (4). In addition, from
2012, the BCSP will introduce flexible sigmoidoscopy screening for all individuals aged 55
yr olds. This extrapolates to approximately 500,000 flexible sigmoidoscopies per year, with
at least one polyp expected to be found in 75,000 procedures.

Greater than 90% of polyps detected at colonoscopy are small (6-9mm) or diminutive (≤5mm),
with the latter making up the majority (5-7). In addition, approximately 50% of small polyps
are non-neoplastic (8), known as adenomas. The number of adenomas present strongly
influences the future risk of the development of advance neoplasia for the individual
patient and therefore determines decisions on future surveillance intervals. As a result
even small polyps, with little risk of harbouring cancer, are currently sent for
histological assessment in order to determine whether or not they are adenomatous (9-11).

The ability to correctly diagnose a small polyp (< 10mm) during colonoscopy as adenomatous
or non-adenomatous from its endoscopic characteristics (optical diagnosis) would allow small
adenomas to be resected and discarded without the need to retrieve the polyp for formal
histological assessment. Additionally, hyperplastic rectosigmoid polyps can be left in situ
thereby reducing the need for polypectomy and the associated risks. Optical diagnosis would
also enable surveillance intervals to be determined immediately after colonoscopy thereby
avoiding the need for out-patient follow up, potentially leading to significant time and
cost savings. Notably, histological assessment is an imperfect current gold standard as
polyps may be lost or be unable to be assessed due to diathermy artefact in 8-25% of cases.
Furthermore, standard histological techniques may misclassify up to 15% of adenomas as
benign lesions.

Narrow band imaging (NBI; Olympus, Japan (12, 13)) is a new 'blue light' optical imaging
modality available at a push of a button on the colonoscope head. By enhancing mucosal
detail and in particular vascular structures it allows assessment of microvascular density
(vascular pattern intensity - VPI (14); meshed brown capillary network (15-17)). Neoplastic
tissue is characterized by increased angiogenesis and, therefore, adenomas appear darker
when viewed with NBI. The use of microvascular assessment appears to have a short learning
curve, as short as 60 histologically verified polyps (18-20), making it a potentially
attractive and practical option for optical diagnosis. There are no known adverse events
associated with NBI.

Two studies to date have assessed clinical implications of endoscopic diagnosis of small
polyps on surveillance intervals using white light in combination with NBI. A study of
diminutive polyps (≤5 mm) performed by a single expert colonoscopist (21), 134 out of 136
(98.5%) of patients would have had the same surveillance intervals when recommendations
based on optical and histological diagnoses were compared. Similar results were reported in
a study performed by three of the co-applicants (AI, JEE, BPS)(22) where 82 out of 130
patients could be given a surveillance interval immediately after colonoscopy based on
optical diagnosis alone and the same interval was found after formal histopathology in 80
patients (98%) using British Society of Gastroenterology guidelines (23). Optical diagnosis
accurately diagnosed 186 of 198 adenomas (sensitivity 0.94; 95% CI 0.90-0.97) and 55 of 62
hyperplastic polyps (specificity 0.89; 0.78 -0.95) with an overall accuracy of 241 of 260
(0.93; 0.89-0.96) for small polyp characterisation. In this study, using simple cost
analysis, the authors estimated that optical diagnosis would have resulted in 77% cost
savings for polyp analysis and clinical follow up (£13343 for 130 patients examined). Using
Markov modelling, Hassan et al modelled the cost-effectiveness of 'resect and discard
policy' and found that using it for diminutive polyps (≤5mm) would result in annual saving
of $33 million when applied to colonoscopy screening of the US population (corresponding to
overall saving of $330 million, assuming cumulative period of 10 years to screen just under
a quarter of US population) (24).

Optical diagnosis may therefore benefit:

1. Patients: Shorter, more accurate examinations with fewer complications as a results of
fewer polypectomies (less perforation and bleeding), reduced anxiety (awaiting
histology results) and more appropriate use of endoscopic surveillance programmes.

2. NHS and other Healthcare providers: Increased efficiency (shorter lists, more exams per
endoscopy list, fewer out-patient appointments, avoids unnecessary use of histology
capacity) and reduced risk (fewer complications and fewer polyp 'misses'). Since the
need for histology is set to greatly increase with an expansion of screening, a move to
the routine use of NBI may substantially reduce the need to expand histology services.

We foresee no significant constraints to adoption of optical diagnosis as financial costs
should be easily offset by savings from the efficiency benefits described above as 90% of
polyps detected at colonoscopy are <10mm in size and therefore suitable for optical biopsy.

Study Design DISCARD 2 is a blinded calibration diagnostic study which will compare NBI
optical diagnosis with histological assessment (as a reference standard) for patients with
small polyps (<10mm) identified at colonoscopy

Recruitment Patients who are due to attend for a routine colonoscopy will be identified
during out-patient clinics, during colonoscopy booking, or on the day of colonoscopy at each
of the participating sites. Patients will be sent or given an information pack containing an
information sheet and consent form. There will be two phases of recruitment to the study.
All consenting patients undergoing colonoscopy are included in phase 1 of the study. Those
who undergo a complete colonoscopy and in whom one or polyp <10mm in diameter is found will
enter phase 2 of the study.

More detail regarding inclusion and exclusion criteria and outcome measures are provided
below.