Introduction

Different random biopsy techniques exist for Barrett Esophagus (BE) surveillance, of which the impact on histopathological quality is unclear. Therefore, we compared the double-biopsy (DB) versus single-biopsy (SB) method, and advance-and-close (A&C) versus turn-and-suction (T&S) technique in a multidesign study.

Aims & Methods

In a multicenter, factorial design trial, BE patients were randomly assigned to one of two biopsy methods (DB or SB) and techniques (A&C or T&S) in a 1:1:1:1 approach, stratified by BE length and hospital. Endpoints were biopsy size, defined as surface area in mm², and time required to obtain biopsies. Assessment of biopsy size was done in a blinded fashion. Data was analyzed with mixed effects regression analyses with a random intercept per patient including stratification factors as fixed effects. We assumed no interaction between the co-primary comparisons.
In a subsequent before-after study, the optimal biopsy method and technique found in the factorial trial was implemented in routine clinical practice. Biopsies before and after implementation were analyzed on biopsy size, using mixed effects regression analyses with a random intercept per patient including BE length as fixed effect.

Results

Table 1: Biopsy size in mm2 per biopsy method and technique (95% CI).	Double-biopsy (DB)	Single-biopsy (SB)
Advance-and-close (A&C)	2.77 (2.44-3.09)	3.14 (2.81-3.46)
Turn-and-suction (T&S)	2.61 (2.29-2.93)	3.54 (3.22-3.86)

In the factorial trial, 107 patients were randomized and 1024 biopsies were assessed. Mean biopsy size for each randomization arm, that is, DB+A&C, DB+T&S, SB+A&C, SB+T&C was 2.77mm² (95%CI 2.44-3.09), 2.61 mm² (95%CI 2.29-2.93), 3.14 mm² (95%CI 2.81-3.46) and 3.54 mm² (95%CI 3.22-3.86), respectively (Table 1). Biopsy size increased with 25% from 2.68mm² (95%CI 2.45-2.92) with the DB method to 3.34mm² (95%CI 3.10-3.57) with the SB method (mean difference 0.65mm², [95% CI 0.34-0.97]; p<0.001). In contrast, average biopsy sizes were 2.95mm² (95% CI 2.72-3.19) and 3.08mm² (95%CI 2.85-3.31) using the A&C and T&S, respectively, translating into an increase of 4% using the T&S technique (mean difference 0.13mm², [95%CI -0.19-0.44]; p=0.44). The interaction term between the co-primary comparisons was not statistically significant (p=0.08).
Time required to obtain biopsies was comparable for biopsies obtained with the DB method and SB method (mean difference 2 seconds per biopsy, [95%CI -1-4]; p=0.26), while biopsy time was significantly longer when biopsies were taken with the T&S technique compared to the A&C technique (mean difference 7 seconds per biopsy, [95%CI 4-10]; p<0.001).
A total of 46 patients (288 biopsies) and 44 patients (256 biopsies) were included before and after implementation of the SB method and the T&S technique, respectively. Before implementation, 93/288 biopsies (32%) were obtained with the A&C technique and 163/288 biopsies (57%) were taken with the DB method. Mean biopsy size increased with 18% from 3.31mm² (95%CI 2.95-3.68) to 3.90mm² (95%CI 3.50-4.29) after implementation of the SB method and T&S technique (mean difference 0.58mm² (95%CI 0.07-1.09); p=0.03). Mean biopsy size did not significantly increase when comparing biopsies before and after implementation (n=117 versus n=97) which were obtained by endoscopists already using the SB method and T&S technique before implementation (3.72mm² [95%CI 2.95-4.48] versus 3.79mm² [95%CI 2.97-4.62], mean difference 0.08mm² [95%CI -0.93-1.08]; p=0.88).

Conclusion

Biopsies in BE patients should be taken with the SB method to increase biopsy size. Implementation of SB-T&S in routine clinical practice resulted in significantly larger biopsies.

Disclosure

B.L.A.M. Weusten is a consultant for Pentax Medical, has received speaker’s fee from Pentax Medical and has received research funding from Aqua Medical and Pentax Medical. The remaining authors declare that there is no conflict of interest.

Introduction

State of the art Barrett’s esophagus (BE) surveillance while-light endoscopy (WLE) is challenged by low detection rates due to the poor contrast offered by early neoplastic lesions. To improve detection, random biopsies are taken according to the Seattle protocol, however this comes with high sampling errors. ^1–4

Aims & Methods

With this phase II study we aim to validate the improvement in lesion detection seen in the phase I study, as well as compare bevacizumab-800CW with another targeted tracer, cetuximab-800CW, as well as an untargeted fluorescent dye, indocyanine green (ICG).
In a Phase II clinical study of 60 BE patients, fluorescence molecular imaging with topical administration of the fluorescent tracer bevacizumab-800CW targeting vascular endothelial growth factor A (VEGF) was evaluated for the detection of dysplasia and early-stage esophageal adenocarcinoma (EAC). Furthermore, we compared bevacizumab-800CW head-to-head with cetuximab-800CW, targeting epidermal growth factor receptor (EGFR), and a non-targeting fluorescent dye, ICG, in groups of 10 patients. Patients underwent a normal endoscopy procedure, in addition the tracers were topically administered and after 5-minute incubation time, fluorescent imaging was done. Target to background ratios (TBR) of both tracers and ICG were calculated by selecting regions of interest (ROI) for EC lesion and background and measuring fluorescent intensity in these RIOs.

Results

We found that FME with bevacizumab-800CW improved real-time dysplastic esophageal lesion detection by a tremendous 112% (70 vs. 33 lesions) compared to the referring general endoscopists and 27% (70 vs. 55 lesions) compared to an expert BE endoscopist. Compared to the fluorescent tracer cetuximab-800CW and fluorescent dye ICG, bevacizumab-800CW showed superior detection ability in each paired 10 patients. Bevacizumab-800CW showed TBR superiority over cetuximab-800CW (median TBR 3.39 versus 2.68 (p=0.0214) and ICG (median TBR 3.72 versus 1.15 (p<0.0001)).

Conclusion

Real-time early EAC and dysplasia detection can be improved by 27% for BE expert endoscopist and by 112% for general endoscopists by using fluorescence endoscopy in combination with bevacizumab-800CW. Bevacizumab-800CW is a superior tracer compared to cetuximab-800CW and compared to an untargeted fluorescent dye, ICG. Furthermore, we show how, besides the obvious and critical improvement of early esophageal cancer detection, FME couldimprove standardizing the quality of BE surveillance endoscopy by enabling community endoscopists to perform similarly to Barrett experts.

References

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2. Spechler SJ, Fitzgerald RC, Prasad GA, Wang KK. History, Molecular Mechanisms, and Endoscopic Treatment of Barrett’s Esophagus. Gastroenterology. 2010;138(3):854. doi:10.1053/J.GASTRO.2010.01.002
3. Fitzgerald RC, Di Pietro M, Ragunath K, et al. British Society of Gastroenterology guidelines on the diagnosis and management of Barrett’s oesophagus. Gut. 2014;63(1):7-42. doi:10.1136/GUTJNL-2013-305372
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