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446 High Definition White Light Endoscopy (Hdwle) Versus High Definition With Chromoendoscopy (Hdce) in the Detection of Dysplasia in Long Standing Ulcerative Colitis: a Randomized Controlled Trial
Abstracts
446 High Definition White Light Endoscopy (Hdwle) Versus High Definition With Chromoendoscopy (Hdce) in the Detection of Dysplasia in Long Standing Ulcerative Colitis: a Randomized Controlled Trial Noor Mohammed2,1, Prashant Kant1, Faisal Abid1, Olorunda Rotimi3, Padmini Prasad3, John P. Hamlin1, Simon Everett1, Bjorn Rembacken1, Mark A. Hull2,1, Venkat Subramanian*2,1 1 Gastroenterology, St James University Hospital, Leeds, United Kingdom; 2 Molecular Gastroenterolgy, Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, United Kingdom; 3Histopathology, St James University Hospital, Leeds, United Kingdom Background: Patients with ulcerative colitis (UC) have an increased risk for colorectal cancer (CRC) compared to the general population. The yield of surveillance can be improved by addition of newer endoscopic methods that enhance the detection of subtle mucosal abnormalities like chromoendoscopy (CE)1 and HDWLE when compared to standard definition endoscopy. CE however is still not widely adopted and no studies have compared HDCE and HDWLE. Aims: To compare the rate of detection of dysplasia in patients with long standing UC with HDWLE compared to high definition with CE (HDCE). Methods: Parallel group randomized controlled trial (clinicaltrials.gov number NCT02138318) in which patients with long standing (O10 years) extensive UC requiring surveillance colonoscopy were randomized to either HDWLE or HDCE (with 0.2% indigo carmine spray). HD scopes (Olympus CF260L or 290L) and processors (Olympus Spectrum CV260 or Elite CV290) and HD monitors were used for all procedures. Time to reach caecum and withdrawal time was recorded. Presence of dysplasia was confirmed by two expert GI histopathologists. Data was analysed according to the number of patients who had dysplastic endoscopic lesions detected (per patient analysis) and also to the number of dysplastic lesions (per lesion analysis). Results: In total 53 patients were randomized to HDWLE and 50 to the HDCE arm. Baseline characteristics including duration of disease, bowel preparation, endoscopists, concomitant PSC and previous dysplasia were similar in both arms. A total of 14 dysplastic lesions (1 with high grade and 13 with low grade dysplasia) were detected in 11 patients (22%) in the HDCE arm and 6 dysplastic lesions (all low grade dysplasia) in 5 patients (9.4%) in the HDWLE arm. HDCE was significantly better (pZ0.04) than HDWLE on a per patient basis for the detection of endoscopically visible dysplastic lesions. HDCE (0.260.6) detected more dysplastic lesions per-patient than HDWLE (0.120.4). Withdrawal time was significantly (p! 0.001) higher in HDCE (21.25.8 min) compared to HDWLE (13.63.3 min). Conclusions: HDCE significantly improves the detection of dysplastic lesions in patients with long standing UC undergoing surveillance endoscopy and should be the procedure of choice in these patients. On average it increases procedure time by 8 minutes over HDWLE.References1. Subramanian V et.al. Meta-analysis: the diagnostic yield of chromoendoscopy for detecting dysplasia in patients with colonic inflammatory bowel disease. Aliment Pharmacol Ther 2011;33:304-312.2. Subramanian V, et.al. High definition versus standard definition endoscopy for detection of dysplasia in colonic inflammatory bowel disease. Inflammatory Bowel Disease 2013;19:350-5
447 Effect of COX and EGFR Inhibition on Duodenal Neoplasia in Familial Adenomatous Polyposis: a Randomized PlaceboControlled Trial N. Jewel Samadder*1, Deborah Neklason1, Priyanka Kanth1, Kathryn R. Byrne1, Wade Samowitz1, Kory Jasperson1, Wendy Kohlmann1, Amanda Gammon1, Marjan Champine1, Deepika Nathan1, Kenneth M. Boucher1, Tom Greene1, Lisa Pappas1, John C. Fang1, John F. Valentine1, Curt Hagedorn1, David Jones1, Sean V. Tavtigian1, Michelle W. Done1, Therese Berry1, Laurel Smith1, Mikaela Larson1, Lindsey Martineau1, Danielle Sample1, Cristina Christenson1, Megan Keener1, Elena G. Strait2, Wendy Mckinnon3, Marc S. Greenblatt3, Patrick M. Lynch4, Randall W. Burt1, Scott K. Kuwada5,1 1 Huntsman Cancer Institute, Salt Lake City, UT; 2Penrose Hospital, Colorado Spring, CO; 3University of Vermont, Burlington, VT; 4MD Anderson Cancer Center, Houston, TX; 5University of Hawaii, Honolulu, HI Background: Familial adenomatous polyposis (FAP) is caused by mutations in the APC gene and is characterized by the development of hundreds of colorectal adenomas and eventually colorectal cancer. FAP patients are also at increased risk for duodenal neoplasia, with duodenal adenomas forming in O50% and up to a 15% lifetime risk of duodenal carcinoma. Multiple studies have shown that sulindac inhibits colorectal adenomas in FAP patients, however, they have failed to show significant reduction in duodenal adenomas. Preclinical data has shown that the combination of COX and EGFR inhibition diminished small intestinal adenoma development by 87% in mice with germline Apc mutations. Aim: These results led us to test the hypothesis that a combination of COX and EGFR inhibition (sulindac and erlotinib) would inhibit duodenal adenoma formation in patients with FAP. Methods:
AB148 GASTROINTESTINAL ENDOSCOPY Volume 81, No. 5S : 2015
We conducted a double blind, randomized, placebo-controlled trial in which FAP patients received combination therapy with 150mg sulindac twice per day and 75mg erlotinib daily or placebo tablets for 6 months. The total number and size of polyps in a segment of duodenum between 0 and 10cm from the bulb were mapped at baseline and 6 months. The primary outcome was change in total polyp burden, calculated as the sum of the diameters of polyps, following six months of treatment. A sample size of 100 patients was estimated to provide 95% power to detect a 30% reduction with treatment. Results: 92 patients had been recruited and randomized when the study was stopped early because statistical guidelines for an early halt were met. 72 randomized patients completed the study and were included in the analysis; 36 patients received sulindac/erlotinib and 36 placebo. Demographic characteristics between the treatment and placebo groups were comparable (Table 1). The major side effects were rash and diarrhea with none exceeding grade 2. The total duodenal polyp burden, defined as the sum of the diameters of polyps, was significantly different between the placebo and sulindac-erlotinib group at 6 months (PZ1 X 10-9), with a 27% increase from baseline in the placebo group and a 40% decrease from baseline in the sulindac-erlotinib group (Table 1 and Figure 1). The total duodenal polyp count showed a similar statistically significant difference between the groups (P!0.0001), with the placebo group having a 10% increase and the therapy group a 20% decrease in total polyp count from baseline. Discussion: In this double-blind, placebo controlled, randomized trial we showed that combination COX and EGFR inhibition with sulindac and erlotinib effectively reduced duodenal polyp burden and polyp number in patients with FAP, as compared to placebo. This effect was evident after only 6 months of therapy. The effect was efficacious in both FAP and AFAP patients, including those with a wide range in polyp numbers. Table 1. Demographic Characteristics of Subjects and Primary
Outcome Characteristic
Sulindac-Erlotinib Group (n[36)
Mean Age - years (SD) 41 (14) Sex - number (%) Male 13 (36%) Female 23 (64%) Height - cm (SD) 169 (10) Weight - kg (SD) 82 (24) Smoking - number (%) Yes 3 (8%) No 33 (92%) Alcohol - number (%) Yes 16 (44%) No 20 (56%) FAP Status Classic FAP 23 (64%) Attenuated FAP 13 (36%) Treatment Group vs Placebo Group Primary Outcome Data Sulindac-Erlotinib Duodenal Polyp Burden Group - Median (sum of diameters, mm) (quartiles) Base-line (month 0) 20 (12, 54) End-point (month 6) 15 (5, 26) Change in polyp burden -8.5 (-17.5, -2.0)
Placebo Group (n[36) 42 (13) 16 (44%) 22 (56%) 169 (10) 90 (25) 8 (22%) 28 (78%) 17 (47%) 19 (53%) 26 (72%) 10 (28%)
Placebo Group Median (quartiles) 22 (12, 44) 28 (15, 80) 6.0 (0, 26.8)
P*
!0.0001
*Two sided Wilcoxon-Mann-Whitney test to compare change in duodenal polyp burden
Figure 1. Waterfall plot of change in duodenal polyp burden from baseline
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446 High Definition White Light Endoscopy (Hdwle) Versus High Definition With Chromoendoscopy (Hdce) in the Detection of Dysplasia in Long Standing Ulcerative Colitis: a Randomized Controlled Trial Noor Mohammed2,1, Prashant Kant1, Faisal Abid1, Olorunda Rotimi3, Padmini Prasad3, John P. Hamlin1, Simon Everett1, Bjorn Rembacken1, Mark A. Hull2,1, Venkat Subramanian*2,1 1 Gastroenterology, St James University Hospital, Leeds, United Kingdom; 2 Molecular Gastroenterolgy, Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, United Kingdom; 3Histopathology, St James University Hospital, Leeds, United Kingdom Background: Patients with ulcerative colitis (UC) have an increased risk for colorectal cancer (CRC) compared to the general population. The yield of surveillance can be improved by addition of newer endoscopic methods that enhance the detection of subtle mucosal abnormalities like chromoendoscopy (CE)1 and HDWLE when compared to standard definition endoscopy. CE however is still not widely adopted and no studies have compared HDCE and HDWLE. Aims: To compare the rate of detection of dysplasia in patients with long standing UC with HDWLE compared to high definition with CE (HDCE). Methods: Parallel group randomized controlled trial (clinicaltrials.gov number NCT02138318) in which patients with long standing (O10 years) extensive UC requiring surveillance colonoscopy were randomized to either HDWLE or HDCE (with 0.2% indigo carmine spray). HD scopes (Olympus CF260L or 290L) and processors (Olympus Spectrum CV260 or Elite CV290) and HD monitors were used for all procedures. Time to reach caecum and withdrawal time was recorded. Presence of dysplasia was confirmed by two expert GI histopathologists. Data was analysed according to the number of patients who had dysplastic endoscopic lesions detected (per patient analysis) and also to the number of dysplastic lesions (per lesion analysis). Results: In total 53 patients were randomized to HDWLE and 50 to the HDCE arm. Baseline characteristics including duration of disease, bowel preparation, endoscopists, concomitant PSC and previous dysplasia were similar in both arms. A total of 14 dysplastic lesions (1 with high grade and 13 with low grade dysplasia) were detected in 11 patients (22%) in the HDCE arm and 6 dysplastic lesions (all low grade dysplasia) in 5 patients (9.4%) in the HDWLE arm. HDCE was significantly better (pZ0.04) than HDWLE on a per patient basis for the detection of endoscopically visible dysplastic lesions. HDCE (0.260.6) detected more dysplastic lesions per-patient than HDWLE (0.120.4). Withdrawal time was significantly (p! 0.001) higher in HDCE (21.25.8 min) compared to HDWLE (13.63.3 min). Conclusions: HDCE significantly improves the detection of dysplastic lesions in patients with long standing UC undergoing surveillance endoscopy and should be the procedure of choice in these patients. On average it increases procedure time by 8 minutes over HDWLE.References1. Subramanian V et.al. Meta-analysis: the diagnostic yield of chromoendoscopy for detecting dysplasia in patients with colonic inflammatory bowel disease. Aliment Pharmacol Ther 2011;33:304-312.2. Subramanian V, et.al. High definition versus standard definition endoscopy for detection of dysplasia in colonic inflammatory bowel disease. Inflammatory Bowel Disease 2013;19:350-5
447 Effect of COX and EGFR Inhibition on Duodenal Neoplasia in Familial Adenomatous Polyposis: a Randomized PlaceboControlled Trial N. Jewel Samadder*1, Deborah Neklason1, Priyanka Kanth1, Kathryn R. Byrne1, Wade Samowitz1, Kory Jasperson1, Wendy Kohlmann1, Amanda Gammon1, Marjan Champine1, Deepika Nathan1, Kenneth M. Boucher1, Tom Greene1, Lisa Pappas1, John C. Fang1, John F. Valentine1, Curt Hagedorn1, David Jones1, Sean V. Tavtigian1, Michelle W. Done1, Therese Berry1, Laurel Smith1, Mikaela Larson1, Lindsey Martineau1, Danielle Sample1, Cristina Christenson1, Megan Keener1, Elena G. Strait2, Wendy Mckinnon3, Marc S. Greenblatt3, Patrick M. Lynch4, Randall W. Burt1, Scott K. Kuwada5,1 1 Huntsman Cancer Institute, Salt Lake City, UT; 2Penrose Hospital, Colorado Spring, CO; 3University of Vermont, Burlington, VT; 4MD Anderson Cancer Center, Houston, TX; 5University of Hawaii, Honolulu, HI Background: Familial adenomatous polyposis (FAP) is caused by mutations in the APC gene and is characterized by the development of hundreds of colorectal adenomas and eventually colorectal cancer. FAP patients are also at increased risk for duodenal neoplasia, with duodenal adenomas forming in O50% and up to a 15% lifetime risk of duodenal carcinoma. Multiple studies have shown that sulindac inhibits colorectal adenomas in FAP patients, however, they have failed to show significant reduction in duodenal adenomas. Preclinical data has shown that the combination of COX and EGFR inhibition diminished small intestinal adenoma development by 87% in mice with germline Apc mutations. Aim: These results led us to test the hypothesis that a combination of COX and EGFR inhibition (sulindac and erlotinib) would inhibit duodenal adenoma formation in patients with FAP. Methods:
AB148 GASTROINTESTINAL ENDOSCOPY Volume 81, No. 5S : 2015
We conducted a double blind, randomized, placebo-controlled trial in which FAP patients received combination therapy with 150mg sulindac twice per day and 75mg erlotinib daily or placebo tablets for 6 months. The total number and size of polyps in a segment of duodenum between 0 and 10cm from the bulb were mapped at baseline and 6 months. The primary outcome was change in total polyp burden, calculated as the sum of the diameters of polyps, following six months of treatment. A sample size of 100 patients was estimated to provide 95% power to detect a 30% reduction with treatment. Results: 92 patients had been recruited and randomized when the study was stopped early because statistical guidelines for an early halt were met. 72 randomized patients completed the study and were included in the analysis; 36 patients received sulindac/erlotinib and 36 placebo. Demographic characteristics between the treatment and placebo groups were comparable (Table 1). The major side effects were rash and diarrhea with none exceeding grade 2. The total duodenal polyp burden, defined as the sum of the diameters of polyps, was significantly different between the placebo and sulindac-erlotinib group at 6 months (PZ1 X 10-9), with a 27% increase from baseline in the placebo group and a 40% decrease from baseline in the sulindac-erlotinib group (Table 1 and Figure 1). The total duodenal polyp count showed a similar statistically significant difference between the groups (P!0.0001), with the placebo group having a 10% increase and the therapy group a 20% decrease in total polyp count from baseline. Discussion: In this double-blind, placebo controlled, randomized trial we showed that combination COX and EGFR inhibition with sulindac and erlotinib effectively reduced duodenal polyp burden and polyp number in patients with FAP, as compared to placebo. This effect was evident after only 6 months of therapy. The effect was efficacious in both FAP and AFAP patients, including those with a wide range in polyp numbers. Table 1. Demographic Characteristics of Subjects and Primary
Outcome Characteristic
Sulindac-Erlotinib Group (n[36)
Mean Age - years (SD) 41 (14) Sex - number (%) Male 13 (36%) Female 23 (64%) Height - cm (SD) 169 (10) Weight - kg (SD) 82 (24) Smoking - number (%) Yes 3 (8%) No 33 (92%) Alcohol - number (%) Yes 16 (44%) No 20 (56%) FAP Status Classic FAP 23 (64%) Attenuated FAP 13 (36%) Treatment Group vs Placebo Group Primary Outcome Data Sulindac-Erlotinib Duodenal Polyp Burden Group - Median (sum of diameters, mm) (quartiles) Base-line (month 0) 20 (12, 54) End-point (month 6) 15 (5, 26) Change in polyp burden -8.5 (-17.5, -2.0)
Placebo Group (n[36) 42 (13) 16 (44%) 22 (56%) 169 (10) 90 (25) 8 (22%) 28 (78%) 17 (47%) 19 (53%) 26 (72%) 10 (28%)
Placebo Group Median (quartiles) 22 (12, 44) 28 (15, 80) 6.0 (0, 26.8)
P*
!0.0001
*Two sided Wilcoxon-Mann-Whitney test to compare change in duodenal polyp burden
Figure 1. Waterfall plot of change in duodenal polyp burden from baseline
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