- Email: [email protected]
Likelihood of missed and recurrent adenomas in the proximal versus the distal colon
ORIGINAL ARTICLE: Clinical Endoscopy
Likelihood of missed and recurrent adenomas in the proximal versus the distal colon Adeyinka O. Laiyemo, MD, MPH, Chyke Doubeni, MD, MPH, Andrew K. Sanderson II, MD, Paul F. Pinsky, PhD, Dilhana S. Badurdeen, MD, V. Paul Doria-Rose, DVM, PhD, Pamela M. Marcus, PhD, Robert E. Schoen, MD, MPH, Elaine Lanza, PhD, Arthur Schatzkin, MD, DrPH, Amanda J. Cross, PhD Washington, DC; Bethesda, Maryland; Worcester, Massachusetts; Pittsburgh, Pennsylvania, USA
Background: Colonoscopy may be less efficacious in reducing colorectal cancer mortality in the proximal compared with the distal colon. A greater likelihood for missed and recurrent adenomas in the proximal colon may contribute to this phenomenon. Objective: To examine whether a proximal adenoma is associated with the risk and location of missed and recurrent adenomas. Design: Prospective. Setting: Polyp Prevention Trial. Participants: A total of 1864 patients with an adenoma at baseline underwent a follow-up colonoscopy 4 years later (adenoma recurrence). Of these, 1731 underwent a clearing colonoscopy 1 year after the baseline examination (missed adenoma). Main Outcome Measurements: Association of baseline adenoma location with the risk and location of adenomas found at colonoscopy performed 1 year and 4 years later. Results: At the year 1 colonoscopy, 598 patients (34.6%) had an adenoma (missed adenoma). Compared with those with a distal-only adenoma at baseline, patients with a proximal-only adenoma at baseline were more likely to have any missed adenomas (relative risk [RR] 1.28; 95% CI, 1.09-1.49) and a proximal-only missed adenoma (RR 2.05; 95% CI, 1.49-2.80). At the year 4 colonoscopy, 733 patients (39.3%) had adenoma recurrence. Patients with a baseline proximal-only adenoma were more likely to have any adenoma recurrence (RR 1.14; 95% CI, 1.00-1.31) and a proximal-only adenoma recurrence (RR 1.52; 95% CI, 1.15-2.02). Sensitivity analyses involving missed adenomas did not materially affect the risk or location of recurrent adenomas at year 4 colonoscopy. Limitation: Lesions may still be missed on repeated colonoscopies. Conclusions: Missed and recurrent adenomas are more likely to be in the proximal colon. (Gastrointest Endosc 2011;74:253-61.)
Abbreviations: PPT, Polyp Prevention Trial; RR, relative risk. DISCLOSURE: The following authors disclosed financial relationships relevant to this publication: Dr. Laiyemo is supported by the National Cancer Institute’s new faculty recruitment supplement to the Comprehensive Minority Institution/Cancer Center Partnership between Howard University Cancer Center and Sidney Kimmel Comprehensive Cancer Center of Johns Hopkins University (5U54CA091431-09 S1). Dr. Doubeni is supported by a mentored career development award (5K01CA12711803) from the National Cancer Institute. This research was funded by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. The other authors disclosed no financial relationships relevant to this publication.
(A.O.L., P.M.M.), Early Detection Research Group (P.F.P.), Division of Cancer Prevention, Health Services and Economics Branch (V.P.D.R.), Division of Cancer Control and Population Sciences, Laboratory of Cancer Prevention (E.L.), Center for Cancer Research, Nutritional Epidemiology Branch (A.S., A.J.C.), Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, Department of Family Medicine (C.D.), University of Massachusetts, Worcester, Massachusetts, Department of Medicine and Epidemiology (R.E.S.), University of Pittsburgh, Pittsburgh, Pennsylvania. Presented in abstract form as an oral presentation at the Digestive Diseases Week, June 1, 2009, Chicago, Illinois (Gastrointest Endosc 2009;69:AB108).
Copyright © 2011 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2011.02.023
Reprint requests: Adeyinka O. Laiyemo, MD, MPH, Division of Gastroenterology, Department of Medicine, Howard University College of Medicine, 2041 Georgia Avenue, NW, Washington, DC 20060.
Received December 16, 2010. Accepted February 25, 2011.
If you would like to chat with an author of this article, you may contact Dr. Laiyemo at [email protected].
Current affiliations: Department of Medicine (A.O.L., A.K.S., D.S.B.), Howard University College of Medicine, Washington, DC, Biometry Research Group
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Missed and recurrent adenoma location
Although 3 randomized, controlled trials of the effect of screening sigmoidoscopy on colorectal cancer mortality are still ongoing,1-3 case-control studies4,5 and 1 randomized, controlled trial6 have demonstrated a reduction in mortality from colon cancer with sigmoidoscopy. This effect is limited to the distal colon, presumably because sigmoidoscopy does not examine the proximal colon. The use of colonoscopy as a colorectal cancer screening modality has been increasing7,8 and was expected to confer benefit in both the distal and proximal colon. However, population-based studies in Canada suggest limited efficacy of colonoscopy in reducing proximal colon cancer incidence9,10 and mortality.11,12 In the United States, Kahi et al13 reported an overall reduction in the incidence of colon cancer in a postpolypectomy cohort compared with Surveillance Epidemiology and End Results (SEER) data, but 5 of the 6 colon cancers diagnosed after colonoscopy were located in the proximal colon. Furthermore, a study from Germany found a reduction in advanced adenoma recurrence in the distal but not in the proximal colon with history of undergoing colonoscopy.14 Although a recent population-based case-control study found an overall 77% reduced risk of colorectal cancer with previous exposure to colonoscopy, the protection conferred by colonoscopy in the proximal colon was only two thirds of the protection in the distal colon (56% vs 84%).15 Although none of the aforementioned studies was a randomized, controlled trial of screening colonoscopy, the consistent pattern of lower benefit of colonoscopy in the proximal colon compared with the distal colon is compelling, albeit not definitive. Although factors such as the quality of the baseline colonoscopy, bowel preparation, endoscopists’ skills, lack of adequate detection of flat, depressed lesions, and missed lesions16,17 may contribute to these findings, it is also possible that the biology of colon cancer differs by tumor location. We proposed that if patients are more likely to have missed adenomas in the proximal colon or more likely to have a proximal adenoma recurrence or if patients with a proximal adenoma are at a higher risk of recurrence in the proximal colon than patients with distal adenomas, then colonoscopy might be less efficacious in the proximal compared with the distal colon. The aim of this investigation was to examine whether a proximal adenoma is associated with the risk and the location of missed and recurrent adenoma using the comprehensive information on adenoma location during colonoscopies performed in participants in the Polyp Prevention Trial (PPT).
METHODS Study population The rationale, design, and results of the PPT were published previously.18-20 In brief, the PPT was a 4-year multicenter, randomized, controlled trial to assess the effect of a low-fat, high-fiber, fruit and vegetable diet on the 254 GASTROINTESTINAL ENDOSCOPY Volume 74, No. 2 : 2011
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Take-home Message ●
Missed lesions tend to occur in the proximal colon, and there is also an increased tendency for adenoma recurrence in the proximal colon. This may contribute to the explanation of why colonoscopy is not as effective in the proximal colon compared with the distal colon.
risk of colorectal adenoma recurrence. A total of 2079 participants who were at least 35 years old and had 1 or more histologically confirmed adenomatous polyps removed within 6 months from a complete colonoscopy were randomized. Exclusion criteria included history of surgical resection of adenomatous polyps, bowel resection, colorectal carcinoma, polyposis syndrome, inflammatory bowel disease, use of any lipid-lowering medications, and body weight more than 150% of the ideal. The clinical trial was approved by the Institutional Review Boards of the National Cancer Institute, and each of the 8 participating clinical centers. All participants gave written informed consent.
Exposure and outcome assessment At baseline, information on the subjects’ demographic characteristics, health-related lifestyle, dietary supplements intake, and medication use was obtained from every participant through direct interview. Per PPT protocol, the participants were scheduled to undergo a clearing colonoscopy approximately 1 year after randomization (T1) to remove any lesion that may have been missed at qualifying colonoscopy (T0). This clearing colonoscopy was completed by 1768 participants. All participants were followed for approximately 4 years after randomization and had an end-of-trial (T4) colonoscopy to ascertain adenoma recurrence. A total of 1905 participants (91.6%) completed the trial by undergoing the T4 colonoscopy. The dietary intervention did not affect adenoma recurrence.20 Forty-one participants had missing information on the location of their baseline adenoma and were excluded from the current analysis. Therefore, our analytic cohort comprises 1864 participants, of whom 1731 (92.9%) underwent a clearing colonoscopy to remove missed lesions 1 year after random assignment. The colonoscopy reports provided information on size, number, and location of polyps. The location of adenomas removed from the rectum to the splenic flexure was defined as distal, whereas proximal location included transverse colon to the cecum. The histology and degree of dysplasia were confirmed by 2 trial pathologists who were masked to the participants’ randomization assignments.18 Advanced adenomas were defined as those 1 cm or more in diameter or with villous histology or high-grade dysplasia.21 www.giejournal.org
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Statistical analyses We estimated the relative risk (RR) and 95% confidence interval by using Poisson regression to evaluate the association between baseline adenoma location and missed adenoma detected at year 1 colonoscopy and adenoma recurrence at year 4 colonoscopy. We used multinomial regression analyses to evaluate the association of baseline adenoma location with missed adenoma location at year 1 colonoscopy and at adenoma recurrence 4 years after randomization as our primary analysis. For baseline adenoma location (exposure), we categorized participants by the location of their adenoma into 3 mutually exclusive groups: those with a distal-only adenoma, those with a proximal-only adenoma, and those with a synchronous proximal and distal adenoma. For any missed adenomas (outcome) and any recurrent adenomas (outcome), we classified the adenomas into 4 mutually exclusive groups according to the findings at the T1 or T4 colonoscopy: those without any adenomas (comparison group), those with a distal-only adenoma, those with a proximal-only adenoma, and those with a synchronous proximal and distal adenoma. We did a similar categorization for advanced adenomas, but there were few participants with a synchronous proximal and distal advanced adenoma. Therefore, those with any missed or recurrent proximal advanced adenomas were included in 1 category for some analyses. Sensitivity analyses on reclassifying advanced adenomas that were found after baseline examination in both locations with distal-only advanced adenomas did not change our findings (data not shown). To evaluate the effect of missed lesions on the risk and location of adenoma recurrence at T4, we reanalyzed our data to include adenomas found at the T1 clearing colonoscopy. Of 1731 participants who underwent T1 colonoscopy, we could not identify the specific location of the adenoma found in 1 participant. Therefore, we excluded this individual in the sensitivity analysis involving T1 colonoscopy. At first, we combined T1 and T4 colonoscopy findings in an analysis on the premise that if T1 colonoscopy had not been performed, the lesions would have been found at T4 as recurrent lesions. We then restricted our cohort to only participants who underwent T1 colonoscopy and added the T1 colonoscopy– detected lesions to the baseline findings and repeated our analysis. For the multivariate models, we adjusted for age (continuous), sex, body mass index (continuous), family history of colorectal cancer in a first-degree relative (yes vs no), use of nonsteroidal anti-inflammatory drugs at least once per month (yes vs no), and the number of adenomas at baseline (continuous). We used Stata statistical software version 9 (StataCorp, College Station, Tex) for all analyses. All reported P values correspond to 2-sided tests. www.giejournal.org
Missed and recurrent adenoma location
RESULTS Baseline characteristics Table 1 shows selected baseline characteristics of study participants by the location of the baseline adenoma. At baseline, 1030 participants (55.3%) had a distal-only adenoma, 503 (27%) had a proximal-only adenoma, and 331 (17.8%) had a synchronous proximal and distal adenoma. A total of 750 patients (37.8%) had an advanced adenoma at baseline: 440 participants (62.4%) had a distal-only advanced adenoma, 111 (15.7%) had a proximal-only advanced adenoma, and 154 (21.8%) had a synchronous proximal and distal advanced adenoma. The mean age of the participants was 61.1 years. The distribution of age, sex, body mass index, family history of colon cancer, and number of adenomas at baseline varied significantly (P ⬍ .05) by baseline adenoma location.
Clearing (T1) colonoscopy for missed lesions Participants who did not undergo clearing (T1) colonoscopy (n ⫽ 133) were comparable to those who did (n ⫽ 1731) except that those who did not were slightly younger (mean age 59.3 years vs 61.2 years; P ⫽ .04) and were more likely to be current smokers (23.3% vs 12.4%; P ⫽ .001). Of those with complete T1 colonoscopy information (n ⫽ 1730), 598 patients (34.6%) had an adenoma at T1 colonoscopy: distal only (n ⫽ 209, 34.9%), proximal only (n ⫽ 284, 47.5%), and synchronous proximal and distal adenoma (n ⫽ 105, 17.6%) (Table 2). When compared with patients with a distal-only adenoma at baseline, patients with a proximal-only adenoma at baseline were more likely to have a missed adenoma (ie, any adenomas found at T1 colonoscopy) (RR 1.28; 95% CI, 1.09-1.49) and a proximal- only missed adenoma (RR 2.05; 95% CI, 1.492.80). A total of 102 patients (5.9%) had an advanced adenoma at T1 colonoscopy, of whom 63 (61.8%) had an advanced adenoma at baseline (T0). Participants with a proximal-only adenoma at baseline (T0) were also more likely to have any missed advanced adenomas (RR 1.79; 95% CI, 1.17-2.75) and any proximal missed advanced adenomas (RR 3.34; 95% CI, 1.75-6.39) (Table 3).
Adenoma recurrence by location For the main analysis assessing the risk and location of recurrent adenomas at T4 colonoscopy, 733 (39.3%) participants had adenoma recurrence, whereas 1131 (60.7%) had no adenoma recurrence. Among those with distalonly, proximal-only, and synchronous proximal and distal adenomas at baseline, recurrence rates were 33.4%, 41.9%, and 53.8%, respectively. Among participants with adenoma recurrence, 228 (31.1%) had distal only, 369 (50.3%) had proximal only, and 136 (18.6%) had synchronous proximal and distal adenoma recurrence, indicating a relative decrease in the percentage of patients with distalonly adenomas at recurrence (55.3% at baseline vs 31.1% at T4), an increase in the percentage of patients with Volume 74, No. 2 : 2011 GASTROINTESTINAL ENDOSCOPY 255
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Table 1. Selected characteristics of the participants at baseline Adenoma location at baseline, no. (%) Distal only (n ⴝ 1030)
Proximal only (n ⴝ 503)
Synchronous proximal and distal (n ⴝ 331)
⬍55
300 (29.1)
112 (22.3)
68 (20.5)
55-59
174 (16.9)
63 (12.5)
49 (14.8)
60-64
182 (17.7)
98 (19.5)
58 (17.5)
65-69
171 (16.6)
96 (18.1)
76 (23.0)
ⱖ70
203 (19.7)
139 (27.7)
80 (24.2)
Male
621 (60.3)
333 (66.2)
245 (74.0)
Female
409 (39.7)
170 (33.8)
86 (26.0)
White
927 (90.0)
447 (88.9)
294 (88.8)
Black
74 (7.2)
50 (9.9)
29 (8.8)
Other*
29 (2.8)
6 (1.2)
8 (2.4)
⬍25
307 (29.8)
117 (23.3)
70 (21.2)
25-29
464 (45.1)
240 (47.7)
172 (52.0)
ⱖ30
259 (25.2)
146 (29.0)
89 (26.9)
Positive family history of colon cancer
262 (25.4)
159 (31.6)
83 (25.1)
.026
Uses NSAIDs at least once per month
362 (35.2)
150 (29.8)
116 (35.1)
.099
1-2
984 (95.5)
454 (90.3)
151 (45.6)
⬍.001
ⱖ3
46 (4.5)
49 (9.7)
180 (54.4)
Baseline characteristics
P value
Age, y
⬍.001
Sex
⬍.001
Race
.125
BMI, kg/m2, no. (%)
.006
No. of adenomas
BMI, Body mass index; NSAIDs, nonsteroidal anti-inflammatory drugs. *Hispanics, Asians, and Native Americans
proximal only at recurrence (27.0% at baseline vs 50.3% at T4), but a similar percentage of patients with synchronous proximal and distal adenomas at baseline and recurrence (17.8% at baseline vs 18.6% at T4) (Table 4). Compared with those with distal-only adenomas at baseline, the risk of adenoma recurrence was higher for those with proximal-only adenomas at baseline (RR 1.14; 95% CI, 1.00-1.31) and for those with synchronous proximal and distal adenomas at baseline (RR 1.20; 95% CI, 1.03-1.40) (Table 4). Proximal only adenoma at baseline was positively associated with proximal-only adenoma recurrence (RR 1.52; 95% CI, 1.15-2.02), but inversely associated with distal only adenoma recurrence (RR 0.67; 95% CI, 0.46-0.97). Combining the T1 results with the T4 results and considering the combination as the recurrence outcome in256 GASTROINTESTINAL ENDOSCOPY Volume 74, No. 2 : 2011
creased the overall adenoma recurrence rate from 39.3% to 54.4%. Although this changed the distribution of recurrent adenoma location by slightly decreasing distal-only and proximal-only adenoma recurrence and increasing synchronous proximal and distal adenoma recurrence, the risk of adenoma recurrence by location was similar (Table 4). Combining the T1 results with the T0 results and considering the combination as baseline increased the synchronous proximal and distal adenoma percentage from 17.8% to 30.3%, but again did not materially change the associations with risk or location of adenoma recurrence (Table 4). Of note, we observed a similar pattern among participants who did not undergo T1 colonoscopy (n ⫽ 133). Forty-eight participants had an adenoma at the end-of-trial colonoscopy (36.1%). Distal-only adenomas decreased www.giejournal.org
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Missed and recurrent adenoma location
Table 2. Risk and location of missed adenoma detected at T1 colonoscopy by baseline adenoma location
Adenoma distribution, no. (%)
Proximal-only missed adenomas, RR (95% CI)
Synchronous proximal and distal missed adenomas, RR (95% CI)
Baseline (T0) (n ⴝ 1730)
Missed (T1) (n ⴝ 598)
Any missed adenomas, RR (95% CI)
Distal-only missed adenomas, RR (95% CI)
Distal only
955 (55.2)
209 (34.9)
Reference
Reference
Reference
Reference
Proximal only
466 (26.9)
284 (47.5)
1.28 (1.09-1.49)
0.97 (0.67-1.39)
2.05 (1.49-2.80)
1.17 (0.69-2.01)
Synchronous proximal and distal
309 (17.9)
105 (17.6)
1.50 (1.26-1.79)
1.62 (0.98-2.68)
2.05 (1.33-3.14)
2.02 (1.12-3.63)
Adenoma location
Models were adjusted for age, sex, body mass index, family history of colorectal cancer, use of nonsteroidal anti-inflammatory drugs, and number of adenomas at baseline. Comparison group ⫽ no missed adenomas (n ⫽ 1132). T0, Qualifying baseline colonoscopy; T1, clearing colonoscopy performed 1 year after enrollment to remove missed lesions; RR, relative risk; CI, confidence interval.
Table 3. Risk and location of missed advanced adenoma detected at T1 colonoscopy by baseline adenoma location
Advanced adenoma distribution, no. (%)
Distal-only missed advanced adenomas, RR (95% CI)
Any proximal missed advanced adenomas, RR (95% CI)
Baseline (T0) (n ⴝ 670)
Missed (T1) (n ⴝ 102)
Any missed advanced adenomas, RR (95% CI)
Distal only
416 (62.1)
43 (42.2)
Reference
Reference
Reference
Proximal only
105 (15.7)
54 (52.9)
1.79 (1.17-2.75)
0.88 (0.41-1.89)
3.34 (1.75-6.39)
Synchronous proximal and distal
149 (22.2)
5 (4.9)
1.72 (1.00-2.95)
0.95 (0.35-2.57)
2.92 (1.23-6.93)
Adenoma location
Models were adjusted for age, sex, body mass index, family history of colorectal cancer, use of nonsteroidal anti-inflammatory drugs, and number of adenomas at baseline. Comparison group ⫽ no missed adenomas (n ⫽ 1132); any proximal missed advanced adenomas ⫽ proximal only plus synchronous proximal and distal missed advanced adenoma (n ⫽ 59). T0, Qualifying baseline colonoscopy; T1, clearing colonoscopy performed 1 year after enrollment to remove missed lesions; RR, relative risk; CI, confidence interval.
from 55.6% at baseline to 22.9% at recurrence, whereas proximal-only adenomas increased from 27.8% to 52.1%, but synchronous proximal and distal adenomas increased from 16.5% to 25%.
of the recurrence (Table 5) or with the baseline adenomas (Table 5).
Advanced adenoma recurrence by location
We evaluated the association between adenoma location at baseline with the risk of adenoma recurrence and the location of the recurrent adenoma in an attempt to assess differences in susceptibility to adenoma recurrence by location. Our study suggests 3 potential mechanisms underlying a lower protective effect of colonoscopy in the proximal colon. First, we report that missed lesions are more common in the proximal colon. Second, recurrent adenomas and advanced adenomas are more likely to be in the proximal colon. Third, compared with the participants with a distal-only adenoma at baseline, participants with a proximal-only adenoma at baseline are more likely to have an adenoma and advanced adenoma recurrence, particularly in the proximal colon. Our sensitivity analyses investigating the effect of missed lesions suggest that
A total of 119 participants had advanced adenoma recurrence (47 distal only, 60 proximal only, and 12 synchronous proximal and distal). The percentage of proximal-only advanced adenomas increased from 15.7% at baseline to 50.4% at recurrence (Table 5). When compared with participants with a distal-only adenoma at baseline, those with proximal-only adenoma at baseline had a borderline increased risk of an advanced adenoma recurrence (RR 1.50; 95% CI, 0.99-2.27) (Table 5) and were more likely to have an advanced adenoma recurrence in a proximal location (RR 3.62; 95% CI, 1.96-6.71), but less likely to have an advanced adenoma recurrence in the distal colon (RR 0.34; 95% CI, 0.13-0.90) (Table 5). This pattern persisted, despite including the T1 lesions as part www.giejournal.org
DISCUSSION
Volume 74, No. 2 : 2011 GASTROINTESTINAL ENDOSCOPY 257
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Table 4. Risk and location of recurrent adenoma by baseline adenoma location A. Risk and location of recurrent adenomas (T4) by baseline adenoma location (T0)
Adenoma distribution, no. (%)
Distal only adenoma recurrence RR (95% CI)
Proximal only adenoma recurrence RR (95% CI)
Synchronous proximal and distal adenoma recurrence RR (95% CI)
At baseline (T0) (n ⴝ 1864)
At recurrence (T4) (n ⴝ 733)
Any adenoma recurrence RR (95% CI)
Distal only
1030 (55.3)
228 (31.1)
Reference
Reference
Reference
Reference
Proximal only
503 (27.0)
369 (50.3)
1.14 (1.00-1.31)
0.67 (0.46-0.97)
1.52 (1.15-2.02)
1.88 (1.21-2.90)
Synchronous proximal and distal
331 (17.8)
136 (18.6)
1.20 (1.03-1.40)
1.00 (0.63-1.60)
1.20 (0.80-1.79)
1.83 (1.04-3.21)
Adenoma location
B. Risk and location of combined missed and recurrent adenomas (T1 ⴙ T4) by baseline adenoma location (T0) Adenoma distribution, no. (%)
At baseline (T0) (n ⴝ 1863)
At recurrence (T1 ⴙ T4) (n ⴝ 1013)
Any adenoma recurrence RR (95% CI)
Distal-only adenoma recurrence RR (95% CI)
Proximal-only adenoma recurrence RR (95% CI)
Synchronous proximal and distal adenoma recurrence RR (95% CI)
Distal only
1029 (55.2)
282 (27.8)
Reference
Reference
Reference
Reference
Proximal only
503 (27.0)
428 (42.3)
1.30 (1.17-1.45)
0.68 (0.48-0.98)
1.89 (1.44-2.50)
1.67 (1.20-2.32)
Synchronous proximal and distal
331 (17.8)
303 (29.9)
1.35 (1.18-1.53)
1.23 (0.75-1.99)
1.47 (0.96-2.23)
1.91 (1.22-2.30)
Adenoma location
C. Risk and location of recurrent adenoma (T4) by combined baseline and missed adenoma location (T0 ⴙ T1)
At recurrence (T4) (n ⴝ 685)
Any adenoma recurrence RR (95% CI)
Distal-only adenoma recurrence RR (95% CI)
Proximal-only adenoma recurrence RR (95% CI)
Synchronous proximal and distal adenoma recurrence RR (95% CI)
813 (47.0)
217 (31.7)
Reference
Reference
Reference
Reference
Proximal only
392 (22.7)
344 (50.2)
1.17 (1.00-1.37)
0.60 (0.39-0.93)
1.64 (1.19-2.25)
2.83 (1.62-4.94)
Synchronous proximal and distal
525 (30.3)
124 (18.1)
1.36 (1.18-1.57)
1.08 (0.74-1.58)
1.66 (1.20-2.31)
3.83 (2.23-6.56)
Adenoma distribution, no. (%) At baseline (T0 ⴙ T1) n ⴝ 1730
Distal only
Adenoma location
Models were adjusted for age, sex, body mass index, family history of colorectal cancer, use of nonsteroidal anti-inflammatory drugs, and number of adenomas at baseline. Comparison group A ⫽ no adenoma recurrence (n ⫽ 1131); comparison group B ⫽ no adenoma recurrence (n ⫽ 850); comparison group C ⫽ no adenoma recurrence (n ⫽ 1045). T0, Qualifying baseline colonoscopy; T4, end-of-trial colonoscopy; RR, relative risk; CI, confidence interval; T1, clearing colonoscopy performed 1 year after enrollment to remove missed lesions.
missed lesions may not explain the differentially increased proportion of proximal adenoma at recurrence. This suggests the possibility of an underlying biological difference in susceptibility to recurrence of colonic neoplasia in the proximal and distal colon and identifies patients with a proximal adenoma as at high risk of recurrence. This may in part explain some of the observed differences in the efficacy of colonoscopy by colon subsite. Further studies on the role of tumor location in the natural history of colorectal neoplasia are needed. We are not aware of any study that evaluated the effect of missed lesions on the risk and location of adenoma 258 GASTROINTESTINAL ENDOSCOPY Volume 74, No. 2 : 2011
recurrence for a direct comparison with our study. Missed lesions at colonoscopy are relatively common, and segmental unblinding of virtual colonoscopy results and tandem back-to-back colonoscopy have reported adenoma miss rates as high as 27%.22-27 A repeat colonoscopy after 1 year in our cohort of patients with a history of adenoma detected additional adenomas in 34.6% of patients and advanced adenomas in 6% of patients. Per the design of the PPT, these were regarded as missed lesions. However, the inclusion or exclusion of these lesions from our analysis did not affect the increased risk of adenoma recurrence that we observed in association with previous proxwww.giejournal.org
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Missed and recurrent adenoma location
Table 5. Risk and location of recurrent advanced adenoma by baseline adenoma location A. Risk and location of recurrent advanced adenoma (T4) by baseline adenoma location (T0) (N ⴝ 1864) Advanced adenoma distribution, no. (%)
Distal-only recurrent advanced adenomas RR (95% CI)
Any proximal recurrent advanced adenomas RR (95% CI)
Baseline (T0) (n ⴝ 705)
Recurrent (T4) (n ⴝ 119)
Any recurrent advanced adenomas RR (95% CI)
Distal only
440 (62.4)
47 (39.5)
Reference
Reference
Reference
Proximal only
111 (15.7)
60 (50.4)
1.50 (0.99-2.27)
0.34 (0.13-0.90)
3.62 (1.96-6.71)
Synchronous proximal and distal
154 (21.8)
12 (10.1)
1.92 (1.14-3.25)
0.94 (0.38-2.37)
4.30 (1.92-9.66)
Adenoma location
B. Risk and location of combined missed and recurrent advanced adenoma (T1 ⴙ T4) by baseline adenoma location (T0) (N ⴝ 1863) Advanced adenoma distribution, no. (%)
Distal-only recurrent advanced adenomas, RR (95% CI)
Any proximal recurrent advanced adenomas, RR (95% CI)
Baseline (T0) (n ⴝ 705)
Recurrent (T1 ⴙ T4) (n ⴝ 196)
Any recurrent advanced adenomas, RR (95% CI)
Distal only
440 (62.4)
76 (38.8)
Reference
Reference
Reference
Proximal only
111 (15.7)
101 (51.5)
1.61 (1.20-2.16)
0.49 (0.24-0.99)
3.91 (2.41-6.33)
Synchronous proximal and distal
154 (21.8)
19 (9.7)
1.77 (1.23-2.53)
0.90 (0.41-1.96)
3.55 (1.82-6.95)
Adenoma location
C. Risk and location of recurrent advanced adenoma (T4) by combined baseline and missed adenoma location (T0 ⴙ T1) (N ⴝ 1730) Advanced adenoma distribution, no. (%)
Distal-only recurrent advanced adenomas, RR (95% CI)
Any proximal recurrent advanced adenomas, RR (95% CI)
Baseline (T0 plus T1) n ⴝ 709
Recurrent (T4) (n ⴝ 112)
Any recurrent advanced adenomas, RR (95% CI)
Distal only
432 (60.9)
43 (38.4)
Reference
Reference
Reference
Proximal only
123 (17.3)
58 (51.8)
1.36 (0.84-2.20)
0.16 (0.04-0.68)
4.21 (2.06-8.63)
Synchronous proximal and distal
154 (21.7)
11 (9.8)
1.62 (1.02-2.57)
1.09 (0.55-2.13)
4.98 (2.48-10.00)
Adenoma location
Models were adjusted for age, sex, body mass index, family history of colorectal cancer, use of nonsteroidal anti-inflammatory drugs, and number of adenomas at baseline. Comparison group A ⫽ no adenoma recurrence (n ⫽ 1131); comparison group B ⫽ no adenoma recurrence (n ⫽ 850); comparison group C ⫽ no adenoma recurrence (n ⫽ 1045); any proximal recurrent advanced adenoma ⫽ proximal only plus synchronous proximal and distal recurrent advanced adenomas. T4, End-of-trial colonoscopy; T0, qualifying baseline colonoscopy; RR, relative risk; CI, confidence interval; T1, clearing colonoscopy performed 1 year after enrollment to remove missed lesions.
imal adenoma or the proximal location of recurrent adenoma. Also, we addressed the possibility that adenomas detected at T1 colonoscopy may be recurrent lesions because of the 1-year interval between T0 and T1 colonoscopy. We added the adenoma at T1 to the end-of-trial colonoscopic findings but the results were unchanged. Our finding of a proximal shift in metachronous adenoma is comparable with the findings of previous studies (Table 6).28-32 Although the magnitude of effect may differ, all of the studies showed a consistent pattern of a decreased percentage of distal adenomas at recurrence, whereas the percentage of proximal adenomas increased. www.giejournal.org
This mirrors the increased proportion of proximal-only adenomas from 27% at baseline to 50.3% at recurrence reported in our study and suggests the possibility of different biological susceptibilities to neoplasia by colon subsite. The increased tendency for recurrence in the proximal colon may offer some explanation why the efficacy of colonoscopy may be lower in that location. However, the current postpolypectomy surveillance guidelines21 do not take adenoma location into consideration for surveillance interval recommendations. Prospective studies evaluating the optimal surveillance intervals after polypectomy in the Volume 74, No. 2 : 2011 GASTROINTESTINAL ENDOSCOPY 259
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Table 6. Previous studies that evaluated adenoma location at baseline and at recurrence
Study Martinez et al,28 2001
Nusko et
al,29
2001
Bonithon-Kopp et al,30 2004
Yamaji et al,31 2007
Nusko et
al,32
2009
Current study*
Distribution of adenomas, no. (%)
Mean follow-up interval, y
Adenoma location
At baseline
At recurrence
3
Distal
704 (54.6)
172 (27.7)
Proximal
349 (27.2)
281 (45.2)
Both
234 (18.2)
169 (27.1)
Distal
606 (55.5)
204 (36.7)
Proximal
246 (22.6)
300 (54.0)
Both
239 (21.9)
52 (9.4)
Any distal
502 (90.9)
82 (67.2)
Any proximal
114 (20.7)
62 (50.8)
Distal
1392 (48.0)
318 (41.4)
Proximal
894 (30.8)
334 (43.4)
Both
614 (21.2)
117 (15.2)
Distal
364 (63.5)
293 (51.2)
Proximal
86 (15.0)
164 (29.7)
Both
123 (21.5)
115 (20.1)
Distal
1030 (55.3)
228 (31.1)
Proximal
503 (27.0)
369 (50.3)
Both
331 (17.8)
136 (18.6)
3.4
3
4
3
4
*Our finding is included for easy comparison.
distal versus the proximal colon and studies focusing on factors (including molecular markers) that reliably predict proximal neoplasia recurrence are needed. Although missed adenomas did not affect proximal versus distal adenoma recurrence in our study, the importance of performing a good-quality colonoscopic examination should be emphasized. Of note, we found more missed lesions in the proximal colon at T1 colonoscopy. The rates of missed lesions vary and are dependent on endoscopists’ experience, withdrawal time, and attention to details. Optimal bowel preparation through splitting the bowel preparation laxatives so that some laxatives are consumed a few hours before the procedure is important as well as ongoing efforts to improve the technology of colonoscopy itself such as the use of high-definition endoscopes, chromoendoscopy, and cap-fitted colonoscopy to minimize the risk of missing important lesions in clinical practice. A recent study reported that endoscopists with low adenoma detection rates perform colonoscopies that are associated with a higher risk of interval cancers.33 There are many strengths of our study. A unique feature of our study is the T1 colonoscopy performed in 93% of our study cohort to remove lesions that might have been missed at baseline colonoscopy, which afforded us the opportunity to evaluate the effect of missed lesions. Our 260 GASTROINTESTINAL ENDOSCOPY Volume 74, No. 2 : 2011
study population is from a large randomized, controlled trial with participants recruited from geographically dispersed areas, information on candidate risk factors was prospectively gathered, all patients had planned colonoscopic assessment for recurrence after an adequate follow-up period, and dedicated central pathologists with expertise in GI tumors examined the adenomas, thereby ensuring consistency. Our study also has limitations. The participants in the PPT were self-selected and may be healthier than comparable members of the general population. The design of the PPT also limited the degree of obesity of participants. Because obesity has been associated with an increased risk of colonic neoplasia,34 the yield of adenomas in our study may be lower than expected in the general population. We could not assess the effect of serrated polyps and flat, and depressed lesions in our study because they were not widely discussed at the time that the trial was conducted. Furthermore, repeated colonoscopies may still miss lesions. In conclusion, we observed an increased tendency for adenoma recurrence in the proximal colon, supporting the current practice of the use of colonoscopy for surveillance regardless of the location of index adenoma. However, further studies are needed to elucidate whether this sugwww.giejournal.org
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gested biological difference warrants modification of postpolypectomy surveillance intervals. REFERENCES 1. Prorok PC, Andriole GL, Bresalier RS, et al. Design of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Control Clin Trials 2000;21(6 Suppl):273S-309S. 2. Segnan N, Senore C, Andreoni B, et al. Baseline findings of the Italian multicenter randomized controlled trial of “once-only sigmoidoscopy” SCORE. J Natl Cancer Inst 2002;94:1763-72. 3. Gondal G, Grotmol T, Hofstad B, et al. The Norwegian Colorectal Cancer Prevention (NORCCAP) screening study: baseline findings and implementations for clinical work-up in age groups 50-64 years. Scand J Gastroenterol 2003;38:635-42. 4. Newcomb PA, Norfleet RG, Storer BE, et al. Screening sigmoidoscopy and colorectal cancer mortality. J Natl Cancer Inst 1992;84:1572-5. 5. Selby JV, Friedman GD, Quesenberry CP Jr, et al. A case-control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med 1992;326:653-7. 6. Atkin WS, Edwards R, Kralj-Hans I, et al; UK Flexible Sigmoidoscopy Trial Investigators. Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet 2010;375:1624-33. 7. Subramanian S, Amonkar MM, Hunt TL. Use of colonoscopy for colorectal cancer screening: evidence from the 2000 National Health Interview Survey. Cancer Epidemiol Biomarkers Prev 2005;14:409-16. 8. Doubeni C, Laiyemo AO, Reed G, et al. Socioeconomic and racial patterns of colorectal cancer screening among Medicare enrollees 20002005. Cancer Epidemiol Biomarkers Prev 2009;18:2170-5. 9. Singh H, Turner D, Xue L, et al. Risk of developing colorectal cancer following a negative colonoscopy examination: evidence for a 10-year interval between colonoscopies. JAMA 2006;295:2366-73. 10. Lakoff J, Paszat LF, Saskin R, et al. Risk of developing proximal versus distal colorectal cancer after a negative colonoscopy: a populationbased study. Clin Gastroenterol Hepatol 2008;6:1117-21. 11. Baxter NN, Goldwasser MA, Paszat LF, et al. Association of colonoscopy and death from colorectal cancer. Ann Intern Med 2009;150:1-8. 12. Singh H, Nugent Z, Demers AA, et al. The reduction in colorectal cancer mortality after colonoscopy varies by site of the cancer. Gastroenterology 2010;139:1128-37. 13. Kahi CJ, Imperiale TF, Juliar BE, et al. Effect of screening colonoscopy on colorectal cancer incidence and mortality. Clin Gastroenterol Hepatol 2009;7:770-5. 14. Brenner H, Hoffmeister M, Arndt V, et al. Protection from right- and leftsided colorectal neoplasms after colonoscopy: population-based study. J Natl Cancer Inst 2010;102:89-95. 15. Brenner H, Chang-Claude J, Seiler CM, et al. Protection from colorectal cancer after colonoscopy: a population-based, case-control study. Ann Intern Med 2011;154:22-30. 16. Rex DK, Eid E. Considerations regarding the present and future roles of colonoscopy in colorectal cancer prevention. Clin Gastroenterol Hepatol 2008;6:506-14.
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17. Pohl H, Robertson DJ. Colorectal cancers detected after colonoscopy frequently result from missed lesions. Clin Gastroenterol Hepatol 2010; 8:858-64. 18. Schatzkin A, Lanza E, Freedman LS, et al. The polyp prevention trial I: rationale, design, recruitment, and baseline participant characteristics. Cancer Epidemiol Biomarkers Prev 1996;5:375-83. 19. Lanza E, Schatzkin A, Ballard-Barbash R, et al. The polyp prevention trial II: dietary intervention program and participant baseline dietary characteristics. Cancer Epidemiol Biomarkers Prev 1996;5:385-92. Erratum in: Cancer Epidemiol Biomarkers Prev 1996;5:584. 20. Schatzkin A, Lanza E, Corle D, et al. Lack of effect of a low-fat, high-fiber diet on the recurrence of colorectal adenomas. Polyp Prevention Trial Study Group. N Engl J Med 2000;342:1149-55. 21. Winawer SJ, Zauber AG, Fletcher RH, et al; US Multi-Society Task Force on Colorectal Cancer; American Cancer Society. Guidelines for colonoscopy surveillance after polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society. Gastroenterology 2006;130:1872-85. 22. Rex DK, Cutler CS, Lemmel GT, et al. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology 1997;112:24-8. 23. van Rijn JC, Reitsma JB, Stoker J, et al. Polyp miss rate determined by tandem colonoscopy: a systematic review. Am J Gastroenterol 2006; 101:343-50. 24. Hixson LJ, Fennerty MB, Sampliner RE, et al. Prospective study of the frequency and size distribution of polyps missed by colonoscopy. J Natl Cancer Inst 1990;82:1769-72. 25. Heresbach D, Barrioz T, Lapalus MG, et al. Miss rate for colorectal neoplastic polyps: a prospective multicenter study of back-to-back video colonoscopies. Endoscopy 2008;40:284-90. 26. Pickhardt PJ, Nugent PA, Mysliwiec PA, et al. Location of adenomas missed by optical colonoscopy. Ann Intern Med 2004;141:352-9. 27. Hewett DG, Rex DK. Cap-fitted colonoscopy: a randomized, tandem colonoscopy study of adenoma miss rates. Gastrointest Endosc 2010;72: 775-81. 28. Martínez ME, Sampliner R, Marshall JR, et al. Adenoma characteristics as risk factors for recurrence of advanced adenomas. Gastroenterology 2001;120:1077-83. 29. Nusko G, Mansmann U, Wiest G, et al. Right-sided shift found in metachronous colorectal adenomas. Endoscopy 2001;33:574-9. 30. Bonithon-Kopp C, Piard F, Fenger C, et al. Colorectal adenoma characteristics as predictors of recurrence. Dis Colon Rectum 2004;47:323-33. 31. Yamaji Y, Mitsushima T, Yoshida H, et al. Right-side shift of metachronous colorectal adenomas after polypectomy. Scand J Gastroenterol 2007;42:1466-72. 32. Nusko G, Hahn EG, Mansmann U. Characteristics of metachronous colorectal adenomas found during long-term follow-up: analysis of four subsequent generations of adenoma recurrence. Scand J Gastroenterol 2009;44:736-44. 33. Kaminski MF, Regula J, Kraszewska E, et al. Quality indicators for colonoscopy and the risk of interval cancer. N Engl J Med 2010;362:1795-803. 34. Jacobs ET, Martínez ME, Alberts DS, et al. Association between body size and colorectal adenoma recurrence. Clin Gastroenterol Hepatol 2007;5: 982-90.
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Likelihood of missed and recurrent adenomas in the proximal versus the distal colon Adeyinka O. Laiyemo, MD, MPH, Chyke Doubeni, MD, MPH, Andrew K. Sanderson II, MD, Paul F. Pinsky, PhD, Dilhana S. Badurdeen, MD, V. Paul Doria-Rose, DVM, PhD, Pamela M. Marcus, PhD, Robert E. Schoen, MD, MPH, Elaine Lanza, PhD, Arthur Schatzkin, MD, DrPH, Amanda J. Cross, PhD Washington, DC; Bethesda, Maryland; Worcester, Massachusetts; Pittsburgh, Pennsylvania, USA
Background: Colonoscopy may be less efficacious in reducing colorectal cancer mortality in the proximal compared with the distal colon. A greater likelihood for missed and recurrent adenomas in the proximal colon may contribute to this phenomenon. Objective: To examine whether a proximal adenoma is associated with the risk and location of missed and recurrent adenomas. Design: Prospective. Setting: Polyp Prevention Trial. Participants: A total of 1864 patients with an adenoma at baseline underwent a follow-up colonoscopy 4 years later (adenoma recurrence). Of these, 1731 underwent a clearing colonoscopy 1 year after the baseline examination (missed adenoma). Main Outcome Measurements: Association of baseline adenoma location with the risk and location of adenomas found at colonoscopy performed 1 year and 4 years later. Results: At the year 1 colonoscopy, 598 patients (34.6%) had an adenoma (missed adenoma). Compared with those with a distal-only adenoma at baseline, patients with a proximal-only adenoma at baseline were more likely to have any missed adenomas (relative risk [RR] 1.28; 95% CI, 1.09-1.49) and a proximal-only missed adenoma (RR 2.05; 95% CI, 1.49-2.80). At the year 4 colonoscopy, 733 patients (39.3%) had adenoma recurrence. Patients with a baseline proximal-only adenoma were more likely to have any adenoma recurrence (RR 1.14; 95% CI, 1.00-1.31) and a proximal-only adenoma recurrence (RR 1.52; 95% CI, 1.15-2.02). Sensitivity analyses involving missed adenomas did not materially affect the risk or location of recurrent adenomas at year 4 colonoscopy. Limitation: Lesions may still be missed on repeated colonoscopies. Conclusions: Missed and recurrent adenomas are more likely to be in the proximal colon. (Gastrointest Endosc 2011;74:253-61.)
Abbreviations: PPT, Polyp Prevention Trial; RR, relative risk. DISCLOSURE: The following authors disclosed financial relationships relevant to this publication: Dr. Laiyemo is supported by the National Cancer Institute’s new faculty recruitment supplement to the Comprehensive Minority Institution/Cancer Center Partnership between Howard University Cancer Center and Sidney Kimmel Comprehensive Cancer Center of Johns Hopkins University (5U54CA091431-09 S1). Dr. Doubeni is supported by a mentored career development award (5K01CA12711803) from the National Cancer Institute. This research was funded by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. The other authors disclosed no financial relationships relevant to this publication.
(A.O.L., P.M.M.), Early Detection Research Group (P.F.P.), Division of Cancer Prevention, Health Services and Economics Branch (V.P.D.R.), Division of Cancer Control and Population Sciences, Laboratory of Cancer Prevention (E.L.), Center for Cancer Research, Nutritional Epidemiology Branch (A.S., A.J.C.), Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, Department of Family Medicine (C.D.), University of Massachusetts, Worcester, Massachusetts, Department of Medicine and Epidemiology (R.E.S.), University of Pittsburgh, Pittsburgh, Pennsylvania. Presented in abstract form as an oral presentation at the Digestive Diseases Week, June 1, 2009, Chicago, Illinois (Gastrointest Endosc 2009;69:AB108).
Copyright © 2011 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2011.02.023
Reprint requests: Adeyinka O. Laiyemo, MD, MPH, Division of Gastroenterology, Department of Medicine, Howard University College of Medicine, 2041 Georgia Avenue, NW, Washington, DC 20060.
Received December 16, 2010. Accepted February 25, 2011.
If you would like to chat with an author of this article, you may contact Dr. Laiyemo at [email protected].
Current affiliations: Department of Medicine (A.O.L., A.K.S., D.S.B.), Howard University College of Medicine, Washington, DC, Biometry Research Group
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Although 3 randomized, controlled trials of the effect of screening sigmoidoscopy on colorectal cancer mortality are still ongoing,1-3 case-control studies4,5 and 1 randomized, controlled trial6 have demonstrated a reduction in mortality from colon cancer with sigmoidoscopy. This effect is limited to the distal colon, presumably because sigmoidoscopy does not examine the proximal colon. The use of colonoscopy as a colorectal cancer screening modality has been increasing7,8 and was expected to confer benefit in both the distal and proximal colon. However, population-based studies in Canada suggest limited efficacy of colonoscopy in reducing proximal colon cancer incidence9,10 and mortality.11,12 In the United States, Kahi et al13 reported an overall reduction in the incidence of colon cancer in a postpolypectomy cohort compared with Surveillance Epidemiology and End Results (SEER) data, but 5 of the 6 colon cancers diagnosed after colonoscopy were located in the proximal colon. Furthermore, a study from Germany found a reduction in advanced adenoma recurrence in the distal but not in the proximal colon with history of undergoing colonoscopy.14 Although a recent population-based case-control study found an overall 77% reduced risk of colorectal cancer with previous exposure to colonoscopy, the protection conferred by colonoscopy in the proximal colon was only two thirds of the protection in the distal colon (56% vs 84%).15 Although none of the aforementioned studies was a randomized, controlled trial of screening colonoscopy, the consistent pattern of lower benefit of colonoscopy in the proximal colon compared with the distal colon is compelling, albeit not definitive. Although factors such as the quality of the baseline colonoscopy, bowel preparation, endoscopists’ skills, lack of adequate detection of flat, depressed lesions, and missed lesions16,17 may contribute to these findings, it is also possible that the biology of colon cancer differs by tumor location. We proposed that if patients are more likely to have missed adenomas in the proximal colon or more likely to have a proximal adenoma recurrence or if patients with a proximal adenoma are at a higher risk of recurrence in the proximal colon than patients with distal adenomas, then colonoscopy might be less efficacious in the proximal compared with the distal colon. The aim of this investigation was to examine whether a proximal adenoma is associated with the risk and the location of missed and recurrent adenoma using the comprehensive information on adenoma location during colonoscopies performed in participants in the Polyp Prevention Trial (PPT).
METHODS Study population The rationale, design, and results of the PPT were published previously.18-20 In brief, the PPT was a 4-year multicenter, randomized, controlled trial to assess the effect of a low-fat, high-fiber, fruit and vegetable diet on the 254 GASTROINTESTINAL ENDOSCOPY Volume 74, No. 2 : 2011
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Take-home Message ●
Missed lesions tend to occur in the proximal colon, and there is also an increased tendency for adenoma recurrence in the proximal colon. This may contribute to the explanation of why colonoscopy is not as effective in the proximal colon compared with the distal colon.
risk of colorectal adenoma recurrence. A total of 2079 participants who were at least 35 years old and had 1 or more histologically confirmed adenomatous polyps removed within 6 months from a complete colonoscopy were randomized. Exclusion criteria included history of surgical resection of adenomatous polyps, bowel resection, colorectal carcinoma, polyposis syndrome, inflammatory bowel disease, use of any lipid-lowering medications, and body weight more than 150% of the ideal. The clinical trial was approved by the Institutional Review Boards of the National Cancer Institute, and each of the 8 participating clinical centers. All participants gave written informed consent.
Exposure and outcome assessment At baseline, information on the subjects’ demographic characteristics, health-related lifestyle, dietary supplements intake, and medication use was obtained from every participant through direct interview. Per PPT protocol, the participants were scheduled to undergo a clearing colonoscopy approximately 1 year after randomization (T1) to remove any lesion that may have been missed at qualifying colonoscopy (T0). This clearing colonoscopy was completed by 1768 participants. All participants were followed for approximately 4 years after randomization and had an end-of-trial (T4) colonoscopy to ascertain adenoma recurrence. A total of 1905 participants (91.6%) completed the trial by undergoing the T4 colonoscopy. The dietary intervention did not affect adenoma recurrence.20 Forty-one participants had missing information on the location of their baseline adenoma and were excluded from the current analysis. Therefore, our analytic cohort comprises 1864 participants, of whom 1731 (92.9%) underwent a clearing colonoscopy to remove missed lesions 1 year after random assignment. The colonoscopy reports provided information on size, number, and location of polyps. The location of adenomas removed from the rectum to the splenic flexure was defined as distal, whereas proximal location included transverse colon to the cecum. The histology and degree of dysplasia were confirmed by 2 trial pathologists who were masked to the participants’ randomization assignments.18 Advanced adenomas were defined as those 1 cm or more in diameter or with villous histology or high-grade dysplasia.21 www.giejournal.org
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Statistical analyses We estimated the relative risk (RR) and 95% confidence interval by using Poisson regression to evaluate the association between baseline adenoma location and missed adenoma detected at year 1 colonoscopy and adenoma recurrence at year 4 colonoscopy. We used multinomial regression analyses to evaluate the association of baseline adenoma location with missed adenoma location at year 1 colonoscopy and at adenoma recurrence 4 years after randomization as our primary analysis. For baseline adenoma location (exposure), we categorized participants by the location of their adenoma into 3 mutually exclusive groups: those with a distal-only adenoma, those with a proximal-only adenoma, and those with a synchronous proximal and distal adenoma. For any missed adenomas (outcome) and any recurrent adenomas (outcome), we classified the adenomas into 4 mutually exclusive groups according to the findings at the T1 or T4 colonoscopy: those without any adenomas (comparison group), those with a distal-only adenoma, those with a proximal-only adenoma, and those with a synchronous proximal and distal adenoma. We did a similar categorization for advanced adenomas, but there were few participants with a synchronous proximal and distal advanced adenoma. Therefore, those with any missed or recurrent proximal advanced adenomas were included in 1 category for some analyses. Sensitivity analyses on reclassifying advanced adenomas that were found after baseline examination in both locations with distal-only advanced adenomas did not change our findings (data not shown). To evaluate the effect of missed lesions on the risk and location of adenoma recurrence at T4, we reanalyzed our data to include adenomas found at the T1 clearing colonoscopy. Of 1731 participants who underwent T1 colonoscopy, we could not identify the specific location of the adenoma found in 1 participant. Therefore, we excluded this individual in the sensitivity analysis involving T1 colonoscopy. At first, we combined T1 and T4 colonoscopy findings in an analysis on the premise that if T1 colonoscopy had not been performed, the lesions would have been found at T4 as recurrent lesions. We then restricted our cohort to only participants who underwent T1 colonoscopy and added the T1 colonoscopy– detected lesions to the baseline findings and repeated our analysis. For the multivariate models, we adjusted for age (continuous), sex, body mass index (continuous), family history of colorectal cancer in a first-degree relative (yes vs no), use of nonsteroidal anti-inflammatory drugs at least once per month (yes vs no), and the number of adenomas at baseline (continuous). We used Stata statistical software version 9 (StataCorp, College Station, Tex) for all analyses. All reported P values correspond to 2-sided tests. www.giejournal.org
Missed and recurrent adenoma location
RESULTS Baseline characteristics Table 1 shows selected baseline characteristics of study participants by the location of the baseline adenoma. At baseline, 1030 participants (55.3%) had a distal-only adenoma, 503 (27%) had a proximal-only adenoma, and 331 (17.8%) had a synchronous proximal and distal adenoma. A total of 750 patients (37.8%) had an advanced adenoma at baseline: 440 participants (62.4%) had a distal-only advanced adenoma, 111 (15.7%) had a proximal-only advanced adenoma, and 154 (21.8%) had a synchronous proximal and distal advanced adenoma. The mean age of the participants was 61.1 years. The distribution of age, sex, body mass index, family history of colon cancer, and number of adenomas at baseline varied significantly (P ⬍ .05) by baseline adenoma location.
Clearing (T1) colonoscopy for missed lesions Participants who did not undergo clearing (T1) colonoscopy (n ⫽ 133) were comparable to those who did (n ⫽ 1731) except that those who did not were slightly younger (mean age 59.3 years vs 61.2 years; P ⫽ .04) and were more likely to be current smokers (23.3% vs 12.4%; P ⫽ .001). Of those with complete T1 colonoscopy information (n ⫽ 1730), 598 patients (34.6%) had an adenoma at T1 colonoscopy: distal only (n ⫽ 209, 34.9%), proximal only (n ⫽ 284, 47.5%), and synchronous proximal and distal adenoma (n ⫽ 105, 17.6%) (Table 2). When compared with patients with a distal-only adenoma at baseline, patients with a proximal-only adenoma at baseline were more likely to have a missed adenoma (ie, any adenomas found at T1 colonoscopy) (RR 1.28; 95% CI, 1.09-1.49) and a proximal- only missed adenoma (RR 2.05; 95% CI, 1.492.80). A total of 102 patients (5.9%) had an advanced adenoma at T1 colonoscopy, of whom 63 (61.8%) had an advanced adenoma at baseline (T0). Participants with a proximal-only adenoma at baseline (T0) were also more likely to have any missed advanced adenomas (RR 1.79; 95% CI, 1.17-2.75) and any proximal missed advanced adenomas (RR 3.34; 95% CI, 1.75-6.39) (Table 3).
Adenoma recurrence by location For the main analysis assessing the risk and location of recurrent adenomas at T4 colonoscopy, 733 (39.3%) participants had adenoma recurrence, whereas 1131 (60.7%) had no adenoma recurrence. Among those with distalonly, proximal-only, and synchronous proximal and distal adenomas at baseline, recurrence rates were 33.4%, 41.9%, and 53.8%, respectively. Among participants with adenoma recurrence, 228 (31.1%) had distal only, 369 (50.3%) had proximal only, and 136 (18.6%) had synchronous proximal and distal adenoma recurrence, indicating a relative decrease in the percentage of patients with distalonly adenomas at recurrence (55.3% at baseline vs 31.1% at T4), an increase in the percentage of patients with Volume 74, No. 2 : 2011 GASTROINTESTINAL ENDOSCOPY 255
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Table 1. Selected characteristics of the participants at baseline Adenoma location at baseline, no. (%) Distal only (n ⴝ 1030)
Proximal only (n ⴝ 503)
Synchronous proximal and distal (n ⴝ 331)
⬍55
300 (29.1)
112 (22.3)
68 (20.5)
55-59
174 (16.9)
63 (12.5)
49 (14.8)
60-64
182 (17.7)
98 (19.5)
58 (17.5)
65-69
171 (16.6)
96 (18.1)
76 (23.0)
ⱖ70
203 (19.7)
139 (27.7)
80 (24.2)
Male
621 (60.3)
333 (66.2)
245 (74.0)
Female
409 (39.7)
170 (33.8)
86 (26.0)
White
927 (90.0)
447 (88.9)
294 (88.8)
Black
74 (7.2)
50 (9.9)
29 (8.8)
Other*
29 (2.8)
6 (1.2)
8 (2.4)
⬍25
307 (29.8)
117 (23.3)
70 (21.2)
25-29
464 (45.1)
240 (47.7)
172 (52.0)
ⱖ30
259 (25.2)
146 (29.0)
89 (26.9)
Positive family history of colon cancer
262 (25.4)
159 (31.6)
83 (25.1)
.026
Uses NSAIDs at least once per month
362 (35.2)
150 (29.8)
116 (35.1)
.099
1-2
984 (95.5)
454 (90.3)
151 (45.6)
⬍.001
ⱖ3
46 (4.5)
49 (9.7)
180 (54.4)
Baseline characteristics
P value
Age, y
⬍.001
Sex
⬍.001
Race
.125
BMI, kg/m2, no. (%)
.006
No. of adenomas
BMI, Body mass index; NSAIDs, nonsteroidal anti-inflammatory drugs. *Hispanics, Asians, and Native Americans
proximal only at recurrence (27.0% at baseline vs 50.3% at T4), but a similar percentage of patients with synchronous proximal and distal adenomas at baseline and recurrence (17.8% at baseline vs 18.6% at T4) (Table 4). Compared with those with distal-only adenomas at baseline, the risk of adenoma recurrence was higher for those with proximal-only adenomas at baseline (RR 1.14; 95% CI, 1.00-1.31) and for those with synchronous proximal and distal adenomas at baseline (RR 1.20; 95% CI, 1.03-1.40) (Table 4). Proximal only adenoma at baseline was positively associated with proximal-only adenoma recurrence (RR 1.52; 95% CI, 1.15-2.02), but inversely associated with distal only adenoma recurrence (RR 0.67; 95% CI, 0.46-0.97). Combining the T1 results with the T4 results and considering the combination as the recurrence outcome in256 GASTROINTESTINAL ENDOSCOPY Volume 74, No. 2 : 2011
creased the overall adenoma recurrence rate from 39.3% to 54.4%. Although this changed the distribution of recurrent adenoma location by slightly decreasing distal-only and proximal-only adenoma recurrence and increasing synchronous proximal and distal adenoma recurrence, the risk of adenoma recurrence by location was similar (Table 4). Combining the T1 results with the T0 results and considering the combination as baseline increased the synchronous proximal and distal adenoma percentage from 17.8% to 30.3%, but again did not materially change the associations with risk or location of adenoma recurrence (Table 4). Of note, we observed a similar pattern among participants who did not undergo T1 colonoscopy (n ⫽ 133). Forty-eight participants had an adenoma at the end-of-trial colonoscopy (36.1%). Distal-only adenomas decreased www.giejournal.org
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Table 2. Risk and location of missed adenoma detected at T1 colonoscopy by baseline adenoma location
Adenoma distribution, no. (%)
Proximal-only missed adenomas, RR (95% CI)
Synchronous proximal and distal missed adenomas, RR (95% CI)
Baseline (T0) (n ⴝ 1730)
Missed (T1) (n ⴝ 598)
Any missed adenomas, RR (95% CI)
Distal-only missed adenomas, RR (95% CI)
Distal only
955 (55.2)
209 (34.9)
Reference
Reference
Reference
Reference
Proximal only
466 (26.9)
284 (47.5)
1.28 (1.09-1.49)
0.97 (0.67-1.39)
2.05 (1.49-2.80)
1.17 (0.69-2.01)
Synchronous proximal and distal
309 (17.9)
105 (17.6)
1.50 (1.26-1.79)
1.62 (0.98-2.68)
2.05 (1.33-3.14)
2.02 (1.12-3.63)
Adenoma location
Models were adjusted for age, sex, body mass index, family history of colorectal cancer, use of nonsteroidal anti-inflammatory drugs, and number of adenomas at baseline. Comparison group ⫽ no missed adenomas (n ⫽ 1132). T0, Qualifying baseline colonoscopy; T1, clearing colonoscopy performed 1 year after enrollment to remove missed lesions; RR, relative risk; CI, confidence interval.
Table 3. Risk and location of missed advanced adenoma detected at T1 colonoscopy by baseline adenoma location
Advanced adenoma distribution, no. (%)
Distal-only missed advanced adenomas, RR (95% CI)
Any proximal missed advanced adenomas, RR (95% CI)
Baseline (T0) (n ⴝ 670)
Missed (T1) (n ⴝ 102)
Any missed advanced adenomas, RR (95% CI)
Distal only
416 (62.1)
43 (42.2)
Reference
Reference
Reference
Proximal only
105 (15.7)
54 (52.9)
1.79 (1.17-2.75)
0.88 (0.41-1.89)
3.34 (1.75-6.39)
Synchronous proximal and distal
149 (22.2)
5 (4.9)
1.72 (1.00-2.95)
0.95 (0.35-2.57)
2.92 (1.23-6.93)
Adenoma location
Models were adjusted for age, sex, body mass index, family history of colorectal cancer, use of nonsteroidal anti-inflammatory drugs, and number of adenomas at baseline. Comparison group ⫽ no missed adenomas (n ⫽ 1132); any proximal missed advanced adenomas ⫽ proximal only plus synchronous proximal and distal missed advanced adenoma (n ⫽ 59). T0, Qualifying baseline colonoscopy; T1, clearing colonoscopy performed 1 year after enrollment to remove missed lesions; RR, relative risk; CI, confidence interval.
from 55.6% at baseline to 22.9% at recurrence, whereas proximal-only adenomas increased from 27.8% to 52.1%, but synchronous proximal and distal adenomas increased from 16.5% to 25%.
of the recurrence (Table 5) or with the baseline adenomas (Table 5).
Advanced adenoma recurrence by location
We evaluated the association between adenoma location at baseline with the risk of adenoma recurrence and the location of the recurrent adenoma in an attempt to assess differences in susceptibility to adenoma recurrence by location. Our study suggests 3 potential mechanisms underlying a lower protective effect of colonoscopy in the proximal colon. First, we report that missed lesions are more common in the proximal colon. Second, recurrent adenomas and advanced adenomas are more likely to be in the proximal colon. Third, compared with the participants with a distal-only adenoma at baseline, participants with a proximal-only adenoma at baseline are more likely to have an adenoma and advanced adenoma recurrence, particularly in the proximal colon. Our sensitivity analyses investigating the effect of missed lesions suggest that
A total of 119 participants had advanced adenoma recurrence (47 distal only, 60 proximal only, and 12 synchronous proximal and distal). The percentage of proximal-only advanced adenomas increased from 15.7% at baseline to 50.4% at recurrence (Table 5). When compared with participants with a distal-only adenoma at baseline, those with proximal-only adenoma at baseline had a borderline increased risk of an advanced adenoma recurrence (RR 1.50; 95% CI, 0.99-2.27) (Table 5) and were more likely to have an advanced adenoma recurrence in a proximal location (RR 3.62; 95% CI, 1.96-6.71), but less likely to have an advanced adenoma recurrence in the distal colon (RR 0.34; 95% CI, 0.13-0.90) (Table 5). This pattern persisted, despite including the T1 lesions as part www.giejournal.org
DISCUSSION
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Table 4. Risk and location of recurrent adenoma by baseline adenoma location A. Risk and location of recurrent adenomas (T4) by baseline adenoma location (T0)
Adenoma distribution, no. (%)
Distal only adenoma recurrence RR (95% CI)
Proximal only adenoma recurrence RR (95% CI)
Synchronous proximal and distal adenoma recurrence RR (95% CI)
At baseline (T0) (n ⴝ 1864)
At recurrence (T4) (n ⴝ 733)
Any adenoma recurrence RR (95% CI)
Distal only
1030 (55.3)
228 (31.1)
Reference
Reference
Reference
Reference
Proximal only
503 (27.0)
369 (50.3)
1.14 (1.00-1.31)
0.67 (0.46-0.97)
1.52 (1.15-2.02)
1.88 (1.21-2.90)
Synchronous proximal and distal
331 (17.8)
136 (18.6)
1.20 (1.03-1.40)
1.00 (0.63-1.60)
1.20 (0.80-1.79)
1.83 (1.04-3.21)
Adenoma location
B. Risk and location of combined missed and recurrent adenomas (T1 ⴙ T4) by baseline adenoma location (T0) Adenoma distribution, no. (%)
At baseline (T0) (n ⴝ 1863)
At recurrence (T1 ⴙ T4) (n ⴝ 1013)
Any adenoma recurrence RR (95% CI)
Distal-only adenoma recurrence RR (95% CI)
Proximal-only adenoma recurrence RR (95% CI)
Synchronous proximal and distal adenoma recurrence RR (95% CI)
Distal only
1029 (55.2)
282 (27.8)
Reference
Reference
Reference
Reference
Proximal only
503 (27.0)
428 (42.3)
1.30 (1.17-1.45)
0.68 (0.48-0.98)
1.89 (1.44-2.50)
1.67 (1.20-2.32)
Synchronous proximal and distal
331 (17.8)
303 (29.9)
1.35 (1.18-1.53)
1.23 (0.75-1.99)
1.47 (0.96-2.23)
1.91 (1.22-2.30)
Adenoma location
C. Risk and location of recurrent adenoma (T4) by combined baseline and missed adenoma location (T0 ⴙ T1)
At recurrence (T4) (n ⴝ 685)
Any adenoma recurrence RR (95% CI)
Distal-only adenoma recurrence RR (95% CI)
Proximal-only adenoma recurrence RR (95% CI)
Synchronous proximal and distal adenoma recurrence RR (95% CI)
813 (47.0)
217 (31.7)
Reference
Reference
Reference
Reference
Proximal only
392 (22.7)
344 (50.2)
1.17 (1.00-1.37)
0.60 (0.39-0.93)
1.64 (1.19-2.25)
2.83 (1.62-4.94)
Synchronous proximal and distal
525 (30.3)
124 (18.1)
1.36 (1.18-1.57)
1.08 (0.74-1.58)
1.66 (1.20-2.31)
3.83 (2.23-6.56)
Adenoma distribution, no. (%) At baseline (T0 ⴙ T1) n ⴝ 1730
Distal only
Adenoma location
Models were adjusted for age, sex, body mass index, family history of colorectal cancer, use of nonsteroidal anti-inflammatory drugs, and number of adenomas at baseline. Comparison group A ⫽ no adenoma recurrence (n ⫽ 1131); comparison group B ⫽ no adenoma recurrence (n ⫽ 850); comparison group C ⫽ no adenoma recurrence (n ⫽ 1045). T0, Qualifying baseline colonoscopy; T4, end-of-trial colonoscopy; RR, relative risk; CI, confidence interval; T1, clearing colonoscopy performed 1 year after enrollment to remove missed lesions.
missed lesions may not explain the differentially increased proportion of proximal adenoma at recurrence. This suggests the possibility of an underlying biological difference in susceptibility to recurrence of colonic neoplasia in the proximal and distal colon and identifies patients with a proximal adenoma as at high risk of recurrence. This may in part explain some of the observed differences in the efficacy of colonoscopy by colon subsite. Further studies on the role of tumor location in the natural history of colorectal neoplasia are needed. We are not aware of any study that evaluated the effect of missed lesions on the risk and location of adenoma 258 GASTROINTESTINAL ENDOSCOPY Volume 74, No. 2 : 2011
recurrence for a direct comparison with our study. Missed lesions at colonoscopy are relatively common, and segmental unblinding of virtual colonoscopy results and tandem back-to-back colonoscopy have reported adenoma miss rates as high as 27%.22-27 A repeat colonoscopy after 1 year in our cohort of patients with a history of adenoma detected additional adenomas in 34.6% of patients and advanced adenomas in 6% of patients. Per the design of the PPT, these were regarded as missed lesions. However, the inclusion or exclusion of these lesions from our analysis did not affect the increased risk of adenoma recurrence that we observed in association with previous proxwww.giejournal.org
Laiyemo et al
Missed and recurrent adenoma location
Table 5. Risk and location of recurrent advanced adenoma by baseline adenoma location A. Risk and location of recurrent advanced adenoma (T4) by baseline adenoma location (T0) (N ⴝ 1864) Advanced adenoma distribution, no. (%)
Distal-only recurrent advanced adenomas RR (95% CI)
Any proximal recurrent advanced adenomas RR (95% CI)
Baseline (T0) (n ⴝ 705)
Recurrent (T4) (n ⴝ 119)
Any recurrent advanced adenomas RR (95% CI)
Distal only
440 (62.4)
47 (39.5)
Reference
Reference
Reference
Proximal only
111 (15.7)
60 (50.4)
1.50 (0.99-2.27)
0.34 (0.13-0.90)
3.62 (1.96-6.71)
Synchronous proximal and distal
154 (21.8)
12 (10.1)
1.92 (1.14-3.25)
0.94 (0.38-2.37)
4.30 (1.92-9.66)
Adenoma location
B. Risk and location of combined missed and recurrent advanced adenoma (T1 ⴙ T4) by baseline adenoma location (T0) (N ⴝ 1863) Advanced adenoma distribution, no. (%)
Distal-only recurrent advanced adenomas, RR (95% CI)
Any proximal recurrent advanced adenomas, RR (95% CI)
Baseline (T0) (n ⴝ 705)
Recurrent (T1 ⴙ T4) (n ⴝ 196)
Any recurrent advanced adenomas, RR (95% CI)
Distal only
440 (62.4)
76 (38.8)
Reference
Reference
Reference
Proximal only
111 (15.7)
101 (51.5)
1.61 (1.20-2.16)
0.49 (0.24-0.99)
3.91 (2.41-6.33)
Synchronous proximal and distal
154 (21.8)
19 (9.7)
1.77 (1.23-2.53)
0.90 (0.41-1.96)
3.55 (1.82-6.95)
Adenoma location
C. Risk and location of recurrent advanced adenoma (T4) by combined baseline and missed adenoma location (T0 ⴙ T1) (N ⴝ 1730) Advanced adenoma distribution, no. (%)
Distal-only recurrent advanced adenomas, RR (95% CI)
Any proximal recurrent advanced adenomas, RR (95% CI)
Baseline (T0 plus T1) n ⴝ 709
Recurrent (T4) (n ⴝ 112)
Any recurrent advanced adenomas, RR (95% CI)
Distal only
432 (60.9)
43 (38.4)
Reference
Reference
Reference
Proximal only
123 (17.3)
58 (51.8)
1.36 (0.84-2.20)
0.16 (0.04-0.68)
4.21 (2.06-8.63)
Synchronous proximal and distal
154 (21.7)
11 (9.8)
1.62 (1.02-2.57)
1.09 (0.55-2.13)
4.98 (2.48-10.00)
Adenoma location
Models were adjusted for age, sex, body mass index, family history of colorectal cancer, use of nonsteroidal anti-inflammatory drugs, and number of adenomas at baseline. Comparison group A ⫽ no adenoma recurrence (n ⫽ 1131); comparison group B ⫽ no adenoma recurrence (n ⫽ 850); comparison group C ⫽ no adenoma recurrence (n ⫽ 1045); any proximal recurrent advanced adenoma ⫽ proximal only plus synchronous proximal and distal recurrent advanced adenomas. T4, End-of-trial colonoscopy; T0, qualifying baseline colonoscopy; RR, relative risk; CI, confidence interval; T1, clearing colonoscopy performed 1 year after enrollment to remove missed lesions.
imal adenoma or the proximal location of recurrent adenoma. Also, we addressed the possibility that adenomas detected at T1 colonoscopy may be recurrent lesions because of the 1-year interval between T0 and T1 colonoscopy. We added the adenoma at T1 to the end-of-trial colonoscopic findings but the results were unchanged. Our finding of a proximal shift in metachronous adenoma is comparable with the findings of previous studies (Table 6).28-32 Although the magnitude of effect may differ, all of the studies showed a consistent pattern of a decreased percentage of distal adenomas at recurrence, whereas the percentage of proximal adenomas increased. www.giejournal.org
This mirrors the increased proportion of proximal-only adenomas from 27% at baseline to 50.3% at recurrence reported in our study and suggests the possibility of different biological susceptibilities to neoplasia by colon subsite. The increased tendency for recurrence in the proximal colon may offer some explanation why the efficacy of colonoscopy may be lower in that location. However, the current postpolypectomy surveillance guidelines21 do not take adenoma location into consideration for surveillance interval recommendations. Prospective studies evaluating the optimal surveillance intervals after polypectomy in the Volume 74, No. 2 : 2011 GASTROINTESTINAL ENDOSCOPY 259
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Table 6. Previous studies that evaluated adenoma location at baseline and at recurrence
Study Martinez et al,28 2001
Nusko et
al,29
2001
Bonithon-Kopp et al,30 2004
Yamaji et al,31 2007
Nusko et
al,32
2009
Current study*
Distribution of adenomas, no. (%)
Mean follow-up interval, y
Adenoma location
At baseline
At recurrence
3
Distal
704 (54.6)
172 (27.7)
Proximal
349 (27.2)
281 (45.2)
Both
234 (18.2)
169 (27.1)
Distal
606 (55.5)
204 (36.7)
Proximal
246 (22.6)
300 (54.0)
Both
239 (21.9)
52 (9.4)
Any distal
502 (90.9)
82 (67.2)
Any proximal
114 (20.7)
62 (50.8)
Distal
1392 (48.0)
318 (41.4)
Proximal
894 (30.8)
334 (43.4)
Both
614 (21.2)
117 (15.2)
Distal
364 (63.5)
293 (51.2)
Proximal
86 (15.0)
164 (29.7)
Both
123 (21.5)
115 (20.1)
Distal
1030 (55.3)
228 (31.1)
Proximal
503 (27.0)
369 (50.3)
Both
331 (17.8)
136 (18.6)
3.4
3
4
3
4
*Our finding is included for easy comparison.
distal versus the proximal colon and studies focusing on factors (including molecular markers) that reliably predict proximal neoplasia recurrence are needed. Although missed adenomas did not affect proximal versus distal adenoma recurrence in our study, the importance of performing a good-quality colonoscopic examination should be emphasized. Of note, we found more missed lesions in the proximal colon at T1 colonoscopy. The rates of missed lesions vary and are dependent on endoscopists’ experience, withdrawal time, and attention to details. Optimal bowel preparation through splitting the bowel preparation laxatives so that some laxatives are consumed a few hours before the procedure is important as well as ongoing efforts to improve the technology of colonoscopy itself such as the use of high-definition endoscopes, chromoendoscopy, and cap-fitted colonoscopy to minimize the risk of missing important lesions in clinical practice. A recent study reported that endoscopists with low adenoma detection rates perform colonoscopies that are associated with a higher risk of interval cancers.33 There are many strengths of our study. A unique feature of our study is the T1 colonoscopy performed in 93% of our study cohort to remove lesions that might have been missed at baseline colonoscopy, which afforded us the opportunity to evaluate the effect of missed lesions. Our 260 GASTROINTESTINAL ENDOSCOPY Volume 74, No. 2 : 2011
study population is from a large randomized, controlled trial with participants recruited from geographically dispersed areas, information on candidate risk factors was prospectively gathered, all patients had planned colonoscopic assessment for recurrence after an adequate follow-up period, and dedicated central pathologists with expertise in GI tumors examined the adenomas, thereby ensuring consistency. Our study also has limitations. The participants in the PPT were self-selected and may be healthier than comparable members of the general population. The design of the PPT also limited the degree of obesity of participants. Because obesity has been associated with an increased risk of colonic neoplasia,34 the yield of adenomas in our study may be lower than expected in the general population. We could not assess the effect of serrated polyps and flat, and depressed lesions in our study because they were not widely discussed at the time that the trial was conducted. Furthermore, repeated colonoscopies may still miss lesions. In conclusion, we observed an increased tendency for adenoma recurrence in the proximal colon, supporting the current practice of the use of colonoscopy for surveillance regardless of the location of index adenoma. However, further studies are needed to elucidate whether this sugwww.giejournal.org
Laiyemo et al
gested biological difference warrants modification of postpolypectomy surveillance intervals. REFERENCES 1. Prorok PC, Andriole GL, Bresalier RS, et al. Design of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Control Clin Trials 2000;21(6 Suppl):273S-309S. 2. Segnan N, Senore C, Andreoni B, et al. Baseline findings of the Italian multicenter randomized controlled trial of “once-only sigmoidoscopy” SCORE. J Natl Cancer Inst 2002;94:1763-72. 3. Gondal G, Grotmol T, Hofstad B, et al. The Norwegian Colorectal Cancer Prevention (NORCCAP) screening study: baseline findings and implementations for clinical work-up in age groups 50-64 years. Scand J Gastroenterol 2003;38:635-42. 4. Newcomb PA, Norfleet RG, Storer BE, et al. Screening sigmoidoscopy and colorectal cancer mortality. J Natl Cancer Inst 1992;84:1572-5. 5. Selby JV, Friedman GD, Quesenberry CP Jr, et al. A case-control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med 1992;326:653-7. 6. Atkin WS, Edwards R, Kralj-Hans I, et al; UK Flexible Sigmoidoscopy Trial Investigators. Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet 2010;375:1624-33. 7. Subramanian S, Amonkar MM, Hunt TL. Use of colonoscopy for colorectal cancer screening: evidence from the 2000 National Health Interview Survey. Cancer Epidemiol Biomarkers Prev 2005;14:409-16. 8. Doubeni C, Laiyemo AO, Reed G, et al. Socioeconomic and racial patterns of colorectal cancer screening among Medicare enrollees 20002005. Cancer Epidemiol Biomarkers Prev 2009;18:2170-5. 9. Singh H, Turner D, Xue L, et al. Risk of developing colorectal cancer following a negative colonoscopy examination: evidence for a 10-year interval between colonoscopies. JAMA 2006;295:2366-73. 10. Lakoff J, Paszat LF, Saskin R, et al. Risk of developing proximal versus distal colorectal cancer after a negative colonoscopy: a populationbased study. Clin Gastroenterol Hepatol 2008;6:1117-21. 11. Baxter NN, Goldwasser MA, Paszat LF, et al. Association of colonoscopy and death from colorectal cancer. Ann Intern Med 2009;150:1-8. 12. Singh H, Nugent Z, Demers AA, et al. The reduction in colorectal cancer mortality after colonoscopy varies by site of the cancer. Gastroenterology 2010;139:1128-37. 13. Kahi CJ, Imperiale TF, Juliar BE, et al. Effect of screening colonoscopy on colorectal cancer incidence and mortality. Clin Gastroenterol Hepatol 2009;7:770-5. 14. Brenner H, Hoffmeister M, Arndt V, et al. Protection from right- and leftsided colorectal neoplasms after colonoscopy: population-based study. J Natl Cancer Inst 2010;102:89-95. 15. Brenner H, Chang-Claude J, Seiler CM, et al. Protection from colorectal cancer after colonoscopy: a population-based, case-control study. Ann Intern Med 2011;154:22-30. 16. Rex DK, Eid E. Considerations regarding the present and future roles of colonoscopy in colorectal cancer prevention. Clin Gastroenterol Hepatol 2008;6:506-14.
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