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Colonoscopy may be less efficacious in reducing colorectal cancer mortality in the proximal as compared with the distal colon. A greater likelihood for missed and recurrent adenomas in the proximal colon may contribute to this phenomenon.
To examine whether a proximal adenoma is associated with the risk and location of missed and recurrent adenomas.
Polyp Prevention Trial
1,864 patients with adenoma at baseline underwent a follow-up colonoscopy four years later (adenoma recurrence). Of these, 1,731 underwent a clearing colonoscopy one year after the baseline examination (missed adenoma).
Association of baseline adenoma location with the risk and location of adenomas found at colonoscopy performed one year and four years later.
At the year 1 colonoscopy, 598 (34.6%) patients had an adenoma (missed adenoma). Compared with those with distal only adenoma at baseline, patients with proximal only adenoma at baseline were more likely to have any missed adenoma (relative risk (RR)=1.28; 95% confidence interval (CI): 1.09–1.49) and proximal only missed adenoma (RR=2.05; 95%CI: 1.49–2.80).
At the year 4 colonoscopy, 733 (39.3%) patients had an adenoma recurrence. Patients with baseline proximal only adenoma were more likely to have any adenoma recurrence (RR=1.14; 95%CI: 1.00–1.31) and 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 four colonoscopy.
Lesions may still be missed with repeated colonoscopies.
Missed and recurrent adenomas are more likely to be in the proximal colon.
Although three randomized controlled trials of the effect of screening sigmoidoscopy on colorectal cancer mortality are still ongoing,1–3 case-control studies4, 5 and one 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 a limited efficacy of colonoscopy in reducing proximal colon cancer incidence9, 10 and mortality.11, 12 In the United States, Kahi et al.13 reported an overall reduction in the incidence of colon cancer in a postpolypectomy cohort when compared with Surveillance Epidemiology and End Results (SEER) data, but 5 out of the 6 colon cancers diagnosed after colonoscopy were located in the proximal colon. Furthermore, a study from Germany reported a reduction in advanced adenoma recurrence in the distal but not in the proximal colon with history of previous colonoscopy.14 Although a recent population-based case-control study reported an overall 77% reduced risk of colorectal cancer with prior exposure to colonoscopy, the protection conferred by colonoscopy in the proximal colon was only two-thirds of the protection in the distal colon (56% versus 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 when 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 for recurrence in the proximal colon than patients with distal adenomas, then colonoscopy might be less efficacious in the proximal when 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 among participants in the Polyp Prevention Trial (PPT).
The rationale, design, and results of the PPT have been 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 risk of colorectal adenoma recurrence. A total of 2,079 participants who were at least 35 years old and had one 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 above 150% of the ideal. The clinical trial was approved by the Institutional Review Boards of the National Cancer Institute, and each of the eight participating clinical centers. All participants gave written informed consent.
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 one year after randomization (T1) to remove any lesion that may have been missed at qualifying colonoscopy (T0). This clearing colonoscopy was completed by 1,768 participants. All participants were followed for approximately four years after randomization, and had an end-of-trial (T4) colonoscopy to ascertain adenoma recurrence. A total of 1,905 (91.6%) participants 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 of 1,864 participants, of whom 1,731 (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 two trial pathologists who were masked to the participants' randomization assignments.18 Advanced adenomas were defined as those with size ≥1 cm in diameter or villous histology or high grade dysplasia.21
We estimated relative risks (RR) and 95% confidence interval (CI) using Poisson regression to evaluate the association between baseline adenoma location and missed adenoma detected at year one colonoscopy and adenoma recurrence at year four colonoscopy. We used multinomial regression analyses to evaluate the association of baseline adenoma location with missed adenoma location at year one 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 three mutually exclusive groups: those with distal only adenoma; those with proximal only adenoma; and those with synchronous proximal and distal adenoma. For any missed adenoma (outcome) and any recurrent adenoma (outcome), we classified adenoma into four mutually exclusive groups according to the findings at the T1 or T4 colonoscopy: those without any adenoma (comparison group); those with distal only adenoma; those with proximal only adenoma and those with synchronous proximal and distal adenoma. We did a similar categorization for advanced adenoma, but there were few participants with synchronous proximal and distal advanced adenoma. Therefore, those with any missed or recurrent proximal advanced adenoma were included in one 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).
In order to evaluate the effect of missed lesions on the risk and location of adenoma recurrence at T4, we re-analyzed our data to include adenomas found at the T1 clearing colonoscopy. Of 1,731 participants who underwent T1 colonoscopy, we could not identify the specific location of the adenoma found in one 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 the 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 versus no), use of non-steroidal anti-inflammatory drugs at least once a month (yes versus no) and number of adenoma at baseline (continuous). We used Stata ® statistical software version 9 (College Station, Texas) for all analyses. All reported P-values correspond to two-sided tests.
Table 1 shows selected baseline characteristics of study participants by the location of baseline adenoma. At baseline, 1,030 (55.3%) participants had distal adenoma only, 503 (27%) had proximal adenoma only and 331 (17.8%) had synchronous proximal and distal adenoma. A total of 750 (37.8%) patients had advanced adenoma at baseline: 440 (62.4%) participants had distal only advanced adenoma, 111 (15.7%) had proximal only advanced adenoma and 154 (21.8%) had 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 adenoma at baseline varied significantly (p< 0.05) by baseline adenoma location.
Participants who did not undergo clearing (T1) colonoscopy (n = 133) were comparable to those who did (n = 1,731) except that those who did not were slightly younger (mean age 59.3 years versus 61.2 years; P value = 0.04) and were more likely to be current smokers (23.3% versus 12.4%; P value = 0.001). Of those with complete T1 colonoscopy information (n = 1,730), 598 (34.6%) patients 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 distal only adenoma at baseline, patients with proximal only adenoma at baseline were more likely to have a missed adenoma (i.e. any adenoma found at T1 colonoscopy) (RR = 1.28; 95%CI: 1.09–1.49) and proximal only missed adenoma (RR = 2.05; 95%CI: 1.49–2.80). A total of 102 (5.9%) patients had an advanced adenoma at T1 colonoscopy, of whom 63 (61.8%) had advanced adenoma at baseline (T0). Participants with proximal only adenoma at baseline (T0) were also more likely to have any missed advanced adenoma (RR = 1.79; 95%CI: 1.17–2.75) and any proximal missed advanced adenoma (RR = 3.34; 95%CI: 1.75–6.39) (Table 3).
For the main analysis assessing the risk and location of recurrent adenoma at T4 colonoscopy, 733 (39.3%) participants had adenoma recurrence whereas 1,131 (60.7%) had no adenoma recurrence. Among those with distal only, proximal only and synchronous proximal and distal adenoma 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 distal only adenoma at recurrence (55.3% at baseline versus 31.1% at T4), an increase in the percentage of patients with proximal only at recurrence (27.0% at baseline versus 50.3% at T4), but similar percentage of patients with synchronous proximal and distal adenoma at baseline and recurrence (17.8% at baseline versus 18.6% at T4) (Table 4A). Compared with those with distal only adenoma at baseline, the risk of adenoma recurrence was higher for those with proximal only adenoma at baseline (RR = 1.14; 95% CI: 1.00–1.31) and for those with synchronous proximal and distal adenoma at baseline (RR = 1.20; 95%CI: 1.03–1.40) (Table 4A). 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 increased 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 recurrence and increasing synchronous proximal and distal recurrence, the risk of adenoma recurrence by location were similar (Table 4B). 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 4C).
Of note, we observed a similar pattern among participants who did not undergo T1 colonoscopy (n = 133). Forty-eight participants had adenoma at the end-of-trial colonoscopy (36.1%). Distal only adenomas decreased 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 adenoma increased from 16.5% to 25%.
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 adenoma increased from 15.7% at baseline to 50.4% at recurrence (Table 5A). 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 5A) 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 distal colon (RR = 0.34; 95%CI: 0.13–0.90) (Table 5A). This pattern persisted, despite including the T1 lesions as part of the recurrence (Table 5B) or with the baseline adenomas (Table 5C).
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 three potential mechanisms underlying a lower protective effect of colonoscopy in the proximal colon. Firstly, we report that missed lesions are more common in the proximal colon. Secondly, recurrent adenoma and advanced adenoma are more likely to be in the proximal colon and thirdly, when compared with the participants with distal only adenoma at baseline, participants with proximal 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 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 high-risk for 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 has evaluated the effect of missed lesions on the risk and location of adenoma 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 adenoma in 34.6% of patients and an advanced adenoma in 6% of patients. Per the design of 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 we observed in association with previous proximal 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 one 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 proximal shift in metachronous adenoma is comparable to previous studies (Table 6).28–32 Although the magnitude of effect may differ, all the studies showed a consistent pattern of reduced percentage of distal adenoma at recurrence whereas the percentage of proximal adenoma increased. This mirrors the increased proportion of proximal only adenoma 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 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 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 gastrointestinal 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. Since 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, flat, and depressed lesions in our study because they were not widely discussed at the time 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 suggested biological difference warrants modification of postpolypectomy surveillance intervals.
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 (5K01CA127118-03) from the National Cancer Institute.
Financial disclosure: This research was funded by the Intramural Research Program of the National Cancer Institute, National Institutes of Health.
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Conflict of interest: None
Disclosure An abstract from this study was presented as an oral presentation at the Digestive Diseases Week in Chicago on June 1, 2009. (Gastrointest Endosc. 2009; 69:AB108)