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Missed polyps, missed opportunities
EDITORIAL
Missed polyps, missed opportunities Colorectal cancer is the third most common cancer and the second leading cause of cancer death in the United States, with an estimated 141,210 new cases and 49,380 deaths in 2011. Fortunately, colorectal cancer remains highly preventable through several available screening modalities that can lead to the detection and removal of adenomatous polyps. Although more resource intensive and invasive than other established alternatives, colonoscopy is traditionally considered by many to be the most effective screening option. Colonoscopy permits immediate polypectomy and removal of macroscopically abnormal tissue in contrast to tests based on radiographic imaging or detection of occult blood or exfoliated DNA in stool. Colonoscopy also directly visualizes the entire extent of the colon and rectum, including segments of the colon that are beyond the reach of flexible sigmoidoscopy. Despite this compelling rationale, recent research has called into question the effectiveness of colonoscopy in its ability to confer protection from proximal colon cancer.1-4 In a study of 54,803 subjects in Manitoba, Singh et al4 observed a 29% reduction in mortality from colorectal cancer associated with colonoscopy. However, the benefit was confined entirely to death associated with distal colorectal cancer (standardized mortality ratio 0.53; 95% CI, 0.42-0.67), but not proximal cancer (standardized mortality ratio 0.95; 95% CI, 0.77-1.17). Similarly, a study from Ontario of 10,292 case patients and 51,460 controls found fewer colorectal cancer deaths from distal (adjusted odds ratio 0.33; 95% CI, 0.28-0.39) but not proximal cancer (OR 0.99; 95% CI, 0.86-1.14).1 However, a caveat of both studies is that a substantial proportion of colonoscopies were performed by non-gastroenterologists; Singh et al4 also showed that the reduction in colorectal cancer mortality was significantly greater after a colonoscopy was performed by a gastroenterologist compared with an internist or general surgeon. Moreover, other studies have had a far less pessimistic view. In a German study, colonoscopy was associated with not only a significant 84% lower risk of distal colorectal cancer but a 56% decrease in risk of proximal colon cancer.5 Similarly, Lakoff et al6 showed that after a colonoscopy without pathological findings, a reduction in the incidence of colorectal cancer persisted for 14 years in the distal colon and 7 years in the proximal
Copyright © 2011 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2011.05.019
262 GASTROINTESTINAL ENDOSCOPY Volume 74, No. 2 : 2011
colon. Taken together, these studies suggest that colonoscopy does prevent cancers of the proximal colon, albeit perhaps with less effectiveness than cancers of the left colon or rectum.7
Continuing investigation into relevant clinical and biological predictors of recurrent or interval lesions, considered according to anatomic location in the colon, will facilitate optimal risk stratification.
There are several potential explanations for this apparent disparity. First, the proximal colon is often more difficult to cleanse than the distal colorectum, leading to suboptimal mucosal visualization. Some studies have suggested that the use of split-dose laxatives, with the last dose consumed a few hours before the procedure, may help ameliorate this problem. Second, the proximal colon may harbor a greater prevalence of neoplastic lesions that are macroscopically more difficult to distinguish from normal mucosa—“flat” or nonpolypoid lesions—that may more likely contain invasive carcinoma.8 Proximal lesions may also be more likely to be located on or behind mucosal folds, eluding the view of a standard forward-viewing colonoscope.9 In a CT simulation study, East et al10 estimated that only 87% of the colonic surface area was routinely visualized during an examination using a standard colonoscope. Several techniques and technological advances have been developed to improve inspection of mucosa behind folds, including increasing the field of view to 170 degrees to achieve nearly complete visualization. However, a randomized trial of high-definition wideangle colonoscopy compared with standard colonoscopy did not demonstrate a significant difference in the yield of polyps or adenomas.11 Similarly, narrow-band imaging and chromoendoscopy appear to better discriminate adenomatous from nonadenomatous polyps, but in practice have not consistently yielded a greater adenoma detection rate.12-16 Finally, a third-eye retroscope inserted through the biopsy channel of a standard colonoscope has shown promise in visualizing areas behind mucosal folds but still requires additional study.17 Are there simpler methods by which we can improve standard colonoscopy’s performance in the proximal cowww.giejournal.org
Ananthakrishnan & Chan
lon? In this issue of Gastrointestinal Endoscopy, Hewett and Rex18 help address this question by evaluating the efficacy of retroflexion in the ascending colon as a simple technique to improve visualization of proximal lesions. In their study of 1000 consecutive patients undergoing a screening or surveillance colonoscopy at a single tertiary center, 1 of 2 expert endoscopists successfully examined the mucosa up to the level of the hepatic flexure in 944 patients (94.4%) in whom they attempted a retroflexed examination after intubating the cecum. Among this cohort, a total of 346 patients (34.6%) were found to have polyps in the proximal colon with 271 patients (27.1%) harboring proximal colon adenomas. Retroflexion visualized an additional 68 polyps (54 adenomas) that would otherwise have been missed without retroflexion. Two thirds of patients with polyps found on retroflexion had a negative forward-viewing examination. Overall, retroflexion was able to detect an additional polyp in 5.8% of patients and an additional adenoma in 4.4% of patients. No patients experienced significant complications from the retroflexed examination. Although an increase in the adenoma detection rate of less than 5% may initially seem modest, these results are promising given the relative ease with which the technique described by Hewett and Rex could be adopted by most gastroenterologists. In contrast to wide-angle colonoscopy or a third-eye retroscope, retroflexion in the proximal colon would not require additional equipment or training because most gastroenterologists are already familiar with retroflexion in the rectum. Thus, this technique may, at least in the short term, have the potential for a greater population-wide public health impact than more technologically complex advances. Nonetheless, these results should be interpreted in the context of previous evidence and certain limitations of the current study. First, an earlier randomized trial examining the value of the retroflexion conducted by this group did not appear to demonstrate a significant benefit with retroflexion.19 In that study, after patients underwent an initial examination in the forward-viewing mode by a gastroenterology fellow, a single expert attending then randomized patients to a second examination from the cecum to the splenic flexure in either the forward or retroflexed mode. The miss rate for polyps (36.8% vs 38.1%) or adenomas (33.3% vs 23.7%) was not significantly different between the 2 groups. Second, in the current study, the presence of adenomas on forward examination predicted the likelihood of polyps visualized on retroflexion and the additional adenomas detected using retroflexion were small with nonadvanced histology. In view of the established 10% to 25% miss rate for adenomas found in tandem colonoscopy studies,20-22 the additional polyps detected by the retroflexed examination could reasonably be inferred to be due to a more careful “second look” rather than the retroflexion technique itself. Last, all procedures were performed by 2 experienced endoscopists. Given the www.giejournal.org
Editorial
limited data on the safety of retroflexion in the right side of the colon and the known association of perforation with retroflexion in the rectum,23 it remains possible that broader use of this technique could still be associated with higher rates of complications. Similarly, the greater than 90% rate of success in performing retroflexion observed in the current study may be difficult to match in the hands of less experienced endoscopists. Nonetheless, improving the performance characteristics of colonoscopy may not completely erase the difference in benefit associated with colonoscopy for cancers of the proximal colon compared with the distal colorectum. Aside from morphological differences, adenomas in the proximal colon may possess biologically distinct characteristics compared with those located more distally. A second study in this issue of Gastrointestinal Endoscopy supports this possibility.24 Laiyemo et al24 used data from the Polyp Prevention Trial, a multicenter trial of 2079 participants who were randomized to a low-fat, high-fiber, high fruit and vegetable intake diet after recent removal of an adenoma on an index examination.25 In their analysis, the investigators examined the rates and anatomic location of recurrent and missed adenomas according to the anatomic location of the initial adenoma in 1864 patients. Among this cohort, 1731 underwent a clearing colonoscopy at 1 year after randomization, and all participants completed a surveillance colonoscopy at 4 years. More than half the participants (55.3%) had only a distal adenoma at baseline, whereas 27% had a proximal adenoma only and 17.8% had both a proximal adenoma and a distal adenoma. At the 1-year colonoscopy, one third (34.6%) had adenomas, which were assumed to be “missed” lesions, with nearly half of these patients having missed lesions confined to the proximal colon. Among those with only a proximal adenoma at baseline, there was a higher risk of missed adenomas (relative risk [RR] 1.28; 95% CI, 1.09-1.49) or missed advanced adenoma (RR 1.79; 95% CI, 1.17-2.75) in any location of the colon, as well as a particularly high risk of missed adenomas in the proximal colon (RR 3.34; 95% CI, 1.75-6.39). At 4 years, 39.3% participants had an adenoma, assumed to be a recurrent adenoma that developed after the 1-year “clearing” examination. Half of these patients had recurrent lesions confined to the proximal colon. As with the findings at the 1-year examination, having a baseline adenoma located in the proximal colon was associated with an increased risk of recurrent adenoma, recurrent advanced adenoma, and recurrent adenoma in the proximal colon. Based on these results, the authors reasonably conclude that having a baseline adenoma in the proximal colon is associated with a higher risk of both missed and recurrent adenomas in any part of the colon as well as the proximal colon. The higher rate of missed adenomas in the proximal colon at the 1-year colonoscopy associated with a baseline proximal adenoma could be related to inadequate bowel cleansing or technical limitations of standard colonoscopy Volume 74, No. 2 : 2011 GASTROINTESTINAL ENDOSCOPY 263
Editorial
in visualizing the proximal colon. However, it could be reasonably expected that such issues would be minimized in the context of the high quality of surveillance examinations that would be expected in the conduct of a clinical trial. In addition, the higher rate of recurrent adenomas in the proximal colon at the 4-year colonoscopy after lesions are “cleared” during the 1-year colonoscopy provides compelling evidence that adenomas in the proximal colon may possess a different biological behavior compared with adenomas in the distal colon. Proximal adenomas may grow at a faster rate and may be a stronger marker of an overall “field defect” in which macroscopically unaffected areas the colon are particularly predisposed to develop a malignant clone of cells.26 Moreover, in separate study of this Polyp Prevention Trial population, different lifestyle factors appeared to be associated with likelihood of recurrence adenoma in the right side of the colon compared with the left side of the colon.27 Taken together with data that colon cancers with distinct molecular features are differentially associated with such lifestyle factors as well as anatomic location,28 these results from the Polyp Prevention Trial support the hypothesis that colon cancer is a heterogeneous disease that is, at least in part, manifested by different anatomic location of tumors. What are the implications of these findings for routine clinical practice? Should surveillance intervals for individuals with a proximal adenoma be shortened and for those with a distal adenoma be extended? Perhaps so, but this interpretation is perhaps oversimplified because the findings of Laiyemo et al also demonstrate that patients with adenomas only found in the distal colon on their index examination are also more likely to have had a synchronous proximal lesion that was missed. Lengthening the surveillance interval in such patients could still result in a higher rate of interval cancers in the right side of the colon. Thus, based on these results alone, it is premature to alter current guidelines regarding surveillance intervals according to the location of the baseline adenoma. There are several components to reducing the public health burden of colorectal cancer. First, wider adoption of routine screening remains critical. Even a decade after Medicare began coverage of colonoscopy for average-risk screenings, the overall rate of screening remains suboptimal, particularly compared with screening rates for other cancers. Second, in individuals who undergo a screening colonoscopy, a high-quality examination characterized by optimal bowel preparation, careful visualization of the mucosal surface with particular attention to areas proximal to folds and at flexures, and an adequate withdrawal time remains fundamentally important. Third, communicating the risk of recurrent lesions to patients and providers will help facilitate adherence to surveillance guidelines. Last, continuing investigation into relevant clinical and biological predictors of recurrent or interval lesions, considered 264 GASTROINTESTINAL ENDOSCOPY Volume 74, No. 2 : 2011
Ananthakrishnan & Chan
according to anatomic location in the colon, will facilitate optimal risk stratification.
DISCLOSURE The authors are supported by the American Gastroenterological Association Research Scholars Award (ANA) and R01 CA137178 (ATC). Dr. Chan is a Damon Runyon Clinical Investigator. The authors disclosed no financial relationships relevant to this publication. Ashwin N. Ananthakrishnan, MD, MPH Andrew T. Chan, MD, MPH Gastrointestinal Unit Massachusetts General Hospital Harvard Medical School Boston, Massachusetts, USA Abbreviation: RR, relative risk.
REFERENCES 1. Baxter NN, Goldwasser MA, Paszat LF, et al. Association of colonoscopy and death from colorectal cancer. Ann Intern Med 2009;150:1-8. 2. 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. 3. 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; quiz 711. 4. 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. 5. 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. 6. 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; quiz 1064. 7. Weinberg DS. Colonoscopy: what does it take to get it “right”? Ann Intern Med 2011;154:68-9. 8. Soetikno RM, Kaltenbach T, Rouse RV, et al. Prevalence of nonpolypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults. JAMA 2008;299:1027-35. 9. Pickhardt PJ, Nugent PA, Mysliwiec PA, et al. Location of adenomas missed by optical colonoscopy. Ann Intern Med 2004;141:352-9. 10. East JE, Saunders BP, Burling D, et al. Surface visualization at CT colonography simulated colonoscopy: effect of varying field of view and retrograde view. Am J Gastroenterol 2007;102:2529-35. 11. Pellise M, Fernandez-Esparrach G, Cardenas A, et al. Impact of wideangle, high-definition endoscopy in the diagnosis of colorectal neoplasia: a randomized controlled trial. Gastroenterology 2008;135:1062-8. 12. Adler A, Pohl H, Papanikolaou IS, et al. A prospective randomised study on narrow-band imaging versus conventional colonoscopy for adenoma detection: does narrow-band imaging induce a learning effect? Gut 2008;57:59-64. 13. Rex DK, Helbig CC. High yields of small and flat adenomas with highdefinition colonoscopes using either white light or narrow band imaging. Gastroenterology 2007;133:42-7. 14. Hurlstone DP, Cross SS, Slater R, et al. Detecting diminutive colorectal lesions at colonoscopy: a randomised controlled trial of pan-colonic versus targeted chromoscopy. Gut 2004;53:376-80.
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15. Le Rhun M, Coron E, Parlier D, et al. High resolution colonoscopy with chromoscopy versus standard colonoscopy for the detection of colonic neoplasia: a randomized study. Clin Gastroenterol Hepatol 2006;4:349-54. 16. Pohl J, Schneider A, Vogell H, et al. Pancolonic chromoendoscopy with indigo carmine versus standard colonoscopy for detection of neoplastic lesions: a randomised two-centre trial. Gut 2011;60:485-90. 17. Leufkens AM, DeMarco DC, Rastogi A, et al. Effect of a retrogradeviewing device on adenoma detection rate during colonoscopy: the TERRACE study. Gastrointest Endosc 2011;73:480-9. 18. Hewett DG, Rex DK. Miss rate of right colon examination during colonoscopy defined by retroflexion: an observational study. Gastrointest Endosc 2011;74:246-52. 19. Harrison M, Singh N, Rex DK. Impact of proximal colon retroflexion on adenoma miss rates. Am J Gastroenterol 2004;99:519-22. 20. 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. 21. Rex DK, Cutler CS, Lemmel GT, et al. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology 1997;112:24-8.
Editorial
22. 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. 23. Quallick MR, Brown WR. Rectal perforation during colonoscopic retroflexion: a large, prospective experience in an academic center. Gastrointest Endosc 2009;69:960-3. 24. Laiyemo AO, Doubeni C, Sanderson AK, et al. Likelihood of missed and recurrent adenomas in the proximal versus the distal colon. Gastrointest Endosc 2011;74:253-61. 25. 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. 26. Chan AT, Giovannucci EL, Schernhammer ES, et al. A prospective study of aspirin use and the risk for colorectal adenoma. Ann Intern Med 2004; 140:157-66. 27. Laiyemo AO, Doubeni C, Pinsky P, et al. Factors associated with distal and proximal adenoma recurrence among participants in the Polyp Prevention Trial. Gastroenterology 2009;136:A-96. 28. Ogino S, Chan AT, Fuchs CS, et al. Molecular pathological epidemiology of colorectal neoplasia: an emerging transdisciplinary and interdisciplinary field. Gut 2010;60:397-411.
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Volume 74, No. 2 : 2011 GASTROINTESTINAL ENDOSCOPY 265
Missed polyps, missed opportunities Colorectal cancer is the third most common cancer and the second leading cause of cancer death in the United States, with an estimated 141,210 new cases and 49,380 deaths in 2011. Fortunately, colorectal cancer remains highly preventable through several available screening modalities that can lead to the detection and removal of adenomatous polyps. Although more resource intensive and invasive than other established alternatives, colonoscopy is traditionally considered by many to be the most effective screening option. Colonoscopy permits immediate polypectomy and removal of macroscopically abnormal tissue in contrast to tests based on radiographic imaging or detection of occult blood or exfoliated DNA in stool. Colonoscopy also directly visualizes the entire extent of the colon and rectum, including segments of the colon that are beyond the reach of flexible sigmoidoscopy. Despite this compelling rationale, recent research has called into question the effectiveness of colonoscopy in its ability to confer protection from proximal colon cancer.1-4 In a study of 54,803 subjects in Manitoba, Singh et al4 observed a 29% reduction in mortality from colorectal cancer associated with colonoscopy. However, the benefit was confined entirely to death associated with distal colorectal cancer (standardized mortality ratio 0.53; 95% CI, 0.42-0.67), but not proximal cancer (standardized mortality ratio 0.95; 95% CI, 0.77-1.17). Similarly, a study from Ontario of 10,292 case patients and 51,460 controls found fewer colorectal cancer deaths from distal (adjusted odds ratio 0.33; 95% CI, 0.28-0.39) but not proximal cancer (OR 0.99; 95% CI, 0.86-1.14).1 However, a caveat of both studies is that a substantial proportion of colonoscopies were performed by non-gastroenterologists; Singh et al4 also showed that the reduction in colorectal cancer mortality was significantly greater after a colonoscopy was performed by a gastroenterologist compared with an internist or general surgeon. Moreover, other studies have had a far less pessimistic view. In a German study, colonoscopy was associated with not only a significant 84% lower risk of distal colorectal cancer but a 56% decrease in risk of proximal colon cancer.5 Similarly, Lakoff et al6 showed that after a colonoscopy without pathological findings, a reduction in the incidence of colorectal cancer persisted for 14 years in the distal colon and 7 years in the proximal
Copyright © 2011 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2011.05.019
262 GASTROINTESTINAL ENDOSCOPY Volume 74, No. 2 : 2011
colon. Taken together, these studies suggest that colonoscopy does prevent cancers of the proximal colon, albeit perhaps with less effectiveness than cancers of the left colon or rectum.7
Continuing investigation into relevant clinical and biological predictors of recurrent or interval lesions, considered according to anatomic location in the colon, will facilitate optimal risk stratification.
There are several potential explanations for this apparent disparity. First, the proximal colon is often more difficult to cleanse than the distal colorectum, leading to suboptimal mucosal visualization. Some studies have suggested that the use of split-dose laxatives, with the last dose consumed a few hours before the procedure, may help ameliorate this problem. Second, the proximal colon may harbor a greater prevalence of neoplastic lesions that are macroscopically more difficult to distinguish from normal mucosa—“flat” or nonpolypoid lesions—that may more likely contain invasive carcinoma.8 Proximal lesions may also be more likely to be located on or behind mucosal folds, eluding the view of a standard forward-viewing colonoscope.9 In a CT simulation study, East et al10 estimated that only 87% of the colonic surface area was routinely visualized during an examination using a standard colonoscope. Several techniques and technological advances have been developed to improve inspection of mucosa behind folds, including increasing the field of view to 170 degrees to achieve nearly complete visualization. However, a randomized trial of high-definition wideangle colonoscopy compared with standard colonoscopy did not demonstrate a significant difference in the yield of polyps or adenomas.11 Similarly, narrow-band imaging and chromoendoscopy appear to better discriminate adenomatous from nonadenomatous polyps, but in practice have not consistently yielded a greater adenoma detection rate.12-16 Finally, a third-eye retroscope inserted through the biopsy channel of a standard colonoscope has shown promise in visualizing areas behind mucosal folds but still requires additional study.17 Are there simpler methods by which we can improve standard colonoscopy’s performance in the proximal cowww.giejournal.org
Ananthakrishnan & Chan
lon? In this issue of Gastrointestinal Endoscopy, Hewett and Rex18 help address this question by evaluating the efficacy of retroflexion in the ascending colon as a simple technique to improve visualization of proximal lesions. In their study of 1000 consecutive patients undergoing a screening or surveillance colonoscopy at a single tertiary center, 1 of 2 expert endoscopists successfully examined the mucosa up to the level of the hepatic flexure in 944 patients (94.4%) in whom they attempted a retroflexed examination after intubating the cecum. Among this cohort, a total of 346 patients (34.6%) were found to have polyps in the proximal colon with 271 patients (27.1%) harboring proximal colon adenomas. Retroflexion visualized an additional 68 polyps (54 adenomas) that would otherwise have been missed without retroflexion. Two thirds of patients with polyps found on retroflexion had a negative forward-viewing examination. Overall, retroflexion was able to detect an additional polyp in 5.8% of patients and an additional adenoma in 4.4% of patients. No patients experienced significant complications from the retroflexed examination. Although an increase in the adenoma detection rate of less than 5% may initially seem modest, these results are promising given the relative ease with which the technique described by Hewett and Rex could be adopted by most gastroenterologists. In contrast to wide-angle colonoscopy or a third-eye retroscope, retroflexion in the proximal colon would not require additional equipment or training because most gastroenterologists are already familiar with retroflexion in the rectum. Thus, this technique may, at least in the short term, have the potential for a greater population-wide public health impact than more technologically complex advances. Nonetheless, these results should be interpreted in the context of previous evidence and certain limitations of the current study. First, an earlier randomized trial examining the value of the retroflexion conducted by this group did not appear to demonstrate a significant benefit with retroflexion.19 In that study, after patients underwent an initial examination in the forward-viewing mode by a gastroenterology fellow, a single expert attending then randomized patients to a second examination from the cecum to the splenic flexure in either the forward or retroflexed mode. The miss rate for polyps (36.8% vs 38.1%) or adenomas (33.3% vs 23.7%) was not significantly different between the 2 groups. Second, in the current study, the presence of adenomas on forward examination predicted the likelihood of polyps visualized on retroflexion and the additional adenomas detected using retroflexion were small with nonadvanced histology. In view of the established 10% to 25% miss rate for adenomas found in tandem colonoscopy studies,20-22 the additional polyps detected by the retroflexed examination could reasonably be inferred to be due to a more careful “second look” rather than the retroflexion technique itself. Last, all procedures were performed by 2 experienced endoscopists. Given the www.giejournal.org
Editorial
limited data on the safety of retroflexion in the right side of the colon and the known association of perforation with retroflexion in the rectum,23 it remains possible that broader use of this technique could still be associated with higher rates of complications. Similarly, the greater than 90% rate of success in performing retroflexion observed in the current study may be difficult to match in the hands of less experienced endoscopists. Nonetheless, improving the performance characteristics of colonoscopy may not completely erase the difference in benefit associated with colonoscopy for cancers of the proximal colon compared with the distal colorectum. Aside from morphological differences, adenomas in the proximal colon may possess biologically distinct characteristics compared with those located more distally. A second study in this issue of Gastrointestinal Endoscopy supports this possibility.24 Laiyemo et al24 used data from the Polyp Prevention Trial, a multicenter trial of 2079 participants who were randomized to a low-fat, high-fiber, high fruit and vegetable intake diet after recent removal of an adenoma on an index examination.25 In their analysis, the investigators examined the rates and anatomic location of recurrent and missed adenomas according to the anatomic location of the initial adenoma in 1864 patients. Among this cohort, 1731 underwent a clearing colonoscopy at 1 year after randomization, and all participants completed a surveillance colonoscopy at 4 years. More than half the participants (55.3%) had only a distal adenoma at baseline, whereas 27% had a proximal adenoma only and 17.8% had both a proximal adenoma and a distal adenoma. At the 1-year colonoscopy, one third (34.6%) had adenomas, which were assumed to be “missed” lesions, with nearly half of these patients having missed lesions confined to the proximal colon. Among those with only a proximal adenoma at baseline, there was a higher risk of missed adenomas (relative risk [RR] 1.28; 95% CI, 1.09-1.49) or missed advanced adenoma (RR 1.79; 95% CI, 1.17-2.75) in any location of the colon, as well as a particularly high risk of missed adenomas in the proximal colon (RR 3.34; 95% CI, 1.75-6.39). At 4 years, 39.3% participants had an adenoma, assumed to be a recurrent adenoma that developed after the 1-year “clearing” examination. Half of these patients had recurrent lesions confined to the proximal colon. As with the findings at the 1-year examination, having a baseline adenoma located in the proximal colon was associated with an increased risk of recurrent adenoma, recurrent advanced adenoma, and recurrent adenoma in the proximal colon. Based on these results, the authors reasonably conclude that having a baseline adenoma in the proximal colon is associated with a higher risk of both missed and recurrent adenomas in any part of the colon as well as the proximal colon. The higher rate of missed adenomas in the proximal colon at the 1-year colonoscopy associated with a baseline proximal adenoma could be related to inadequate bowel cleansing or technical limitations of standard colonoscopy Volume 74, No. 2 : 2011 GASTROINTESTINAL ENDOSCOPY 263
Editorial
in visualizing the proximal colon. However, it could be reasonably expected that such issues would be minimized in the context of the high quality of surveillance examinations that would be expected in the conduct of a clinical trial. In addition, the higher rate of recurrent adenomas in the proximal colon at the 4-year colonoscopy after lesions are “cleared” during the 1-year colonoscopy provides compelling evidence that adenomas in the proximal colon may possess a different biological behavior compared with adenomas in the distal colon. Proximal adenomas may grow at a faster rate and may be a stronger marker of an overall “field defect” in which macroscopically unaffected areas the colon are particularly predisposed to develop a malignant clone of cells.26 Moreover, in separate study of this Polyp Prevention Trial population, different lifestyle factors appeared to be associated with likelihood of recurrence adenoma in the right side of the colon compared with the left side of the colon.27 Taken together with data that colon cancers with distinct molecular features are differentially associated with such lifestyle factors as well as anatomic location,28 these results from the Polyp Prevention Trial support the hypothesis that colon cancer is a heterogeneous disease that is, at least in part, manifested by different anatomic location of tumors. What are the implications of these findings for routine clinical practice? Should surveillance intervals for individuals with a proximal adenoma be shortened and for those with a distal adenoma be extended? Perhaps so, but this interpretation is perhaps oversimplified because the findings of Laiyemo et al also demonstrate that patients with adenomas only found in the distal colon on their index examination are also more likely to have had a synchronous proximal lesion that was missed. Lengthening the surveillance interval in such patients could still result in a higher rate of interval cancers in the right side of the colon. Thus, based on these results alone, it is premature to alter current guidelines regarding surveillance intervals according to the location of the baseline adenoma. There are several components to reducing the public health burden of colorectal cancer. First, wider adoption of routine screening remains critical. Even a decade after Medicare began coverage of colonoscopy for average-risk screenings, the overall rate of screening remains suboptimal, particularly compared with screening rates for other cancers. Second, in individuals who undergo a screening colonoscopy, a high-quality examination characterized by optimal bowel preparation, careful visualization of the mucosal surface with particular attention to areas proximal to folds and at flexures, and an adequate withdrawal time remains fundamentally important. Third, communicating the risk of recurrent lesions to patients and providers will help facilitate adherence to surveillance guidelines. Last, continuing investigation into relevant clinical and biological predictors of recurrent or interval lesions, considered 264 GASTROINTESTINAL ENDOSCOPY Volume 74, No. 2 : 2011
Ananthakrishnan & Chan
according to anatomic location in the colon, will facilitate optimal risk stratification.
DISCLOSURE The authors are supported by the American Gastroenterological Association Research Scholars Award (ANA) and R01 CA137178 (ATC). Dr. Chan is a Damon Runyon Clinical Investigator. The authors disclosed no financial relationships relevant to this publication. Ashwin N. Ananthakrishnan, MD, MPH Andrew T. Chan, MD, MPH Gastrointestinal Unit Massachusetts General Hospital Harvard Medical School Boston, Massachusetts, USA Abbreviation: RR, relative risk.
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