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Realistic Expectations After Negative Colonoscopy
Editorial Realistic Expectations After Negative Colonoscopy
G
astroenterologists and the public have embraced the idea that colonoscopy can prevent most colorectal cancers. The idea was first proposed after the recognition that the majority of colorectal cancer began with benign adenomas—the so-called adenoma carcinoma sequence.1 Removing adenomas could interrupt the sequence and potentially prevent cancer. Indeed, publication of results from the National Polyp Study offered evidence that colonoscopic polypectomy could reduce the incidence of colorectal cancer.2 However, there remain unanswered questions. How long are patients protected after a negative colonoscopy? Is the protection comparable for the right and left colon? How much is the risk reduced? In this issue of Clinical Gastroenterology and Hepatology, Lakoff et al3 reported that individuals who have a negative colonoscopy have a significantly decreased risk of colorectal cancer for each of the 14 years of follow-up evaluation after the first year. However, the risk reduction for proximal cancers was found for only half of the follow-up years, and mainly after 7 years of follow-up evaluation. The study methods were strong. The investigators took advantage of linked administrative databases in Ontario to assemble a huge cohort of 110,402 individuals aged 50 to 80 years who had a negative complete colonoscopy between January 1, 1992, and December 31, 1997. The cohort then was followed up through 2005. The cancer experience of the colonoscopy cohort was compared with the remaining Ontario population. For distal colorectal cancer the relative risk was decreased by more than half for all follow-up years, and was reduced by nearly 80% at 14 years (relative risk, 0.21; 95% confidence interval, 0.05– 0.36). The lower risks with longer follow-up evaluations most likely are explained by the fact that missed lesions are more likely to become apparent in the earlier years of follow-up evaluation. For proximal cancers, on the other hand, the relative risk was not reduced consistently until year 8, and the level of reduction was not nearly as pronounced as it was for distal cancers. At 8 years of follow-up evaluation the relative risk for distal cancer was 0.30 (95% confidence interval, 0.20 – 0.40) compared with a relative risk of 0.68 (95% confidence interval, 0.49 – 0.87) for proximal cancer. Because the study relied on administrative databases, the investigators were limited to some extent. They were not able to distinguish between screening and diagnostic colonoscopies. They also were unaware of the indications for colonoscopy, or whether the individuals had a family history that might increase their risk, particularly their risk for proximal cancers. The location of the colorectal cancer was not known for a sizeable percentage of patients, although in sensitivity analyses this did not alter the findings. The results were not stratified by the specialty of the physician performing the examination. These results are not completely unexpected. Similar results have been reported previously in a cohort study from Manitoba where colorectal cancer rates were lower for 10 years after a negative colonoscopy.4 In that study, too, the risks for proximal cancer were not decreased.
How can we explain the fact that colonoscopy performed better for distal cancers than proximal cancers? There are a number of possibilities. (1) Incomplete exams. Although the study was limited to cases where the endoscopist reported reaching the cecum, it is likely that some proportion of procedures were not really complete. (2) Missed lesions. There is growing appreciation for flat polyps and cancers that might not have been recognized or removed.5 Flat lesions are subtle and are recognized by color change or minor elevation or depression. They can be seen with white light endoscopy, but may be easier to see using narrow band imaging or chromoendoscopy. Flat lesions are easy to overlook unless colonoscopists are both trained to recognize them and are vigilant. (3) Suboptimal preparation. Suboptimal preparation in the proximal colon might increase the chance of missing polyps or early cancers, particularly flat ones. Preparations are more likely to be suboptimal in the proximal colon which further challenges the endoscopist. (4) Biological differences. The biological behavior of proximal cancers might be different. We know that there are molecular differences in right-sided cancers than might influence their growth potential. For example, right sided cancers are more likely to have microsatellite instability.6 If proximal cancers grow rapidly they may develop within a few years after a negative colonoscopy. The proximal cancers that developed in the present study may be ones that are new rather than ones that were missed. A recent study from Manitoba reported that the incidence rates of right-sided cancer are increasing over time.7 The reasons are unknown but further illustrate the fact that we have much to learn about the risk factors and biology of right-sided cancers. (5) Operator factors. The disappointing results for proximal cancer could be related to the skill of the colonoscopists. In this study 41% of the exams were done by general surgeons, 42% by internists and family physicians, and 16% by gastroenterologists, although prior to 2000 –2001 many gastroenterologists were classified in the internal medicine group in Ontario. There is some evidence that colorectal specialists are better at detecting abnormalities than generalists. The idea that colonoscopy could prevent the majority of colorectal cancers was first promoted by the National Polyp Study.2 The investigators of that study contrasted the observed number of cancers in their cohort to the number that would be expected in several different historical control groups. They reported a 76% to 90% reduction in colorectal cancer incidence with colonoscopy. Subsequent studies have presented a somewhat less enthusiastic picture. Robertson et al8 assembled data from 3 different chemotherapy trials. By using a similar comparator as the National Polyp Study they did not find a decreased risk of colorectal cancer. Similarly, the incidence of colorectal cancer in the Polyp Prevention Trial9 and the WheatBran Fiber Trial10 were not nearly as low as in the National Polyp Study. Although differences in the design and execution of these studies may explain the results, in the aggregate, the evidence suggests that colonoscopy is an excellent screening test but is not perfect. The location of the examination and the training of the examiner may have an important impact on the outcome. Bressler et al11 examined potential factors that might predict new or missed cancers in a cohort study from Ontario. In that CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2008;6:1068 –1069
October 2008
analysis, examinations that were performed in an office (as opposed to a hospital) and examinations performed by an internist or family physician were among the factors that predicted new or missed lesions. Another Canadian study reported that individuals who had procedures performed in a rural setting, particularly when performed by a family physician, were more likely to develop colorectal cancer after a negative colonoscopy.12 Rex et al13 found that colonoscopy performed by gastroenterologists was more sensitive (97.3%) for cancer than colonoscopy performed by nongastroenterologists (87%). There is growing recognition that the ability to detect neoplastic lesions in the large bowel is operator-dependent. In a study from a private practice in Rockford, IL, there was a 10-fold difference in the adenoma detection rate among 12 experienced gastroenterologists.14 The speed of withdrawal was one of the factors that predicted adenoma detection. A study at Indiana University Hospital found a 4-fold difference in adenoma detection, with the highest detector finding more patients with larger adenomas and more patients with 3 or more adenomas.15 A recent abstract from a Veterans Hospital in Los Angeles noted that the first colonoscopy of the day detected more adenomas than subsequent examinations.16 The skill and the care of the colonoscopist may prove to be an important factor in cancer prevention. The take-home message from this study is clear. When a colonoscopy is negative, there is a lower risk of cancer for 14 years. The fact that the risk was not lower for proximal cancers could be due to biology, patient factors such as the quality of the preparation, or operator factors. To reduce the risk of proximal cancer we need well-trained endoscopists, excellent preparations, meticulous examination of the bowel, and slow withdrawal.17 Additional advances in technology with wider fields of view and advanced optics also will be of help. Colonoscopy is the best available test to diagnose and prevent colorectal cancer. After a negative examination, the risk for colorectal cancer remains low for many years. However, patients and their physicians need to have realistic expectations because the risk of subsequent cancer is not zero.
ROBERT S. SANDLER, MD, MPH Division of Gastroenterology and Hepatology University of North Carolina at Chapel Hill Chapel Hill, North Carolina References 1. Muto T, Bussey HJR, Morson BC. The evolution of cancer of the colon and rectum. Cancer 1975;36:2251–2270. 2. Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 1993;329:1977–1981.
NEGATIVE COLONOSCOPY
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3. Lakoff J, Paszat LF, Saskin R, et al. Risk of developing proximal versus distal colorectal cancer following a negative colonoscopy: a population based study. Clin Gastroenterol Hepatol 2008;6: 1117–1121. 4. 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 –2373. 5. Soetikno RM, Kaltenbach T, Rouse RV, et al. Prevalence of nonpolypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults. JAMA 2008;299:1027–1035. 6. Sugai T, Habano W, Jiao YF, et al. Analysis of molecular alterations in left- and right-sided colorectal carcinomas reveals distinct pathways of carcinogenesis: proposal for new molecular profile of colorectal carcinomas. J Mol Diagn 2006;8:193–201. 7. Singh H, Demers AA, Xue L, et al. Time trends in colon cancer incidence and distribution and lower gastrointestinal endoscopy utilization in Manitoba. Am J Gastroenterol 2008;103:1249 – 1256. 8. Robertson DJ, Greenberg ER, Beach M, et al. Colorectal cancer in patients under close colonoscopic surveillance. Gastroenterology 2005;129:34 – 41. 9. 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 – 1155. 10. Alberts DS, Martinez ME, Roe DJ, et al. Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal adenomas. Phoenix Colon Cancer Prevention Physicians’ Network. N Engl J Med 2000;342:1156 –1162. 11. Bressler B, Paszat LF, Chen Z, et al. Rates of new or missed colorectal cancers after colonoscopy and their risk factors: a population-based analysis. Gastroenterology 2007;132:96 –102. 12. Singh H, Turner D, Xue L, et al. Colorectal cancers after a negative colonoscopy. Gastroenterology 2007;132:A149. 13. Rex DK, Rahmani EY, Haseman JH, et al. Relative sensitivity of colonoscopy and barium enema for detection of colorectal cancer in clinical practice. Gastroenterology 1997;112:17–23. 14. Barclay RL, Vicari JJ, Doughty AS, et al. Colonoscopic withdrawal times and adenoma detection during screening colonoscopy. N Engl J Med 2006;355:2533–2541. 15. Chen SC, Rex DK. Endoscopist can be more powerful than age and male gender in predicting adenoma detection at colonoscopy. Am J Gastroenterol 2007;102:856 – 861. 16. Chan MY, Cohen H, Spiegel BM. Does the first colonoscopy of the day yield more polyps than cases performed later? Gastroenterology 2008;134(Suppl 1):A-37. 17. Rex DK, Eid E. Considerations regarding the present and future roles of colonoscopy in colorectal cancer prevention. Clin Gastroenterol Hepatol 2008;6:506 –514.
doi:10.1016/j.cgh.2008.06.012
G
astroenterologists and the public have embraced the idea that colonoscopy can prevent most colorectal cancers. The idea was first proposed after the recognition that the majority of colorectal cancer began with benign adenomas—the so-called adenoma carcinoma sequence.1 Removing adenomas could interrupt the sequence and potentially prevent cancer. Indeed, publication of results from the National Polyp Study offered evidence that colonoscopic polypectomy could reduce the incidence of colorectal cancer.2 However, there remain unanswered questions. How long are patients protected after a negative colonoscopy? Is the protection comparable for the right and left colon? How much is the risk reduced? In this issue of Clinical Gastroenterology and Hepatology, Lakoff et al3 reported that individuals who have a negative colonoscopy have a significantly decreased risk of colorectal cancer for each of the 14 years of follow-up evaluation after the first year. However, the risk reduction for proximal cancers was found for only half of the follow-up years, and mainly after 7 years of follow-up evaluation. The study methods were strong. The investigators took advantage of linked administrative databases in Ontario to assemble a huge cohort of 110,402 individuals aged 50 to 80 years who had a negative complete colonoscopy between January 1, 1992, and December 31, 1997. The cohort then was followed up through 2005. The cancer experience of the colonoscopy cohort was compared with the remaining Ontario population. For distal colorectal cancer the relative risk was decreased by more than half for all follow-up years, and was reduced by nearly 80% at 14 years (relative risk, 0.21; 95% confidence interval, 0.05– 0.36). The lower risks with longer follow-up evaluations most likely are explained by the fact that missed lesions are more likely to become apparent in the earlier years of follow-up evaluation. For proximal cancers, on the other hand, the relative risk was not reduced consistently until year 8, and the level of reduction was not nearly as pronounced as it was for distal cancers. At 8 years of follow-up evaluation the relative risk for distal cancer was 0.30 (95% confidence interval, 0.20 – 0.40) compared with a relative risk of 0.68 (95% confidence interval, 0.49 – 0.87) for proximal cancer. Because the study relied on administrative databases, the investigators were limited to some extent. They were not able to distinguish between screening and diagnostic colonoscopies. They also were unaware of the indications for colonoscopy, or whether the individuals had a family history that might increase their risk, particularly their risk for proximal cancers. The location of the colorectal cancer was not known for a sizeable percentage of patients, although in sensitivity analyses this did not alter the findings. The results were not stratified by the specialty of the physician performing the examination. These results are not completely unexpected. Similar results have been reported previously in a cohort study from Manitoba where colorectal cancer rates were lower for 10 years after a negative colonoscopy.4 In that study, too, the risks for proximal cancer were not decreased.
How can we explain the fact that colonoscopy performed better for distal cancers than proximal cancers? There are a number of possibilities. (1) Incomplete exams. Although the study was limited to cases where the endoscopist reported reaching the cecum, it is likely that some proportion of procedures were not really complete. (2) Missed lesions. There is growing appreciation for flat polyps and cancers that might not have been recognized or removed.5 Flat lesions are subtle and are recognized by color change or minor elevation or depression. They can be seen with white light endoscopy, but may be easier to see using narrow band imaging or chromoendoscopy. Flat lesions are easy to overlook unless colonoscopists are both trained to recognize them and are vigilant. (3) Suboptimal preparation. Suboptimal preparation in the proximal colon might increase the chance of missing polyps or early cancers, particularly flat ones. Preparations are more likely to be suboptimal in the proximal colon which further challenges the endoscopist. (4) Biological differences. The biological behavior of proximal cancers might be different. We know that there are molecular differences in right-sided cancers than might influence their growth potential. For example, right sided cancers are more likely to have microsatellite instability.6 If proximal cancers grow rapidly they may develop within a few years after a negative colonoscopy. The proximal cancers that developed in the present study may be ones that are new rather than ones that were missed. A recent study from Manitoba reported that the incidence rates of right-sided cancer are increasing over time.7 The reasons are unknown but further illustrate the fact that we have much to learn about the risk factors and biology of right-sided cancers. (5) Operator factors. The disappointing results for proximal cancer could be related to the skill of the colonoscopists. In this study 41% of the exams were done by general surgeons, 42% by internists and family physicians, and 16% by gastroenterologists, although prior to 2000 –2001 many gastroenterologists were classified in the internal medicine group in Ontario. There is some evidence that colorectal specialists are better at detecting abnormalities than generalists. The idea that colonoscopy could prevent the majority of colorectal cancers was first promoted by the National Polyp Study.2 The investigators of that study contrasted the observed number of cancers in their cohort to the number that would be expected in several different historical control groups. They reported a 76% to 90% reduction in colorectal cancer incidence with colonoscopy. Subsequent studies have presented a somewhat less enthusiastic picture. Robertson et al8 assembled data from 3 different chemotherapy trials. By using a similar comparator as the National Polyp Study they did not find a decreased risk of colorectal cancer. Similarly, the incidence of colorectal cancer in the Polyp Prevention Trial9 and the WheatBran Fiber Trial10 were not nearly as low as in the National Polyp Study. Although differences in the design and execution of these studies may explain the results, in the aggregate, the evidence suggests that colonoscopy is an excellent screening test but is not perfect. The location of the examination and the training of the examiner may have an important impact on the outcome. Bressler et al11 examined potential factors that might predict new or missed cancers in a cohort study from Ontario. In that CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2008;6:1068 –1069
October 2008
analysis, examinations that were performed in an office (as opposed to a hospital) and examinations performed by an internist or family physician were among the factors that predicted new or missed lesions. Another Canadian study reported that individuals who had procedures performed in a rural setting, particularly when performed by a family physician, were more likely to develop colorectal cancer after a negative colonoscopy.12 Rex et al13 found that colonoscopy performed by gastroenterologists was more sensitive (97.3%) for cancer than colonoscopy performed by nongastroenterologists (87%). There is growing recognition that the ability to detect neoplastic lesions in the large bowel is operator-dependent. In a study from a private practice in Rockford, IL, there was a 10-fold difference in the adenoma detection rate among 12 experienced gastroenterologists.14 The speed of withdrawal was one of the factors that predicted adenoma detection. A study at Indiana University Hospital found a 4-fold difference in adenoma detection, with the highest detector finding more patients with larger adenomas and more patients with 3 or more adenomas.15 A recent abstract from a Veterans Hospital in Los Angeles noted that the first colonoscopy of the day detected more adenomas than subsequent examinations.16 The skill and the care of the colonoscopist may prove to be an important factor in cancer prevention. The take-home message from this study is clear. When a colonoscopy is negative, there is a lower risk of cancer for 14 years. The fact that the risk was not lower for proximal cancers could be due to biology, patient factors such as the quality of the preparation, or operator factors. To reduce the risk of proximal cancer we need well-trained endoscopists, excellent preparations, meticulous examination of the bowel, and slow withdrawal.17 Additional advances in technology with wider fields of view and advanced optics also will be of help. Colonoscopy is the best available test to diagnose and prevent colorectal cancer. After a negative examination, the risk for colorectal cancer remains low for many years. However, patients and their physicians need to have realistic expectations because the risk of subsequent cancer is not zero.
ROBERT S. SANDLER, MD, MPH Division of Gastroenterology and Hepatology University of North Carolina at Chapel Hill Chapel Hill, North Carolina References 1. Muto T, Bussey HJR, Morson BC. The evolution of cancer of the colon and rectum. Cancer 1975;36:2251–2270. 2. Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 1993;329:1977–1981.
NEGATIVE COLONOSCOPY
1069
3. Lakoff J, Paszat LF, Saskin R, et al. Risk of developing proximal versus distal colorectal cancer following a negative colonoscopy: a population based study. Clin Gastroenterol Hepatol 2008;6: 1117–1121. 4. 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 –2373. 5. Soetikno RM, Kaltenbach T, Rouse RV, et al. Prevalence of nonpolypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults. JAMA 2008;299:1027–1035. 6. Sugai T, Habano W, Jiao YF, et al. Analysis of molecular alterations in left- and right-sided colorectal carcinomas reveals distinct pathways of carcinogenesis: proposal for new molecular profile of colorectal carcinomas. J Mol Diagn 2006;8:193–201. 7. Singh H, Demers AA, Xue L, et al. Time trends in colon cancer incidence and distribution and lower gastrointestinal endoscopy utilization in Manitoba. Am J Gastroenterol 2008;103:1249 – 1256. 8. Robertson DJ, Greenberg ER, Beach M, et al. Colorectal cancer in patients under close colonoscopic surveillance. Gastroenterology 2005;129:34 – 41. 9. 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 – 1155. 10. Alberts DS, Martinez ME, Roe DJ, et al. Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal adenomas. Phoenix Colon Cancer Prevention Physicians’ Network. N Engl J Med 2000;342:1156 –1162. 11. Bressler B, Paszat LF, Chen Z, et al. Rates of new or missed colorectal cancers after colonoscopy and their risk factors: a population-based analysis. Gastroenterology 2007;132:96 –102. 12. Singh H, Turner D, Xue L, et al. Colorectal cancers after a negative colonoscopy. Gastroenterology 2007;132:A149. 13. Rex DK, Rahmani EY, Haseman JH, et al. Relative sensitivity of colonoscopy and barium enema for detection of colorectal cancer in clinical practice. Gastroenterology 1997;112:17–23. 14. Barclay RL, Vicari JJ, Doughty AS, et al. Colonoscopic withdrawal times and adenoma detection during screening colonoscopy. N Engl J Med 2006;355:2533–2541. 15. Chen SC, Rex DK. Endoscopist can be more powerful than age and male gender in predicting adenoma detection at colonoscopy. Am J Gastroenterol 2007;102:856 – 861. 16. Chan MY, Cohen H, Spiegel BM. Does the first colonoscopy of the day yield more polyps than cases performed later? Gastroenterology 2008;134(Suppl 1):A-37. 17. Rex DK, Eid E. Considerations regarding the present and future roles of colonoscopy in colorectal cancer prevention. Clin Gastroenterol Hepatol 2008;6:506 –514.
doi:10.1016/j.cgh.2008.06.012