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Role of Colonoscopy and Polyp Characteristics in Colorectal Cancer After Colonoscopic Polyp Detection: A Population-Based Case–Control Study

Hermann Brenner, MD, MPH; Jenny Chang-Claude, PhD; Lina Jansen, PhD; Christoph M. Seiler, MD, MSc; and Michael Hoffmeister, PhD
[+] Article and Author Information

From the German Cancer Research Center and University of Heidelberg, Heidelberg, Germany.

Acknowledgment: The authors are grateful to the study participants and the interviewers who collected the data. They thank the following hospitals and cooperating institutions that recruited patients for this study: Chirurgische Universitätsklinik Heidelberg, Klinik am Gesundbrunnen Heilbronn, Sankt Vincentiuskrankenhaus Speyer, Sankt Josefskrankenhaus Heidelberg, Chirurgische Universitätsklinik Mannheim, Diakonissenkrankenhaus Speyer, Krankenhaus Salem Heidelberg, Kreiskrankenhaus Schwetzingen, Sankt Marien- und Sankt Annastiftkrankenhaus Ludwigshafen, Klinikum Ludwigshafen, Stadtklinik Frankenthal, Diakoniekrankenhaus Mannheim, Kreiskrankenhaus Sinsheim, Klinikum am Plattenwald Bad Friedrichshall, Kreiskrankenhaus Weinheim, Kreiskrankenhaus Eberbach, Kreiskrankenhaus Buchen, Kreiskrankenhaus Mosbach, Enddarmzentrum Mannheim, Kreiskrankenhaus Brackenheim, and Cancer Registry of Rhineland-Palatinate, Mainz. The authors also thank Ute Handte-Daub, Renate Hettler-Jensen, Petra Bächer, and Utz Benscheid for excellent technical assistance.

Grant Support: By grants BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, and CH 117/1-1 from the German Research Council (Deutsche Forschungsgemeinschaft) and grants 01KH0404 and 01ER0814 from the German Federal Ministry of Education and Research.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-0247.

Reproducible Research Statement:Study protocol and data set: Not available. Statistical code: Available by request from and written agreement with Dr. Brenner (e-mail, h.brenner@dkfz.de).

Requests for Single Reprints: Hermann Brenner, MD, MPH, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany; e-mail, h.brenner@dkfz.de.

Current Author Addresses: Drs. Brenner, Jansen, and Hoffmeister: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.

Dr. Chang-Claude: Division of Cancer Epidemiology, Unit of Genetic Epidemiology, Division of Cancer Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.

Dr. Seiler: Department of General, Visceral and Trauma Surgery, University Clinic Heidelberg, University of Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany.

Author Contributions: Conception and design: H. Brenner, J. Chang-Claude.

Analysis and interpretation of the data: H. Brenner.

Drafting of the article: H. Brenner.

Critical revision of the article for important intellectual content: H. Brenner, J. Chang-Claude, L. Jansen, C.M. Seiler, M. Hoffmeister.

Final approval of the article: H. Brenner, J. Chang-Claude, L. Jansen, C.M. Seiler, M. Hoffmeister.

Provision of study materials or patients: C.M. Seiler.

Statistical expertise: H. Brenner.

Obtaining of funding: H. Brenner, J. Chang-Claude.

Collection and assembly of data: H. Brenner, L. Jansen, C.M. Seiler, M. Hoffmeister.


Ann Intern Med. 2012;157(4):225-232. doi:10.7326/0003-4819-157-4-201208210-00002
Text Size: A A A

Background: Studies have identified characteristics of adenomas detected on colonoscopy to be predictive of adenoma recurrence.

Objective: To assess the role of both colonoscopy-related factors and polyp characteristics on the risk for colorectal cancer after colonoscopic polyp detection.

Design: Population-based case–control study (3148 case participants and 3274 control participants).

Setting: Rhine-Neckar region of Germany.

Patients: Case and control participants with physician-validated detection of polyps (other than hyperplastic polyps) at a previous colonoscopy in the past 10 years.

Measurements: Detailed history and results of previous colonoscopies were obtained through interviews and medical records. Case and control participants were compared according to colonoscopy-related factors (incompleteness, poor bowel preparation, incomplete removal of all polyps, and no surveillance colonoscopy within 5 years) and polyp characteristics (≥1 cm, villous components or high-grade dysplasia, ≥3 polyps, and ≥1 proximal polyp). Odds ratios (ORs) and attributable fractions were derived by using multiple logistic regression and the Levin formula.

Results: 155 case participants and 260 control participants with physician-validated polyp detection in the past 10 years were identified. The following characteristics were significantly more common among case participants than among control participants: not all polyps completely removed (29.0% vs. 9.6%; OR, 3.73 [95% CI, 2.11 to 6.60]), no surveillance colonoscopy within 5 years (26.5% vs. 11.5%; OR, 2.96 [CI, 1.70 to 5.16]), and detection of 3 or more polyps (14.2% vs. 7.3%; OR, 2.21 [CI, 1.07 to 4.54]). Odds ratios ranged from 1.12 to 1.42 and CIs included 1.00 for all other variables. Overall, 41.1% and 21.7% of cancer cases were statistically attributable to colonoscopy-related factors and polyp characteristics, respectively.

Limitation: This was an observational study with potential for residual confounding and selection bias.

Conclusion: Colonoscopy-related factors are more important than polyp characteristics for stratification of colorectal cancer risk after colonoscopic polyp detection in the community setting.

Primary Funding Source: German Research Council and German Federal Ministry of Education and Research.

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Colonoscopy-related factors vs. polyp characteristics: they are not mutually exclusive
Posted on August 27, 2012
Ashish K Tiwari, MD
Michigan State University, East Lansing, MI
Conflict of Interest: None Declared

The article by Brenner and colleagues(1) highlights the point that colonoscopy-related factors are more important predictors of the risk of colorectal cancer than polyp characteristics observed on previous colonoscopy; and as authors mentioned, this study seemed to directly validate observations made in a previous study(2) that compared colonoscopy-related factors and polyp characteristics with risk of detection of advanced adenoma on follow-up colonoscopy. However there are certain caveats in the study that should be addressed.First, despite including a wide-range of population (age 30-80 yrs), women represented only about one third of cases (CRC patients) in this study. Cancer statistics(3) have always suggested that in terms of incidence and mortality, CRC is largely gender-neutral. Therefore, although control population in the study is gender-matched with cases, it’s possible that conclusions of the study might not be uniformly applicable. Moreover, authors have made an important observation that association of polyp size with CRC risk reached statistical significance in men only. This is because substantial gender differences exist in the adenoma/carcinoma paradigm that lies at the heart of colonoscopic CRC screening. For example, polyps/adenomas are less reliable markers of risk of future neoplasia in women; women tend to have more proximal and more flat lesions; and a negative colonoscopic examination does not offer similar protection against CRC in women as in men(4). Therefore, unless the study is gender-balanced, it is fraught with risk of erroneously gender-neutral application of conclusions to entire population.Second, there are more number of cases than controls in age group 30-50 (relatively young age-group for CRC diagnosis, indicating that some of them might have increased baseline risk for CRC, such as Familial adenomatous polyposis or inflammatory bowel disease patients). Authors should clarify if high-risk population was included, because in such individuals the recommended colonoscopy interval is much less than 5 yrs (usually 1-3 years), which means that colonoscopy interval of >5 yrs (colonoscopy-related factor) automatically puts them at increased risk of being diagnosed with CRC. Moreover, in many inflammatory bowel disease patients (if included as cases), CRC could also evolve from flat dysplastic lesions, where polyp-characteristics would not be of help. These events might skew the data in favor of colonoscopy-related factors.Third, this study suggests that two colonoscopy-related factors (colonoscopy >5 yrs ago and not removing all polyps completely) are the most important determinants of CRC risk, whereas among polyp characteristics, only presence of more than 3 polyps on previous colonoscopy seemed to be narrowly statistically significant factor to portend increased risk of CRC. In fact, logically, it won’t be unreasonable to assume that more number of polyps (>3) would increase the likelihood that not all of them will be completely removed for reasons such as small size, difficult location or time-pressure to keep up with schedule. Therefore, presence of >3 polyps (polyp-characteristic) might confound the observation regarding incomplete removal of detected polyps (colonoscopy-related factor). This needs to be taken into account.Fourth, current recommendations for follow up colonoscopy take into account polyp characteristics, and have been successful in preventing many cases of CRC, especially in compliant patients. Although implausible, the only way to truly test which of the two (colonoscopy-related factors vs. polyp characteristics) is more important predictor of CRC occurrence would be to design a study where follow up colonoscopy interval is determined either by colonoscopy-related factors or polyp characteristics separately and compare the CRC occurrence in each group. Therefore, at this point, the overall conclusion of the study should be to emphasize upon the importance of colonoscopy-related factors and not undermine the importance of polyp characteristics-based risk determination for follow up colonoscopy intervals.

Reference:

(1)Brenner, H., Chang-Claude, J., Jansen, L., Seiler, C. M. & Hoffmeister, M. Role of colonoscopy and polyp characteristics in colorectal cancer after colonoscopic polyp detection: a population-based case-control study. Ann Intern Med. 21 August 2012;157(4):225-232

(2) Laiyemo AO, Murphy G, Albert PS, Sansbury LB, Wang Z, Cross AJ. et al., Postpolypectomy colonoscopy surveillance guidelines: predictive accuracy for advanced adenoma at 4 years.. Ann Intern Med. 2008;148419-26

(3) Siegel, R., Naishadham, D. & Jemal, A. Cancer statistics, 2012. CA Cancer J Clin. 2012; 62, 10-29(4) Roy, H. K. & Bianchi, L. K. Differences in colon adenomas and carcinomas among women and men: potential clinical implications. JAMA. 2009; 302,1696-1697

Deviating from the standard of care is the greatest risk factor for colorectal cancer risk after colonoscopic polyp detection
Posted on September 11, 2012
Joseph D. Feuerstein MD, Daniel A. Leffler MD MS
Beth Israel Deaconess Medical Center, Harvard Medical School
Conflict of Interest: None Declared

We read the article by Brenner et al.(1) with interest. In this article, the authors report that risk factors for development of colon cancer in the control group were incomplete polyp removal, detection of three or more polyps, and no surveillance colonoscopy within the past five years. Additionally, incomplete colonoscopy, defined as failure to intubate the cecum, was noted in 7.7% of the control group. These findings are consistent with what has already been accepted as the standard quality metrics in the United States for an adequate screening colonoscopy program (2). In contrast to this study’s findings is the study by Kaminski et al. (3). Amongst the 188,788 person years followed 92.9% of interval colorectal cancers developed in patients who had no prior adenomas and 83.3% had no family history. Only one subject’s interval colorectal cancer was attributed to ineffective polypectomy. However, cases of ineffective polypectomy have been associated with 19-27% of interval cancers due to remaining adenomatous tissue (2). Guidelines are well established for appropriate colonoscopy surveillance following polypectomy. In the setting of ≥three adenomas or one adenoma ≥ 1cm in size or with high grade dysplasia, current recommendations, as well as past guidelines, recommend three year follow up interval (2). The finding that underutilization of colonoscopic surveillance in high risk patients is associated with an increased risk of colon cancer, as noted by Brenner et al., should come at no surprise. A key feature which may be related to the higher interval cancer rate is the quality indicator of the adenoma detection rate. Kaminski et al. found endoscopists with rates < 20% had a significantly higher interval cancer rate over the ensuing five years (3). Additionally, studies have also shown that patients who underwent colonoscopy by endoscopists who achieved a cecal intubation rates > 95% compared to < 80% were less likely to have interval cancers (4). For screening colonoscopy, ≥95% cecal intubation rate is considered standard (5). While the authors conclude that “colonoscopy-related factors are more important than polyp characteristics for stratification of colorectal cancer risk after colonoscopic polyp detection”, we believe a more appropriate conclusion is that this study adds to the robust body of data suggesting that inadequate colonoscopy cancer screening programs are ineffective at reducing colorectal cancer incidence. Rather than questioning the effectiveness of colonoscopy-based colorectal cancer screening, one wonders if improved technique and adherence to guidelines may have reduced the number of cases of colorectal cancer in this study.

Joseph D. Feuerstein, MD  Gastroenterology Fellow Division of Gastroenterology at Beth Israel Deaconess Medical Center Boston, MA

Daniel A. Leffler, MD, MS   Director of Quality ImprovementDivision of Gastroenterology at Beth Israel Deaconess Medical Center Boston, MA

References

1. Brenner H, Chang-Claude J, Jansen L, Seiler CM, Hoffmeister M. Role of Colonoscopy and Polyp Characteristics in Colorectal Cancer After Colonoscopic Polyp Detection. Annals of internal medicine. 2012;157:225–232

2. Lieberman DA, Rex DK, Winawer SJ, Giardiello FM, Johnson DA, Levin, TR. Guidelines for Colonoscopy Surveillance After Screening and Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2012;143(3):844–57. [PMID 22763141]

3. Kaminski MF, Regula J, Kraszewska E, Polkowski M, Wojciechowska U, Didkowska J, et al. Quality indicators for colonoscopy and the risk of interval cancer. The New England journal of medicine. 2010;362(19):1795–803. [PMID: 20463339]

4. Baxter NN, Sutradhar R, Forbes SS, Paszat LF, Saskin R, Rabeneck L. Analysis of administrative data finds endoscopist quality measures associated with post colonoscopy colorectal cancer. Gastroenterology. 2011;140(1):65–72. [PMID 20854818]

5. Rex DK, Petrini JL, Baron TH, Chak A, Cohen J, Deal SE, et al. Quality indicators for colonoscopy. American journal of gastroenterology.2006;101(4):873-885. [PMID 16635231]

Author's Response
Posted on October 5, 2012
Hermann Brenner, MD, MPH 1, Jenny Chang-Claude , PhD 2, Michael Hoffmeister, PhD 1
1: Div of Clin Epidemiology & Aging Research, German Cancer Research Ctr, Heidelberg, Germany 2: Div of Cancer Epidemiology, Unit of Genetic Epidemiology, German Cancer Research Ctr, Heidelberg
Conflict of Interest: None Declared

We thank Drs. Feuerstein and Leffler for their interest in our article (1). Our article did not “question effectiveness of colonoscopy-based colorectal cancer screening”. In fact, the effectiveness of colonoscopy to reduce colorectal cancer risk in the population setting has been well demonstrated in our preceding publication from the same study (2) which had found an overall 77% reduction of colorectal cancer risk within 10 years after colonoscopy.

We agree that improved techniques and adherence to guidelines may have reduced the number of colorectal cancers, and we emphasized the need and potential of improvement in our conclusion (1). In fact, the very aim of our analysis was to provide quantitative estimates of the proportions of cancers occurring after colonoscopic polypectomy that might have been prevented by improved techniques or guideline adherence in routine application of screening colonoscopy, and to compare those estimates with proportions of cancers statistically attributable to specific polyp characteristics (1). Such estimates have not previously been available.

A closer look at the populations studied is warranted in the comparisons with other studies cited by Feuerstein and Leffler. For example, while our recent article specifically focused on cases and controls with preceding polypectomy (1), cases with preceding polypectomy were a minority of the overall number of colorectal cancer patients in both our study (4) and the study of Kaminski et al (3). The apparent difference from the finding in the study by Kaminski et al, that 92.9% of new cancers developed in patients who had no prior adenomas, is therefore well explained by differences in the populations studied. In summary, our study strongly supports rather than questions effectiveness of colonoscopy based screening, and at the same time indicates that the small remaining risk of colorectal cancer after polypectomy is likely further reduced by enhanced adherence to follow-up procedures and surveillance.

Hermann Brenner, MD, MPH, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany

Jenny Chang-Claude, PhD, Division of Cancer Epidemiology, Unit of Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany

Michael Hoffmeister, PhD, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany

References

1. Brenner H, Chang-Claude J, Jansen L, Seiler CM, Hoffmeister M. Role of colonoscopy and polyp characteristics in colorectal cancer after colonoscopic polyp detection. Ann Intern Med 2012;157:225–32.

2. Brenner H, Chang-Claude J, Seiler CM, Rickert A, Hoffmeister M. Protection from colorectal cancer after colonoscopy: a population-based case-control study. Ann Intern Med 2011;154:22–30.

3. Kaminski MF, Regula J, Kraszewska E, Polkowski M, Wojciechowska U, Didkowska J, et al. Quality indicators for colonoscopy and the risk of interval cancer. N Engl J Med 2010;362:1795–803.

4. Brenner H, Chang-Claude J, Rickert A, Seiler CM, Hoffmeister M. Risk of colorectal cancer after detection and removal of adenomas at colonoscopy: population-based case-control study. J Clin Oncol 2012;30:2969–76.

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