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GASTROENTEROLOGY 2009;136:832–841

Pooled Analysis of Advanced Colorectal Neoplasia Diagnoses Afterolonoscopic Polypectomy

ARÍA ELENA MARTÍNEZ,*,‡ JOHN A. BARON,§ DAVID A. LIEBERMAN,� ARTHUR SCHATZKIN,¶ ELAINE LANZA,#

IDNEY J. WINAWER,** ANN G. ZAUBER,‡‡ RUIYUN JIANG,*,‡ DENNIS J. AHNEN,§§ JOHN H. BOND,� �

IMOTHY R. CHURCH,¶¶ DOUGLAS J. ROBERTSON,## STEPHANIE A. SMITH–WARNER,*** ELIZABETH T. JACOBS,*,‡

AVID S. ALBERTS,*,‡,‡‡‡ and E. ROBERT GREENBERG§,§§§

Arizona Cancer Center, ‡Mel and Enid Zuckerman Arizona College of Public Health, ‡‡‡Department of Medicine, University of Arizona, Tucson, Arizona;Departments of Medicine and Community and Family Medicine, Dartmouth Medical School, Lebanon, New Hampshire; �Department of Veterans Affairsedical Center, Portland, Oregon; ¶Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, #Center for Cancer Research, Nationalancer Institute, National Institutes of Health, Rockville, Maryland; **Department of Gastroenterology and Nutrition Science, ‡‡Department of Epidemiology andiostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York; §§Department of Veterans Affairs Medical Center, Denver, Colorado;

�Department of Medicine, Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota; ¶¶Division of Environmental Health Sciences, University ofinnesota School of Public Health, Minneapolis, Minnesota; ##Department of Veterans Affairs Medical Center, White River Junction, Vermont; ***Departments ofutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts; and the §§§Cancer Prevention Program, Fred Hutchinson Cancer Research

enter, Seattle, Washington

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See related article, van den Broek FJC et al,on page 288 in CGH.

ackground & Aims: Limited data exist regardinghe actual risk of developing advanced adenomasnd cancer after polypectomy or the factors thatetermine risk. Methods: We pooled individualata from 8 prospective studies comprising 9167en and women aged 22 to 80 with previously

esected colorectal adenomas to quantify their riskf developing subsequent advanced adenoma orancer as well as identify factors associated with theevelopment of advanced colorectal neoplasmsuring surveillance. Results: During a median fol-

ow-up period of 47.2 months, advanced colorectaleoplasia was diagnosed in 1082 (11.8%) of theatients, 58 of whom (0.6%) had invasive cancer.isk of a metachronous advanced adenoma wasigher among patients with 5 or more baselinedenomas (24.1%; standard error, 2.2) and thoseith an adenoma 20 mm in size or greater (19.3%;

tandard error, 1.5). Risk factor patterns were sim-lar for advanced adenomas and invasive cancer. In

ultivariate analyses, older age (P < .0001 forrend) and male sex (odds ratio [OR], 1.40; 95%onfidence interval [CI], 1.19 –1.65) were associatedignificantly with an increased risk for metachro-ous advanced neoplasia, as were the number andize of prior adenomas (P < .0001 for trend), theresence of villous features (OR, 1.28; 95% CI, 1.07–.52), and proximal location (OR, 1.68; 95% CI,.43–1.98). High-grade dysplasia was not associatedndependently with metachronous advanced neo-

lasia after adjustment for other adenoma charac-

eristics. Conclusions: Occurrence of advancedolorectal neoplasia is common after polypectomy.actors that are associated most strongly with riskf advanced neoplasia are patient age and the num-er and size of prior adenomas.

n the United States, colorectal cancer is the third mostcommon cancer in both men and women and the

econd leading cause of cancer death, accounting forearly 150,000 new cases and 50,000 deaths annually.1

olonoscopy screening with removal of adenomas is anffective strategy for reducing colorectal cancer incidencend mortality,2,3 and it is one of several accepted screen-ng modalities in the United States.4 Among individualsho have one or more adenomas removed at colonos-

opy, 20%–50% will be found to have a metachronousesion when undergoing follow-up (surveillance) colonos-opy within 3–5 years.5–9 As many as 20% of patientsiagnosed with neoplasms during surveillance have ad-anced adenomas, defined as those with a diameter 10m or larger, having greater than 25% villous features, or

aving high-grade dysplasia,5–10 and a small, althoughot negligible, proportion are newly diagnosed with in-asive colorectal cancer.7,11–16

Professional groups have developed guidelines for sur-eillance colonoscopy intervals after polypectomy3,17 withhe goal of more efficient detection of early cancers ordvanced adenomas, the latter carrying a presumedigher risk of progressing to invasive cancer. These guide-

ines use the characteristics of neoplasia at the most

Abbreviations used in this paper: BMI, body mass index; CI, confi-ence interval; OR, odds ratio.

© 2009 by the AGA Institute0016-5085/09/$36.00

doi:10.1053/j.gastro.2008.12.007

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March 2009 COLORECTAL NEOPLASIA AFTER POLYPECTOMY 833

ecent colonoscopy to classify patients as either higher orower risk. Knowledge of the relation between patientharacteristics or features of the baseline adenoma withisk of metachronous neoplasms, however, is based on amall body of scientific evidence.18 Relatively few reports,ncluding one meta-analysis,19 have addressed this issue,nd none has been large enough to provide precise esti-ates of risk of advanced adenomas or invasive cancer.o clarify these issues, we pooled data from 8 prospective

tudies to estimate absolute risks of metachronous ad-anced adenoma, colorectal cancer, and their combina-ion (advanced colorectal neoplasia), and to identify pa-ient characteristics and adenoma features that aressociated independently with risk of these outcomes.

Materials and MethodsStudy PopulationThe pooled analyses used patient-level data from

North American studies6,7,10,12,20 –23 of patients withporadic colorectal adenoma (Table 1). Six studies wereandomized controlled trials,6,7,12,20,21,22 and in 2 of thesetudies7,20 a modest degree of efficacy of the interventionas shown on the primary end point. Eligibility criteria

or the chemoprevention trials generally were similar.owever, study populations in the nonintervention stud-

es10,23 included average-risk individuals with a first-timeiagnosis of adenomatous polyps. We aimed to include studieshat met the following criteria: (1) 800 or more study partici-ants; (2) study protocol requiring complete baseline colonos-opy with removal of one or more adenomas and removalf all visualized lesions; (3) a specified schedule of sur-eillance follow-up colonoscopies; and (4) availability ofnd point data regarding the number, size, and histopa-hology of adenomas and colorectal cancers detected inollow-up examinations. To our knowledge, we includedll studies meeting these criteria that had reported find-ngs by June 2005. Of the 10,021 men and women whoere enrolled in the individual studies, we excluded pa-

ients who had a colorectal cancer present at baselinen � 27) and those who did not have a follow-upolonoscopy performed after the first 6 months of studyn � 827) because these likely were individuals who wereot under typical postpolypectomy surveillance. Thus,ata for 9167 (91.5%) patients remained for inclusion inur pooled analyses.

Study End PointsWe considered as end points all colorectal neo-

lasms that were diagnosed during an interval beginningmonths after the baseline examination and ending on

he date of the last protocol-specified colonoscopic ex-mination. We excluded neoplasms found at colonosco-ies conducted in the first 6 months after the baselineolonoscopy because these examinations appeared to

ave been performed primarily to address problems iden- Ta N

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834 MARTÍNEZ ET AL GASTROENTEROLOGY Vol. 136, No. 3

ified during the baseline colonoscopy and were not per-ormed as surveillance procedures. In the course of eachf the parent studies, staff reviewed the endoscopy andathology reports to abstract data on number, size, and

ocation of all neoplasms. For our analyses, we catego-ized the anatomic locations of lesions as proximal (ce-um, ascending colon, hepatic flexure, transverse colon,nd splenic flexure) or distal (descending colon, sigmoidolon, and rectum). Histologic features of colorectal neo-lasms were determined from pathology reports gener-ted by either an independent study pathologist or aommunity pathologist, depending on the individualtudy protocol (Table 1). Definitions for adenomas weres follows: tubular (�25% villous component), tubulov-llous (26%–75% villous component), or villous (�75%illous component). We considered advanced adenomaso be those that had one or more of the following fea-ures: 10 mm in diameter or larger, presence of high-rade dysplasia, or greater than 25% villous features (alsolassified as tubulovillous or villous histology). We fur-her combined advanced adenomas and invasive cancernto an end point of advanced colorectal neoplasia. Vil-ous histology was included in our definition of advanceddenomas, although this was not the case in each of theriginal studies.10 We tested whether villous features,igh-grade dysplasia, and adenoma size were predictive ofach of the features used to define advanced adenomas.he associations were similar across each of the featuressed to define advanced metachronous adenoma, sug-esting that the inclusion of villous histology in ourefinition of advanced adenoma did not significantly

nfluence the observed associations.

Risk Factor DataThe studies had used self-administered question-

aires to obtain data on sociodemographic variables (age,ex, and race), cigarette smoking, family history of colo-ectal cancer in first-degree relatives, and history of pol-ps or adenomas before the baseline examination. Ciga-ette smoking status was classified as never, former, orurrent. Patient weight and height had been measured orelf-reported according to study protocol. We calculatedody mass index (BMI) by dividing weight (kg) by thequare of height (m). Weight, height, and cigarette smok-ng were not ascertained in the National Polyp Study.10

istory of adenomas or polyps diagnosed before theaseline examination had been assessed by self-report;he Veterans Affairs Cooperative Study23 and the Na-ional Polyp Study10 only included individuals whoserst adenoma was diagnosed at the baseline examination.Data on baseline adenoma characteristics (number,

ize, location, histology, and high-grade dysplasia) hadeen ascertained from review of clinical and pathologyeports. There were 957 patients whose pathology reportsid not specify the presence or absence of villous features,

hese were included in the tubular adenoma group be- i

ause their association with outcomes of interest wereimilar. The Antioxidant Polyp Prevention Study24 andhe Calcium Polyp Prevention Study20 did not collectata regarding the presence or absence of high-gradeysplasia in baseline adenomas.

Statistical AnalysisWe generated summary descriptive data for base-

ine characteristics and end points for each study and forhe total population. For each baseline characteristic, westimated the absolute risk of colorectal neoplasia duringhe stipulated follow-up period for each specific out-ome: nonadvanced adenoma(s), one or more advanceddenoma(s), and invasive cancer. We also compared thebsolute risk of advanced adenoma and cancer amongatients defined as being at higher or lower risk accord-

ng to the most recent surveillance guidelines.3 In thisategorization, the low-risk group included patients withor 2 small (�1 cm), tubular adenoma(s) with low-gradeysplasia; the high-risk group included patients with 3 orore adenomas, or any adenomas 1 cm or larger, or with

reater than 25% villous features, or with high-gradeysplasia.We estimated pooled adjusted odds ratios (ORs) for

he study end points using logistic regression modelshat controlled for study, age, sex, race, smoking status,MI, family history of colorectal cancer, history of polypr adenoma before the baseline examination, and theaseline adenoma characteristics. There were too fewancers diagnosed in the study population to permit aull multivariate analysis of this outcome separately.

eterogeneity between study-specific risk estimatesas assessed for each exposure variable separately by

onducting a log likelihood ratio test25 comparing theultivariate model presented in the tables with a multi-

ariate model including additional interaction terms be-ween each study indicator variable and the exposureariable of interest. Heterogeneity was assumed to beresent when the likelihood ratio test yielded a P value lesshan .05. Given the lack of evidence of heterogeneity basedn this criterion (P � .09 for high-grade dysplasia and P �

30 for all other variables), pooled ORs and 95% confidencentervals (CIs) computed from all individual data in unor-ered polytomous logistic regression models are presentedor 2 principal outcomes: nonadvanced and advanced neo-lasms (advanced adenomas and invasive cancer).

We also conducted random-effects modeling using a-stage method in which study-specific ORs and 95% CIsere first estimated, followed by estimation of summaryRs, weighted by the inverse of their variance.26 These

esults were not materially different from those of thexed-effects models presented. We considered the likeli-ood that differential follow-up times across studiesight confound the observed associations. However, in-

lusion of a variable for follow-up time in the multivar-

ate models did not appreciably alter the results. Tests for

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March 2009 COLORECTAL NEOPLASIA AFTER POLYPECTOMY 835

rend were conducted in separate analyses in which thexposure variable was modeled as an ordinal variableith values corresponding to the categorization level of

hat variable in the original analyses.If a study, by design, had not collected information for a

pecific variable, we excluded it from the analyses that per-ained to that factor (eg, the National Polyp Study data wereot included in analyses of risk associated with BMI andmoking). In the case of data that were missing/unknownor other reasons, we first created a missing data indicatorariable for missing responses and then compared theodel results with those in which the missing data obser-

ations were dropped from the analyses. The overall resultsere not appreciably different between models using these 2pproaches, and we present here the results from the mod-

able 2. Baseline Characteristics of Patients

APPS(N � 837)

NPS(N � 939)

CPPS(N � 913) (N

ge, mean (SD) (y) 61.1 � 8.3 61.0 � 9.9 61.0 � 9.1 60ex (%)Male 79.2 71.5 72.3Female 20.8 28.5 27.7

ace (%)White 85.0 90.5 85.1Black 6.8 7.0 8.0Other 8.2 2.4 6.9

amily history of colorectalcancer, (%)a

No 78.5 77.6 67.6Yes 19.4 22.4 21.2Unknown 2.2 0.0 11.2

igarette smoking status (%)Never 30.9 NAb 33.4Former 45.4 NA 47.4Current 21.5 NA 19.2Unknown 2.2 NA 0.0

MI in kg/m2 (%)c�25 31.6 NAb 31.325 to �30 48.9 NA 44.230� 19.6 NA 24.5

revious polyp (%)dNo 75.4 100.0 78.0Yes 23.5 0.0 21.5Unknown 1.1 0.0 0.5ean no. of adenomase 1.9 � 1.4 1.9 � 1.5 1.9 � 1.4 1

ocation (%)Distal colorectum 58.7 60.4 52.8Proximal only 19.1 14.7 24.1Proximal and distal 22.2 21.4 22.9Unknown 0.0 3.5 0.2

ize of largest adenoma,mean (SD) (mm)f

8.7 � 6.0 11.2 � 7.3 7.4 � 5.6 8

denoma histology (%)Tubularg 57.2 81.8 81.1Tubulovillous/villous 42.8 18.2 18.9

igh-grade dysplasia (%)No 96.2 91.1 NAh

Yes 3.8 8.9 NA

A, not applicable.ata were from the APPS, Antioxidant Polyp Prevention Study21; NPS, National PPT, Polyp Prevention Trial6; VA, Veterans Affairs Cooperative Study23; AFT, AsHistory of colorectal cancer in one or more parents, siblings, or children.No data available for NPS study patients.Excludes 15 patients with missing data.History of previous polyps or adenomas before qualifying colonoscopy; NPS aExcludes 55 participants with missing data.Excludes 353 participants with missing data.Includes 957 participants with adenomas in which histology was not specifiedNo data available for CPPS and AFT participants.

ls that included the missing data indicator variable. o

Results

The study population of 9167 patients was pre-ominantly male (71.2%) and Caucasian (89.1%), with aean age of 62.0 years (Table 2). The median follow-up

eriod for the entire group was 47.2 months (range ofedians among studies, 36.9 –59.0 mo), and 46.7% of

atients had at least one neoplasm diagnosed during thiseriod (Table 3). Advanced adenomas were found duringollow-up evaluation in 1024 patients (11.2% of the totalopulation), and 58 (0.6%) had invasive colorectal cancer.The proportions of patients diagnosed during follow-up

valuation with advanced adenoma or invasive cancer in-reased with age, male sex, and history of polyps or ade-oma before the baseline examination (Table 4). Risk varied

24)WBF

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0.0 65.7 � 8.8 63.0 � 6.9 57.4 � 9.6 65.8 � 8.5 62.0 � 9.5

66.8 98.0 63.5 67.5 71.233.2 2.0 36.5 32.5 28.8

96.1 83.2 85.6 93.0 89.10.8 9.6 5.8 0.7 5.73.1 7.1 8.6 6.4 5.2

75.8 84.5 51.4 71.3 71.417.0 15.5 30.7 27.8 22.87.2 0.0 18.0 0.9 5.8

34.2 23.0 42.4 30.0 34.152.1 55.1 42.5 56.3 49.613.6 21.8 15.0 11.9 15.80.2 0.1 0.1 1.8 0.5

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79.0 94.7 NAh 92.6 90.521.0 5.3 NA 7.4 9.5

tudy8; CPPS, Calcium Polyp Prevention Study20; WBF, Wheat Bran Fiber study12;olate Trial7; UDCA, Ursodeoxycholic Acid study.22

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836 MARTÍNEZ ET AL GASTROENTEROLOGY Vol. 136, No. 3

ancer, smoking history, or BMI. Both advanced adenomand invasive cancer occurred more often in patients withaseline adenomas that were larger, more numerous, were

ocated proximally, had villous features, or had high-gradeysplasia. Risk of a metachronous advanced adenoma ap-roached 20% in patients who had 4 or more baselinedenomas, or whose largest baseline adenoma was 20 mmn size or greater (Table 4). Risk of invasive cancer was 1.2%n patients who had larger (�20 mm) baseline adenomasnd 1.3% in those who had prior lesions with high-gradeysplasia. Analyses that assessed risk according to surveil-

ance guidelines’ risk stratification categories3 showed aoderate degree of discrimination. Compared with patientsho could be categorized as low risk, those deemed high

isk were more often diagnosed with both advanced ade-oma (15.5% vs 6.9%) and colorectal cancer (0.8% vs 0.5%).here was essentially no difference in the occurrence ofonadvanced neoplasms.In light of the similar risk factor patterns for advanced

denoma and invasive cancer (Table 4), we combined theseoutcomes into a category of advanced colorectal neo-

lasms for subsequent analyses. Results of the multivariateodels (Table 5) indicate that after adjustment for other

ariables, older age was associated strongly with risk ofdvanced neoplasms (P trend � .0001). The odds of ad-anced neoplasms was modestly higher in men (OR, 1.40;5% CI, 1.19–1.65) and in patients who reported a history ofrevious polyps (OR, 1.76; 95% CI, 1.48–2.09); it was notlearly associated with race, family history of colorectalancer, current cigarette smoking, or obesity (defined as aMI of �30 kg/m2). Adenoma number was associatedtrongly and independently with the odds of both advancednd nonadvanced metachronous neoplasms (P trend �

0001). Patients with larger adenomas also were more likelyo develop advanced neoplasms. Relative to patients with aaseline adenoma of less than 5 mm, the adjusted odds fordvanced neoplasms for those with an adenoma 10–19 mmas 2.27 (95% CI, 1.84–2.78), and for those with at least 1denoma 20 mm or larger it was 2.99 (95% CI, 2.24–4.00).he presence of any proximal adenoma at baseline wasssociated significantly with metachronous advanced neo-lasms (adjusted OR, 1.68; 95% CI, 1.43–1.98). The strongssociation observed in the unadjusted statistical modeletween baseline villous histology and metachronous ad-anced neoplasia was attenuated in the multivariate analy-is, and the association with baseline high-grade dysplasiassentially disappeared once adenoma size, histology, andocation were included in the multivariate model. Study-pecific analyses for baseline adenoma characteristics anddvanced neoplasms showed consistent results across stud-es (Figure 1), a finding that supports the lack of statisticallyignificant heterogeneity between study-specific risk esti-

ates. For those studies that entailed an intervention, when aariable for treatment assignment was included in our multi-

variate models it did not materially alter any of our results.Ta Me

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March 2009 COLORECTAL NEOPLASIA AFTER POLYPECTOMY 837

DiscussionThis pooled analysis of postpolypectomy pa-

ients showed that after a median of 4 years of fol-ow-up surveillance, roughly 1 in 10 patients was di-

able 4. Risk of New Neoplasia at Follow-Up Evaluation, Acc

Characteristic Number (%) Nonadvanced

ge (y)�40 154 (1.7) 18.840–49 804 (8.8) 27.750–59 2397 (26.1) 34.960–69 3676 (40.1) 36.070–79 2074 (22.6) 36.980� 62 (0.7) 33.9

exFemale 2642 (28.8) 29.0Male 6525 (71.2) 37.3

aceWhite 8166 (89.1) 35.0Black 527 (5.7) 37.6Other 474 (5.2) 29.1

amily history of colorectal cancera

No 6547 (71.4) 34.5Yes 2089 (22.8) 36.7Unknown 531 (5.8) 32.2

igarette smoking statusb

Never 2805 (34.1) 33.6Former 4081 (49.6) 36.9Current 1299 (15.8) 36.8Unknown 43 (0.5) 34.9

MI (kg/m)2c

�25 2332 (28.4) 32.225 to �30 3771 (45.9) 36.630� 2110 (25.7) 38.1

revious polypd

No 6941 (75.7) 33.4Yes 2057 (22.4) 39.5Unknown 169 (1.8) 38.5

denoma numbere

1 5465 (60.0) 30.22 2054 (22.5) 38.33 890 (9.8) 45.44 326 (3.6) 45.45� 377 (4.1) 51.2

denoma locationDistal colorectum 4434 (48.4) 30.4Proximal only 2620 (28.6) 37.3Proximal and distal 1754 (19.1) 44.2Unknown 359 (3.9) 26.7

denoma size (mm)f�5 2540 (28.8) 36.45 to �10 3115 (35.3) 36.810 to �20 2487 (28.2) 31.420� 672 (7.6) 31.8

denoma histologyTubularg 7268 (79.3) 35.1Tubulovillous/villoush 1899 (20.7) 33.9

igh-grade dysplasiai

No 6485 (90.5) 35.3Yes 683 (9.5) 35.9

ow-risk groupj 4644 (50.7) 34.5igh-risk group 4523 (49.3) 35.3

Percentage of patients with a particular outcome reported during surveillanceHistory of colorectal cancer in one or more parents, siblings, or children.No data available for National Polyp Study participants (n � 939). Excludes 1History of previous polyps or adenomas before qualifying colonoscopy; Nationdenoma (n � 1810).Number of adenomas detected at qualifying examination; excludes 55 participSize of largest adenoma; excludes 353 participants with missing data.Includes participants with adenomas in which histology was not specified, unkOne or more adenoma(s) with greater than 25% villous features.One or more adenoma(s) with high-grade dysplasia. No data available for 199Defined according to the most recent surveillance guidelines.3 The low-risk grysplasia; the high-risk group includes patients with 3 or more adenomas, or anigh-grade dysplasia.

gnosed with an advanced colorectal neoplasm, and w

pproximately 1 in 150 was diagnosed with colorectalancer. Development of metachronous advanced colo-ectal neoplasia was associated with the number, size,ocation, and histologic features of prior adenomas, as

g to Baseline Patient and Adenoma Characteristics

ma, % (95% CI) Advanced adenoma, % (95% CI) Cancer, % (95% CI)

–25.0) 3.9 (0.8–7.0) 0.0–30.8) 6.3 (4.7–8.0) 0.1 (0.0–0.4)–36.8) 8.6 (7.5–9.8) 0.3 (0.1–0.6)–37.5) 12.2 (11.1–13.2) 0.6 (0.3–0.8)–39.0) 14.5 (13.0–16.0) 1.3 (0.8–1.7)–45.7) 17.7 (8.2–27.3) 1.6 (0.0–4.7)

–30.7) 9.8 (8.7–10.9) 0.3 (0.10.5)–38.4) 11.7 (10.9–12.5) 0.8 (0.6–1.0)

–36.1) 11.4 (10.7–12.0) 0.6 (0.4–0.8)–41.7) 10.4 (7.8–13.0) 0.8 (0.0–1.5)–33.2) 8.9 (6.3–11.4) 1.3 (0.3–2.3)

–35.7) 11.0 (10.3–11.8) 0.6 (0.4–0.8)–38.7) 11.6 (10.3–13.0) 0.6 (0.3–0.9)–36.2) 11.1 (8.4–13.8) 1.3 (0.3–2.3)

–35.4) 11.1 (9.9–12.2) 0.5 (0.2–0.8)–38.4) 12.1 (11.1–13.1) 0.9 (0.6–1.2)–39.4) 11.8 (10.0–13.5) 0.2 (0.0–0.5)–49.1) 9.3 (0.6–18.0) 2.3 (0.0–6.8)

–34.1) 11.7 (10.4–13.1) 0.5 (0.2–0.8)–38.1) 11.6 (10.6–12.7) 0.7 (0.4–1.0)–40.2) 11.6 (10.2–12.9) 0.8 (0.4–1.2)

–34.5) 9.8 (9.1–10.5) 0.6 (0.4–0.8)–41.6) 15.2 (13.7–16.8) 0.8 (0.4–1.2)–45.8) 16.6 (11.0–22.2) 0.6 (0.0–1.7)

–31.4) 8.6 (7.8–9.3) 0.5 (0.4–0.7)–40.4) 12.7 (11.3–14.1) 0.5 (0.2–0.9)–48.7) 15.3 (12.9–17.6) 1.1 (0.4–1.8)–50.8) 19.6 (15.3–23.9) 1.2 (0.0–2.4)–56.2) 24.1 (19.8–28.5) 0.8 (0.0–1.7)

–31.8) 8.5 (7.7–9.3) 0.4 (0.2–0.6)–39.1) 11.8 (10.6–13.1) 0.8 (0.5–1.2)–46.6) 17.5 (15.7–19.3) 1.0 (0.6–1.5)–31.3) 8.1 (5.3–10.9) 0.0

–38.3) 7.7 (6.6–8.7) 0.5 (0.2–0.8)–38.5) 8.7 (7.7–9.7) 0.5 (0.2–0.7)–33.3) 15.9 (14.5–17.4) 0.8 (0.5–1.2)–35.4) 19.3 (16.4–22.3) 1.2 (0.4–2.0)

–36.2) 9.7 (9.0–10.4) 0.6 (0.4–0.7)–36.0) 16.8 (15.1–18.5) 0.9 (0.5–1.4)

–36.5) 10.6 (9.8–11.3) 0.5 (0.4–0.7)–39.5) 16.0 (13.2–18.7) 1.3 (0.5–2.2)–35.8) 6.9 (6.2–7.6) 0.5 (0.3–0.7)–36.7) 15.5 (14.5–16.6) 0.8 (0.5–1.0)

ndard error.

icipants with missing data.yp Study and VA Cooperative Study included only participants with a first-time

with missing data.

, or other histologies (n � 957).

ium Polyp Prevention Study and Aspirin Folate Trial participants.cludes patients with 1–2 small (�1 cm), tubular adenoma(s) with low-grade

nomas 1 cm or larger in size, or with greater than 25% villous features, or with

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838 MARTÍNEZ ET AL GASTROENTEROLOGY Vol. 136, No. 3

able 5. Pooled Odds Ratios of Colorectal Neoplasia for Baseline Patient and Adenoma Characteristics

Characteristic

Crude OR (95% CI) Adjusted ORa (95% CI)

Nonadvanced Advanced Nonadvanced Advanced

ge (y)�40 0.39 (0.26–0.59) 0.32 (0.14–0.73) 0.47 (0.31–0.72) 0.41 (0.18–0.94)40–49 0.68 (0.57–0.81) 0.61 (0.45–0.85) 0.72 (0.60–0.87) 0.67 (0.48–0.93)50–59 1.00 1.00 1.00 1.0060–69 1.13 (1.01–1.26) 1.56 (1.31–1.86) 1.10 (0.98–1.24) 1.39 (1.16–1.68)70–79 1.25 (1.10–1.43) 2.09 (1.72–2.52) 1.21 (1.05–1.38) 1.72 (1.40–2.11)80� 1.16 (0.66–2.05) 2.59 (1.30–5.15) 1.24 (0.69–2.25) 2.70 (1.31–5.57)

P trend � .0001 P trend � .0001exFemale 1.00 1.00 1.00 1.00Male 1.56 (1.41–1.72) 1.50 (1.29–1.74) 1.45 (1.30–1.62) 1.40 (1.19–1.65)

aceWhite 1.00 1.00 1.00 1.00Black 1.11 (0.92–1.34) 0.97 (0.73–1.30) 1.12 (0.92–1.37) 1.08 (0.79–1.47)Other 0.72 (0.59–0.89) 0.74 (0.54–1.01) 0.83 (0.67–1.03) 0.83 (0.60–1.16)

amily history of colorectal cancerb

No 1.00 1.00 1.00 1.00Yes 1.12 (1.00–1.24) 1.11 (0.94–1.29) 1.15 (1.03–1.29) 1.17 (0.99–1.38)

igarette smoking statusc

Never 1.00 1.00 1.00 1.00Former 1.20 (1.08–1.33) 1.23 (1.05–1.43) 1.07 (0.96–1.20) 1.08 (0.92–1.27)Current 1.17 (1.02–1.35) 1.11 (0.90–1.38) 1.16 (1.00–1.35) 1.13 (0.90–1.42)

ody mass index (kg/m)2d

�25 1.00 1.00 1.00 1.0025 to �30 1.23 (1.10–1.38) 1.09 (0.93–1.29) 1.10 (0.98–1.24) 1.00 (0.84–1.19)30� 1.32 (1.16–1.51) 1.13 (0.94–1.36) 1.23 (1.08–1.41) 1.13 (0.93–1.38)

P trend � .003 P trend � .226revious polype

No 1.00 1.00 1.00 1.00Yes 1.50 (1.34–1.66) 1.95 (1.68–2.26) 1.37 (1.21–1.55) 1.76 (1.48–2.09)

denoma number1 1.00 1.00 1.00 1.002 1.58 (1.42–1.77) 1.81 (1.54–2.14) 1.46 (1.30–1.64) 1.39 (1.17–1.66)3 2.38 (2.04–2.79) 2.85 (2.30–3.54) 2.05 (1.73–2.42) 1.85 (1.46–2.34)4 2.70 (2.09–3.48) 4.11 (2.99–5.63) 2.23 (1.71–2.92) 2.41 (1.71–3.40)5� 4.30 (3.33–5.56) 6.94 (5.12–9.40) 3.63 (2.76–4.78) 3.87 (2.76–5.42)

P trend � .0001 P trend � .0001denoma locationf

Distal colorectum 1.00 1.00 1.00 1.00Any proximal 1.78 (1.62–1.95) 2.27 (1.98–2.60) 1.29 (1.16–1.44) 1.68 (1.43–1.98)

ize of largest adenoma, mm�5 1.00 1.00 1.00 1.005 to �10 1.03 (0.92–1.16) 1.15 (0.95–1.39) 1.01 (0.90–1.14) 1.17 (0.95–1.42)10 to �20 0.92 (0.82–1.04) 2.18 (1.82–2.62) 0.94 (0.82–1.08) 2.27 (1.84–2.78)20� 1.02 (0.84–1.23) 2.92 (2.28–3.73) 1.00 (0.80–1.25) 2.99 (2.24–4.00)

P trend � .4944 P trend � .0001denoma histologyTubularg 1.00 1.00 1.00 1.00Tubulovillous/villoush 1.09 (0.97–1.22) 1.96 (1.69–2.27) 1.05 (0.92–1.20) 1.28 (1.07–1.52)

igh-grade dysplasiaNo 1.00 1.00 1.00 1.00Yes 1.16 (0.97–1.38) 1.77 (1.41–2.22) 1.04 (0.86–1.26) 1.05 (0.81–1.35)

Adjusted for age, sex, race, family history of colorectal cancer, previous polyp, cigarette smoking, BMI, baseline number of adenomas, adenomaize, location, histology, high-grade dysplasia, and study.History of colorectal cancer in one or more parents, siblings, or children. Excludes 531 patients with unknown or missing data.No data available for NPS study participants (n � 939); excludes 43 participants with unknown or missing data from other studies.No data available for NPS study participants (n � 939); excludes 15 participants with missing data from other studies.History of previous polyps or adenomas before qualifying colonoscopy. Excludes 169 participants with unknown or missing data.Excludes 359 participants with unknown or missing data on location.Includes 957 participants with adenomas in which histology was not specified, unknown, or other histologies.

Adenomas with greater than 25% villous features.

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March 2009 COLORECTAL NEOPLASIA AFTER POLYPECTOMY 839

actors, patient age and adenoma size and number hadhe strongest association with risk.

Prior reports have indicated that risk of metachronousdvanced adenoma and cancer is increased with adenomaultiplicity,9,10,27–31 villous features,9,29,31,32 high-grade

ysplasia,9,27,29,31,33,34 and adenoma size.5,9,28 –31,34,35 The

igure 1. Study-specific and pooled multivariate ORs of advancedolorectal neoplasia (advanced adenoma and cancer) for baseline ad-noma characteristics. ORs are adjusted for age, sex, race, smokingtatus, BMI, family history of colorectal cancer, history of polyp or ad-noma before the baseline examination, and the baseline adenomaharacteristics. ORs for number and size of adenomas represent an

ncrease in risk per adenoma and per 10-mm increment, respectively.he black squares and horizontal lines correspond to the study-specificultivariate ORs and 95% CIs, respectively. The area of the black

quare reflects the study-specific weight (inverse of the variance). Theooled ORs are based on data from 8814 patients because of missingata on baseline adenoma size and number for 353 individuals. Theiamond represents the pooled multivariate OR and 95% CIs. The solid

ine represents an OR of 1.0. APPS, Antioxidant Polyp Preventiontudy; NPS, National Polyp Study; PPT, Polyp Prevention Trial;PPS, Calcium Polyp Prevention Study; WBF, Wheat Bran Fibertudy; VA, Veterans Affairs Cooperative Study; AFT, Aspirin Folaterial; UDCA, Ursodeoxycholic Acid study.

resence of proximal adenomas also has been associated f

ith a higher likelihood of metachronous advanced colo-ectal neoplasia in some studies.5,27,32 However, reportsrom individual studies have been based on relativelymall numbers of patients with metachronous advancedeoplasms and the estimates of risk have been imprecise.

report from one meta-analysis19 also indicated thatrior adenoma number and high-grade dysplasia wereredictive of subsequent advanced adenoma, but the in-estigators did not use subject-level data, and their con-lusions were based on only 4 studies for adenoma num-er and 2 studies for high-grade dysplasia.

The large number of patients and end points in ourooling study allowed us to generate more precise riskstimates and to perform multivariate analyses to assessndependent contributions of various factors to risk ofdvanced neoplasia. In our data, both patient age andumber of prior adenomas were strong predictors of risk;he proportion of patients who developed advanced neo-lasia increased almost linearly with increases in theseactors. Our multivariate analyses confirmed the inde-endent importance of these 2 factors, as well as priordenoma size and proximal location, in determining risk.e found that once other factors were accounted for, the

resence of villous histology in a prior adenoma wasssociated only modestly with subsequent advanced neo-lasia. We observed no independent association betweenamily history and subsequent advanced colorectal neo-lasia among postpolypectomy patients, unlike thetronger associations typically seen for family history inpidemiologic studies of colorectal cancer incidence.36

urther, there were no clear associations between meta-hronous advanced neoplasia and current cigarettemoking or obesity; thus, these factors seem unlikely todd much information in assessing risk.

In our univariate analyses, high-grade dysplasia wasssociated clearly with risk, however, this association wasargely explicable by other factors (eg, prior adenoma size,ocation, and villous features). We are uncertain why ouresults in this regard differ from those in some,9,29,34,35

lthough not all,27,33 prior reports of an increased risk ofetachronous advanced neoplasms associated with high-

rade dysplasia. The apparent discordance in results mayeflect differences in the extent to which other risk fac-ors were taken into account in the various reports. Otherossible explanations include differences in study popu-

ations or in the definition of high-grade dysplasia, whichn our data was derived from reports produced by pa-hologists who were based in both academic and com-

unity hospital settings. Lastly, in our data only 3% ofatients who had small tubular adenomas also had high-rade dysplasia, the small number of these patients didot permit us to assess whether an isolated finding ofigh-grade dysplasia might be associated with increasedisk.

Our pooled analyses were based on patients who were

ollowed up prospectively for 4 years on average, accord-

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840 MARTÍNEZ ET AL GASTROENTEROLOGY Vol. 136, No. 3

ng to well-defined protocols, and with relatively fewosses to follow-up evaluation, thereby lessening the like-ihood that differential follow-up intensity could bias thessociations we observed. However, eligibility criteria forll the studies included in our analyses required an ade-uate colonic preparation and a full examination to theecum, thus we were unable to assess the potential effectsf variations in the quality of baseline colonoscopy ex-minations. Colonoscopy quality may be an importantactor in routine clinical practice, and missed and incom-letely excised lesions are thought to be likely explana-ions for some of the advanced adenomas and cancersound during surveillance.11,15,16,32,37,38 Missing data forome variables also posed a challenge in our analyses.lthough we used 2 different methods to address this

ssue, we cannot exclude the possibility of bias resultingrom these approaches.39

The goal of surveillance is to minimize (not eliminate)he risk of interval cancer. Current risk stratificationuidelines3 are based on small individual studies. Ourooled data represent a large cohort of patients who havead systematic surveillance colonoscopy. These datahow relatively good discrimination between low-risk andigh-risk groups (6.9% vs 15.5%) using current risk-strat-

fication guidelines. Thus, our results strengthen the con-ept of risk stratification and should lead to improvedhysician adherence to these guidelines. Enhanced adher-nce would have an improved impact on decreasing theesources allocated inappropriately to intensive surveil-ance in the lower-risk group, which constitutes approx-mately 75% of those under surveillance.40 Nevertheless,he guidelines are not perfect; 7.4% of patients in ournalyses who would be categorized as low risk by theuidelines developed an advanced adenoma or invasiveancer during follow-up evaluation. Our data warrantonsideration of additional risk factors, such as proximalocation, sex, and age in the next iteration of the surveil-ance guidelines. Lastly, a formal prediction-modelingnalysis would be helpful in determining which combi-ation of factors would maximally distinguish the risk ofecurrent advanced adenomas and cancers.

Results of our pooled data show that occurrence of colo-ectal neoplasia is common after colonoscopic polypec-omy. Several patient characteristics and features of therior adenoma are associated with advanced colorectal neo-lasia at surveillance colonoscopy, the most important ofhese being the number and size of prior adenomas andatient age. Although current guidelines help stratify pa-ients into high-risk and low-risk groups, it may be possibleo further refine estimates of risk by developing predictivetatistical models; our analyses point to a promising set ofactors to include in the models.

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Received August 8, 2008. Accepted December 1, 2008.

eprint requestsAddress requests for reprints to: María Elena Martínez, PhD,

niversity of Arizona, Arizona Cancer Center, PO Box 245024, Tucson,rizona 85724. e-mail: emartinez@azcc.arizona.edu; fax: (520) 626-275.

cknowledgmentsThe authors are indebted to all the patients, staff, and clinical

nvestigators at the individual study sites. The authors thank Erinshbeck and Dr Donna Spiegelman for their contributions to thereparation of the manuscript.

onflicts of interestThe authors disclose no conflicts.

undingThe authors disclose the following: this work was supported by

ublic Health Service grants CA-41108, CA-23074, CA95060,A37287, CA104869, CA23108, CA59005, and CA26852 from theational Cancer Institute. Dr Jacobs is supported by a K07 Careerevelopment Award (CA106269) from the National Cancer Institute.unding for the Veteran’s Affairs Study was supported by the

ooperative Studies Program, Department of Veterans Affairs.