Ann G. Zauber

Prevention of Colorectal Cancer by Colonoscopic Polypectomy

BACKGROUND The current practice of removing adenomatous polyps of the colon and rectum is based on the belief that this will prevent colorectal cancer. To address the hypothesis that colonoscopic polypectomy reduces the incidence of colorectal cancer, we analyzed the results of the National Polyp Study with reference to other published results. METHODS The study cohort consisted of 1418 patients who had a complete colonoscopy during which one or more adenomas of the colon or rectum were removed. The patients subsequently underwent periodic colonoscopy during an average follow-up of 5.9 years, and the incidence of colorectal cancer was ascertained. The incidence rate of colorectal cancer was compared with that in three reference groups, including two cohorts in which colonic polyps were not removed and one general-population registry, after adjustment for sex, age, and polyp size. RESULTS Ninety-seven percent of the patients were followed clinically for a total of 8401 person-years, and 80 percent returned for one or more of their scheduled colonoscopies. Five asymptomatic early-stage colorectal cancers (malignant polyps) were detected by colonoscopy (three at three years, one at six years, and one at seven years). No symptomatic cancers were detected. The numbers of colorectal cancers expected on the basis of the rates in the three reference groups were 48.3, 43.4, and 20.7, for reductions in the incidence of colorectal cancer of 90, 88, and 76 percent, respectively (P < 0.001). CONCLUSIONS Colonoscopic polypectomy resulted in a lower-than-expected incidence of colorectal cancer. These results support the view that colorectal adenomas progress to adenocarcinomas, as well as the current practice of searching for and removing adenomatous polyps to prevent colorectal cancer.

Colonoscopic Polypectomy and Long-Term Prevention of Colorectal-Cancer Deaths

BACKGROUND In the National Polyp Study (NPS), colorectal cancer was prevented by colonoscopic removal of adenomatous polyps. We evaluated the long-term effect of colonoscopic polypectomy in a study on mortality from colorectal cancer. METHODS We included in this analysis all patients prospectively referred for initial colonoscopy (between 1980 and 1990) at NPS clinical centers who had polyps (adenomas and nonadenomas). The National Death Index was used to identify deaths and to determine the cause of death; follow-up time was as long as 23 years. Mortality from colorectal cancer among patients with adenomas removed was compared with the expected incidence-based mortality from colorectal cancer in the general population, as estimated from the Surveillance Epidemiology and End Results (SEER) Program, and with the observed mortality from colorectal cancer among patients with nonadenomatous polyps (internal control group). RESULTS Among 2602 patients who had adenomas removed during participation in the study, after a median of 15.8 years, 1246 patients had died from any cause and 12 had died from colorectal cancer. Given an estimated 25.4 expected deaths from colorectal cancer in the general population, the standardized incidence-based mortality ratio was 0.47 (95% confidence interval [CI], 0.26 to 0.80) with colonoscopic polypectomy, suggesting a 53% reduction in mortality. Mortality from colorectal cancer was similar among patients with adenomas and those with nonadenomatous polyps during the first 10 years after polypectomy (relative risk, 1.2; 95% CI, 0.1 to 10.6). CONCLUSIONS These findings support the hypothesis that colonoscopic removal of adenomatous polyps prevents death from colorectal cancer. (Funded by the National Cancer Institute and others.).

Annual Report to the Nation on the Status of Cancer, 1975-2006, Featuring Colorectal Cancer Trends and Impact of Interventions (Risk Factors, Screening, and Treatment) to Reduce Future Rates

The American Cancer Society, the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR) collaborate annually to provide updated information regarding cancer occurrence and trends in the United States. This years report includes trends in colorectal cancer (CRC) incidence and death rates and highlights the use of microsimulation modeling as a tool for interpreting past trends and projecting future trends to assist in cancer control planning and policy decisions.

Randomized Comparison of Surveillance Intervals after Colonoscopic Removal of Newly Diagnosed Adenomatous Polyps

BACKGROUND The identification and removal of adenomatous polyps and post-polypectomy surveillance are considered to be important for the control of colorectal cancer. In current practice, the intervals between colonoscopies after polypectomy are variable, often a year long, and not based on data from randomized clinical trials. We sought to determine whether follow-up colonoscopy at three years would detect important colonic lesions as well as follow-up colonoscopy at both one and three years. METHODS Patients were eligible if they had one or more adenomas, no previous polypectomy, and a complete colonoscopy and all their polyps had been removed. They were randomly assigned to have follow-up colonoscopy at one and three years or at three years only. The two study end points were the detection of any adenoma, and the detection of adenomas with advanced pathological features (defined as those > 1 cm in diameter and those with high-grade dysplasia or invasive cancer). RESULTS Of 2632 eligible patients, 1418 were randomly assigned to the two follow-up groups, 699 to the two-examination group and 719 to the one-examination group. The percentage of patients with adenomas in the group examined at one and three years was 41.7 percent, as compared with 32.0 percent in the group examined at three years (P = 0.006). The percentage of patients with adenomas with advanced pathological features was the same in both groups (3.3 percent). CONCLUSIONS Colonoscopy performed three years after colonoscopic removal of adenomatous polyps detects important colonic lesions as effectively as follow-up colonoscopy after both one and three years. An interval of at least three years is recommended before follow-up colonoscopy after both one and three years. An interval of at least three years is recommended before follow-up examination after colonoscopic removal of newly diagnosed adenomatous polyps. Adoption of this recommendation nationally should reduce the cost of post-polypectomy surveillance and screening.

A comparison of colonoscopy and double-contrast barium enema for surveillance after polypectomy

BACKGROUND After patients have undergone colonoscopic polypectomy, it is uncertain whether colonoscopic examination or a barium enema is the better method of surveillance. METHODS As part of the National Polyp Study, we offered colonoscopic examination and double-contrast barium enema for surveillance to patients with newly diagnosed adenomatous polyps. Although barium enema was performed first, the endoscopist did not know the results. RESULTS A total of 973 patients underwent one or more colonoscopic examinations for surveillance. In the case of 580 of these patients, we performed 862 paired colonoscopic examinations and barium-enema examinations that met the requirements of the protocol. The findings on barium enema were positive in 222 (26 percent) of the paired examinations, including 139 of the 392 colonoscopic examinations in which one or more polyps were detected (rate of detection, 35 percent; 95 percent confidence interval, 31 to 40 percent). The proportion of examinations in which adenomatous polyps were detected by barium enema colonoscopy was significantly related to the size of the adenomas (P=0.009); the rate was 32 percent for colonoscopic examinations in which the largest adenomas detected were 0.5 cm or less, 53 percent for those in which the largest adenomas detected were 0.6 to 1.0 cm, and 48 percent for those in which the largest adenomas detected exceeded 1.0 cm. Among the 139 paired examinations with positive results on barium enema and negative results on colonoscopic examination in the same location, 19 additional polyps, 12 of which were adenomas, were detected on colonoscopic reexamination. CONCLUSIONS In patients who have undergone colonoscopic polypectomy, colonoscopic examination is a more effective method of surveillance than double-contrast barium enema.

Evaluating Test Strategies for Colorectal Cancer Screening: A Decision Analysis for the U.S. Preventive Services Task Force

Despite recent declines in both incidence and mortality (1), colorectal cancer remains the second most common cause of death from cancer in the United States (2). Screening for colorectal cancer reduces mortality by allowing physicians to detect cancer at earlier, more treatable stages, as well as to identify and remove adenomatous polyps (asymptomatic benign precursor lesions that may lead to colorectal cancer). Many tests are available for screening, such as fecal occult blood tests (FOBTs), flexible sigmoidoscopy, and colonoscopy. Screening with FOBT (Hemoccult II, Beckman Coulter, Fullerton, California) has been shown to reduce colorectal cancer mortality by 15% to 33% in randomized, controlled trials (35), and screening with more sensitive FOBTs, flexible sigmoidoscopy, colonoscopy, or combinations of these tests may reduce the burden of colorectal cancer even more (6, 7). In the absence of adequate clinical trial data on several recommended screening strategies, microsimulation modeling can provide guidance on the risks, benefits, and testing resources required for different screening strategies to reduce the burden of colorectal cancer. In July 2002, the U.S. Preventive Services Task Force (USPSTF) concluded that there was sufficient evidence to recommend strongly that all average-risk adults 50 years of age or older should be offered colorectal cancer screening (8). However, the logistics of screening, such as the type of screening test, screening interval, and age at which to stop screening, were not evaluated in terms of the balance of benefits and potential harms. The USPSTF has again addressed recommendations for colorectal cancer screening with a systematic review of the evidence (9) on screening tests. For this assessment, the USPSTF requested a decision analysis to project expected outcomes of various strategies for colorectal cancer screening. Two independent microsimulation modeling groups from the Cancer Intervention and Surveillance Modeling Network (CISNET), funded by the National Cancer Institute, used a comparative modeling approach to compare life-years gained relative to resource use of different strategies for colorectal cancer screening. Methods We used 2 microsimulation models, MISCAN (MIcrosimulation Screening Analysis) (1012) and SimCRC (Simulation Model of Colorectal Cancer) (13), to estimate the life-years gained relative to no screening and the colonoscopies required (that is, an indicator for resource use and risk for complications) for different colorectal cancer screening strategies defined by test, age at which to begin screening, age at which to stop screening, and screening interval. We aimed to identify a set of recommendable strategies with similar clinical benefit and an efficient use of colonoscopy resources. Using 2 models (that is, a comparative modeling approach) adds credibility to the results and serves as a sensitivity analysis on the underlying structural assumptions of the models, particularly pertaining to the unobservable natural history of colorectal cancer. Microsimulation Models The Appendix describes the MISCAN and SimCRC models, and standardized model profiles are available at cisnet.cancer.gov/profiles/. In brief, both models simulate the life histories of a large population of individuals from birth to death. As each individual ages, there is a chance that an adenoma will develop. One or more adenomas can occur in an individual, and each adenoma can independently develop into preclinical (that is, undiagnosed) colorectal cancer (Figure 1). The risk for developing an adenoma depends on age, sex, and baseline individual risk. The models track the location and size of each adenoma; these characteristics influence disease progression and the chance that the adenoma will be found by screening. The size of adenomas can progress from small (5 mm) to medium (6 to 9 mm) to large (10 mm). Some adenomas eventually become malignant, transforming to stage I preclinical cancer. Preclinical cancer has a chance of progressing through stages I to IV and may be diagnosed by symptoms at any stage. Survivorship after diagnosis depends on the stage of disease. Figure 1. Natural history of disease as modeled by the Microsimulation Screening Analysis and Simulation Model of Colorectal Cancer models. The opportunity to intervene in the natural history through screening is noted. The natural history component of each model was calibrated to 19751979 clinical incidence data (14) and adenoma prevalence from autopsy studies in the same period (1524). We used this period because incidence rates and adenoma prevalence had not yet been affected by screening. We corrected the adenoma prevalence for studies of non-U.S. populations by using standardized colorectal cancer incidence ratios. The models use all-cause mortality estimates from the U.S. life tables and stage-specific data on colorectal cancer survival from the 19961999 Surveillance, Epidemiology, and End Results program (14). Table 1 compares outcomes from the natural history components of the models. Table 1. Comparison of the Natural History Outcomes from the Microsimulation Screening Analysis (MISCAN) and Simulation Model of Colorectal Cancer (SimCRC) Models The effectiveness of a screening strategy is modeled through a tests ability to detect lesions (that is, adenomas or preclinical cancer). Once screening is introduced, a simulated person who has an underlying lesion has a chance of having it detected during a screening round depending on the sensitivity of the test for that lesion and whether the lesion is within the reach of the test. Screened persons without an underlying lesion can have a false-positive test result and undergo unnecessary follow-up colonoscopy. Hyperplastic polyps are not modeled explicitly, but their detection is reflected in the specificity of the screening tests. The models incorporate the risk for fatal complications associated with perforation during colonoscopy. Both models have been validated against the long-term reductions in incidence and mortality of colorectal cancer with annual FOBT reported in the Minnesota Colon Cancer Control Study (3, 25, 26) and show good concordance with the trial results. Strategies for Colorectal Cancer Screening In consultation with the USPSTF, we included the following basic strategies: 1) no screening, 2) colonoscopy, 3) FOBT (Hemoccult II, Hemoccult SENSA [Beckman Coulter], or fecal immunochemical testing), 4) flexible sigmoidoscopy (with biopsy), and 5) flexible sigmoidoscopy combined with Hemoccult SENSA. For each basic strategy, we evaluated start ages of 40, 50, and 60 years and stop ages of 75 and 85 years. For the FOBT strategies, we considered screening intervals of 1, 2, and 3 years, and for the sigmoidoscopy and colonoscopy strategies, we considered intervals of 5, 10, and 20 years. These variations resulted in 145 strategies: 90 single-test strategies, 54 combination-test strategies, and 1 no-screening strategy. The stop age reflects the oldest possible age at which to screen, but the actual stopping age is dictated by the start age and screening interval. In the base case, we assumed 100% adherence for screening tests, follow-up of positive findings, and surveillance of persons found to have adenomas. Individuals with a positive FOBT result or with an adenoma detected by sigmoidoscopy were referred for follow-up colonoscopy. For years in which both tests were due for the combined strategy, the FOBT was performed first; if the result was positive, the patient was referred for follow-up colonoscopy. In those years, flexible sigmoidoscopy was done only for patients with a negative FOBT result. If findings on follow-up colonoscopy were negative, the individual was assumed to undergo subsequent screening with colonoscopy with a 10-year interval (as long as results of the repeated colonoscopy were negative) and did not return to the initial screening schedule, as is the recommendation of the U.S. Multi-Society Task Force and American Cancer Society (7, 27). All individuals with an adenoma detected were followed with colonoscopy surveillance per the Multi-Society guidelines (27, 28). The surveillance interval depended on the number and size of the adenomas detected on the last colonoscopy; it ranged from 3 to 5 years and was assumed to continue for the remainder of the persons lifetime. We estimated the test characteristics of colorectal cancer screening from a review of the available literature (Table 2) (29). We conducted this review independently of and parallel in time with the systematic evidence review performed for the USPSTF (9). Table 2. Test Characteristics Used in the Microsimulation Screening Analysis and Simulation Model of Colorectal Cancer Models Evaluation of Outcomes Determination of Efficient Strategies The most effective strategy was defined as the one with the greatest life-years gained relative to no screening. However, it is important to consider the relative intensity of test use required to achieve those gains. The more effective strategies tended to be associated with more colonoscopies on average in a persons lifetime, which translated into an increased risk for colonoscopy-related complications. We used an approach that mirrors that of cost-effectiveness analysis (30) to identify the set of efficient, or dominant, strategies within each test category. A strategy was considered dominant when no other strategy or combination of strategies provided more life-years with the same number of colonoscopies. We conducted this analysis separately for each of the 5 basic screening strategies because the number of noncolonoscopy tests differed by strategy. We then ranked the efficient screening strategies by increasing effectiveness and calculated the incremental number of colonoscopies (COL) per 1000, the incremental life-years gained (LYG) per 1000, and the incremental number of colonoscopies necessary to achieve 1 year of life (COL/

A Pooled Analysis of Advanced Colorectal Neoplasia Diagnoses After Colonoscopic Polypectomy

BACKGROUND & AIMS Limited data exist regarding the actual risk of developing advanced adenomas and cancer after polypectomy or the factors that determine risk. METHODS We pooled individual data from 8 prospective studies comprising 9167 men and women aged 22 to 80 with previously resected colorectal adenomas to quantify their risk of developing subsequent advanced adenoma or cancer as well as identify factors associated with the development of advanced colorectal neoplasms during surveillance. RESULTS During a median follow-up period of 47.2 months, advanced colorectal neoplasia was diagnosed in 1082 (11.8%) of the patients, 58 of whom (0.6%) had invasive cancer. Risk of a metachronous advanced adenoma was higher among patients with 5 or more baseline adenomas (24.1%; standard error, 2.2) and those with an adenoma 20 mm in size or greater (19.3%; standard error, 1.5). Risk factor patterns were similar for advanced adenomas and invasive cancer. In multivariate analyses, older age (P < .0001 for trend) and male sex (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.19-1.65) were associated significantly with an increased risk for metachronous advanced neoplasia, as were the number and size of prior adenomas (P < .0001 for trend), the presence of villous features (OR, 1.28; 95% CI, 1.07-1.52), and proximal location (OR, 1.68; 95% CI, 1.43-1.98). High-grade dysplasia was not associated independently with metachronous advanced neoplasia after adjustment for other adenoma characteristics. CONCLUSIONS Occurrence of advanced colorectal neoplasia is common after polypectomy. Factors that are associated most strongly with risk of advanced neoplasia are patient age and the number and size of prior adenomas.

Effect of Celecoxib on Cardiovascular Events and Blood Pressure in Two Trials for the Prevention of Colorectal Adenomas

Background— Cyclooxygenase-2 (COX-2) inhibitors have been shown to reduce colorectal adenomas but have been associated with increased cardiovascular risk. Methods and Results— The Adenoma Prevention With Celecoxib (APC) trial studied celecoxib 200 mg twice daily and 400 mg twice daily and the Prevention of Spontaneous Adenomatous Polyps (PreSAP) trial used 400 mg once daily to test the efficacy and safety of celecoxib against placebo in reducing colorectal adenoma recurrence after polypectomy. An independent safety committee for both studies adjudicated and categorized serious cardiovascular events and then combined individual patient data from these long-term trials to improve the estimate of the cardiovascular risk and blood pressure changes associated with celecoxib compared with placebo. For adjudicated cardiovascular events, 77% and 54% in APC and PreSAP, respectively, had 37 months of follow-up. For APC and PreSAP combined, 83 patients experienced cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or heart failure. The hazard ratio for this prespecified composite end point was 2.6 (95% confidence interval [CI], 1.1 to 6.1) in patients taking 200 mg twice daily, 3.4 (95% CI, 1.5 to 7.9) in patients taking 400 mg twice daily in APC, and 1.3 (95% CI, 0.6 to 2.6) in patients taking 400 mg once daily in PreSAP (P for heterogeneity=0.13 comparing the combined doses in APC with the dose in PreSAP). The overall hazard ratio for this composite end point was 1.9 (95% CI, 1.1 to 3.1). Both dose groups in APC showed significant systolic blood pressure elevations at 1 and 3 years (200 mg twice daily: 1 year, 2.0 mm Hg; 3 years, 2.6 mm Hg; 400 mg twice daily: 1 year, 2.9 mm Hg; 3 years, 5.2 mm Hg); however, the 400 mg once daily group in PreSAP did not (P<0.0001 between studies). Conclusions— Celecoxib at 200 or 400 mg twice daily or 400 mg once daily showed a nearly 2-fold–increased cardiovascular risk. The trend for a dose-related increase in cardiovascular events and blood pressure raises the possibility that lower doses or other dose intervals may be associated with less cardiovascular risk.

The Advanced Adenoma as the Primary Target of Screening

The advanced adenoma bridges benign and malignant states and may be the most valid neoplastic surrogate marker for present and future colorectal cancer risk. We define the advanced adenoma as an adenoma with significant villous features (>25%), size of 1.0 cm or more, high-grade dysplasia, or early invasive cancer. Prevention studies should demonstrate a high efficacy in reducing the number of advanced adenomas. We should use the advanced adenoma in the evaluation of new screening technology, nutritional interventions, and chemoprevention agents because the advanced adenoma is a more desirable target for screening efficacy than is the more uncommon but life-threatening cancer stage or the more common but early, less significant small adenoma stage.

Colorectal cancers soon after colonoscopy: a pooled multicohort analysis

Objective Some individuals are diagnosed with colorectal cancer (CRC) despite recent colonoscopy. We examined individuals under colonoscopic surveillance for colonic adenomas to assess possible reasons for diagnosing cancer after a recent colonoscopy with complete removal of any identified polyps. Design Primary data were pooled from eight large (>800 patients) North American studies in which participants with adenoma(s) had a baseline colonoscopy (with intent to remove all visualised lesions) and were followed with subsequent colonoscopy. We used an algorithm based on the time from previous colonoscopy and the presence, size and histology of adenomas detected at prior exam to assign interval cancers as likely being new, missed, incompletely resected (while previously an adenoma) or due to failed biopsy detection. Results 9167 participants (mean age 62) were included in the analyses, with a median follow-up of 47.2 months. Invasive cancer was diagnosed in 58 patients (0.6%) during follow-up (1.71 per 1000 person-years follow-up). Most cancers (78%) were early stage (I or II); however, 9 (16%) resulted in death from CRC. We classified 30 cancers (52%) as probable missed lesions, 11 (19%) as possibly related to incomplete resection of an earlier, non-invasive lesion and 14 (24%) as probable new lesions. The cancer diagnosis may have been delayed in three cases (5%) because of failed biopsy detection. Conclusions Despite recent colonoscopy with intent to remove all neoplasia, CRC will occasionally be diagnosed. These cancers primarily seem to represent lesions that were missed or incompletely removed at the prior colonoscopy and might be avoided by increased emphasis on identifying and completely removing all neoplastic lesions at colonoscopy.