Perspective from Aberrant Crypt Foci in the Adenoma Prevention with Celecoxib Trial

Perspective on this Article from Five-Year Efficacy and Safety Analysis of the Adenoma Prevention with Celecoxib Trial

Supplementary Information from Five-Year Efficacy and Safety Analysis of the Adenoma Prevention with Celecoxib Trial

Familial adenomatous polyposis (FAP) is a rare genetic disease. Without treatment, FAP patients have a 100% lifetime risk of developing colorectal cancer. This study was conducted to evaluate the effect of celecoxib treatment in prolonging the time to FAP-related events and to document the safety profile of the long-term use of celecoxib (≥6 months) in FAP patients. FAP patients receiving celecoxib in routine clinical practice were individually matched with historical/concurrent FAP patients not receiving celecoxib. The study population included patients aged 12 years or older registered in national and regional FAP registries in Denmark, the United States, Spain, and Canada. Descriptive statistics were used to summarize dose and duration among celecoxib treated patients. The primary study endpoints, time-to-next-FAP events, were examined with Kaplan–Meier method. Fifty four celecoxib-treated patients were recruited and a matched control was identified for 13 of these patients. The Kaplan–Meier estimated probability of not having a polypectomy 12 and 60 months post- ileorectal anastomosis in the celecoxib-treated patients (n = 33) was 60.6% and 42.2%, respectively. The estimated probability of not having a polypectomy 6–60 months post-ileal pouch-anal anastomosis the celecoxib-treated patients (n = 24) was 100%. The median total daily dose of celecoxib was 698.9 mg with the majority treated more than 24 months. Five celecoxib-treated patients experienced 6 serious adverse events with one of these events (rash) considered related to celecoxib. Long term celecoxib treatment appeared to be well tolerated in FAP patients with or without FAP-related surgeries.

OBJECTIVES:Subjects in the Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trial (PRESAP/NCT00141193/www.clinicaltrials.gov) were studied to determine efficacy and safety at a year 5 assessment. METHODS:In this randomized, placebo-controlled, double-blind trial, 1,561 subjects with diagnosed colorectal adenomas removed within 3 months of the study's initiation were assessed after ~ 3 years on celecoxib followed by 2 years off. Studied in 107 primary and secondary care settings, subjects were stratified by cardioprotective aspirin use and randomized to receive orally 400 ng celecoxib (933 subjects) or placebo (628 subjects) once daily. Efficacy was measured by colonoscopy at years 1, 3, and 5, and safety was measured by investigators for the on-treatment period and collected by subject self-report over 2 years post-treatment. RESULTS:At year 5, the primary outcome measure was the rate of new adenomas measured cumulatively from baseline. This rate was statistically significantly lower in the celecoxib group (51.4%) than in the placebo group (57.5%; P<0.001). Similarly, the cumulative rate of new advanced adenomas was significantly lower in the celecoxib group (10.0%) than in the placebo group (13.8%; P=0.007). However, the year 5 interval measure, which was not cumulative and did not take the rates of previous years into account, showed that after 2 years off treatment, the celecoxib group (27.0%) was 1.66 times more likely to have new adenomas than the placebo group (16.3%; P<0.0001). Similarly, the percentage of patients with new advanced adenomas was significantly higher in the celecoxib group (5.0%) than in the placebo group (3.8%) (P=0.0072). The evaluation of safety from baseline through year 5 indicated that the risks of serious cardiac disorders (relative risk (RR) 1.66; 95% confidence interval (CI) 1.01-2.73), selected renal/hypertension events (RR 1.35; 95% CI 1.09-1.68), and general vascular (RR 1.34; 95% CI 1.08-1.68) and cardiac disorders (RR 1.59; 95% CI 1.12-2.26) were higher in those taking celecoxib than in those on placebo. CONCLUSIONS:The year 5 cumulative measures of the incidence of new and advanced adenomas were significantly lower in the celecoxib group than in the placebo group, but the year 5 interval rates of these measures were significantly lower in the placebo group than the celecoxib group, perhaps suggesting a release of cyclooxygenase-2 inhibition. Consistent with what has been previously reported, increased risk of renal/hypertension events and cardiac disorders associated with celecoxib therapy mandates caution in patient selection.

Abstract Discussant: John A. Baron, Dartmouth Medical School, Lebanon, NH. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-173.

Statins are widely prescribed for cardiovascular disease prevention and also commonly used in patients at high risk for colorectal cancer. We report the results of a planned secondary analysis of the relationship between statin use and colorectal adenoma risk in a large chemoprevention trial. The Adenoma Prevention with Celecoxib (APC) trial randomized 2,035 adenoma patients to receive placebo (679 patients), 200 mg celecoxib twice daily (bid; 685 patients), or 400 mg celecoxib bid (671 patients). The study collected complete medical history and medication use data and performed colonoscopic surveillance to 5 years after study enrollment. The effects of statin use on newly detected adenomas and cardiovascular adverse events were analyzed as time-dependent variables by multivariable Cox regression. Statins were used by 36% (n = 730) of APC trial participants. When adjusted for covariates including cardioprotective aspirin use, age, and sex, participants on the placebo arm who used statins at any time had no benefit over 5 years compared with never users (risk ratio, 1.24; 95% confidence interval, 0.99-1.56; P = 0.065). Statin use for >3 years increased adenoma risk over 5 years (risk ratio, 1.39; 95% confidence interval, 1.04-1.86; P = 0.024). For all comparisons of patients treated with celecoxib, adenoma detection rates for statin users and nonusers were equivalent. Consistent with their use in patients at high risk, cardiovascular serious adverse events were more common among statin users. For patients at high risk of colorectal cancer, statins do not protect against colorectal neoplasms and may even increase the risk of developing colorectal adenomas. Cancer Prev Res; 3(5); 588–96. ©2010 AACR.

The Adenoma Prevention with Celecoxib Trial examined the efficacy and safety of the cyclooxygenase (Cox)-2 inhibitor, celecoxib, for sporadic colorectal adenoma prevention in patients at high risk for colorectal cancer. The trial randomized 2,035 subjects to receive either placebo, celecoxib 200 mg twice daily, or celecoxib 400 mg twice daily. The primary study safety and efficacy analyses involved 3 years of treatment. The results showed significant antitumor effect but also indicated increased cardiovascular adverse events in patients treated with celecoxib compared with placebo. A total of 933 patients participated in an extension of the Adenoma Prevention with Celecoxib Trial, with a planned total treatment and surveillance duration of 5 years. Study medication was stopped early, resulting in a median treatment duration of 3.1 years for those with a year 5 colonoscopy. Patients treated on the placebo arm had a cumulative adenoma incidence of 68.4% over 5 years of observation. This figure was 59.0% (P < 0.0001) for those receiving low-dose celecoxib, and 60.1% (P < 0.0001) for those receiving high-dose celecoxib. The cumulative incidence of advanced adenomas over 5 years was 21.3% of those taking placebo, 12.5% (P < 0.0001) of those taking low dose celecoxib and 15.8% (P < 0.0001) of those taking high-dose celecoxib. Investigator reported treatment emergent adverse events were similar across all treatment groups for categories including renal and hypertensive events and gastrointestinal ulceration and hemorrhage events. For a category composed of cardiovascular and thrombotic events, the risk relative to placebo was 1.6 (95% confidence interval, 1.0, 2.5) for those using 200 mg twice daily celecoxib and 1.9 (95% confidence interval, 1.2, 3.1) for those using 400 mg twice daily celecoxib. Secondary analysis showed an interaction between a baseline history of atherosclerotic heart disease and study drug use with respect to cardiovascular and thrombotic adverse events (P = 0.004). These results confirm the inhibitory effect of celecoxib on colorectal adenoma formation, and provide additional safety data indicating an elevated risk for cardiovascular and thrombotic adverse events, particularly for patients with preexisting atherosclerotic heart disease.

Background & Aims: Variants in the cytochrome P450 2C9 (CYP2C9) gene are associated with impaired metabolism of celecoxib. We examined the influence of CYP2C9*2 (R144C) and CYP2C9*3 (I359L) variants on dose-related response or toxicity in a randomized trial of celecoxib. Methods: We identified individuals with CYP2C9*2 and CYP2C9*3 genotypes (>= 1 variant allele) in the Adenoma Prevention with Celecoxib trial. Following adenoma removal, patients were assigned randomly to groups given placebo or low-dose (200 mg twice daily) or high-dose (400 mg twice daily) celecoxib and underwent follow-up colonoscopies at 1 and/or 3 years. Results: Among 1660 patients, 21% were CYP2C9*2, and 12% were CYP2C9*3 genotypes. Overall, celecoxib was associated with a dose-dependent reduction in adenoma, compared with placebo, with relative risks (RR) of 0.65 (95% confidence interval [CI]: 0.56-0.76) for the low-dose and 0.54 (95% CI: 0.46-0.63) for the high-dose groups. However, the additional protective effect of the high dose, compared with the low-dose, was observed only in those with CYP2C9*3 genotypes (RR, 0.51; 95% CI: 0.30-0.87). The high dose, compared with low dose, was not associated with significant risk reduction among those with CYP2C9*2 (RR, 0.83; 95% Cl: 0.57-1.21) or wild-type (RR, 0.89; 95% CI: 0.72-1.11) genotypes. Compared with placebo, a higher incidence of cardiovascular events was associated with both doses among patients with wild-type genotypes but only with the high dose among patients with variant genotypes. Conclusions: The greater efficacy of high-dose celecoxib, compared with the low-dose, in preventing colorectal adenoma appears confined to individuals with slow metabolizer (CYP2C9*3) genotypes. Genetic variability influences susceptibility to the potential benefits and hazards of celecoxib.

Background: The cyclooxygenase-2 inhibitor celecoxib has demonstrated its utility as a chemopreventive of adenomatous polyps, yet its safety remains under scrutiny. In a 3-year randomized, placebo-controlled, double-blind study of 1,561 adenoma-prone patients, investigators in the Prevention of Colorectal Sporadic Adenomatous Polyps study found on colonoscopy that patients treated with a single 400-mg daily dose of celecoxib had lower rates of adenomas than those treated with placebo at year 1 (20.8% vs 32.5%) and year 3 (16.1% vs 24.9%).

Abstract Aberrant crypt foci (ACF) are the earliest visible neoplastic lesions in the colorectum. The natural history of these lesions and their role in the adenoma-carcinoma sequence are unknown. We studied ACF in a subset of patients randomized to placebo (n = 17), celecoxib (200 mg twice daily; n = 15), or celecoxib (400 mg twice daily; n = 13) in the Adenoma Prevention with Celecoxib (APC) trial. Magnification chromoendoscopy was done to identify, count, and biopsy ACF within the rectum at baseline and after 8 to 12 months of treatment. A total of 655 ACF were identified in 45 patients. We examined 70 of these ACF histologically, and all 70 were nondysplastic. Cohort characteristics and APC trial treatment results for substudy patients were similar to those of the overall APC trial. There was no significant modulation of ACF by celecoxib (versus placebo; P = 0.77). Immunohistochemical comparison of ACF with adjacent normal mucosa showed that ACF had an increased proliferative index as determined by Ki-67 (P < 0.0001), but lacked other features of neoplasia such as increased cyclooxygenase-2 expression and microvessel density, nuclear localization of β-catenin, or decreased expression of the tumor suppressors SMAD4, Estrogen Receptor α, or MGMT. Only baseline SMAD4 expression in ACF correlated with posttreatment adenoma recurrence (independent of treatment arm; P = 0.01). The presence or number of nondysplastic ACF did not correlate with a higher risk of synchronous advanced or recurrent adenomas. Our overall results indicated that nondysplastic ACF were not accurate surrogate endpoint biomarkers of recurrent colorectal adenomas in the APC trial.

Aberrant crypt foci (ACF) are the earliest visible neoplastic lesions in the colorectum. The natural history of these lesions and their role in the adenoma-carcinoma sequence are unknown. We studied ACF in a subset of patients enrolled in the Adenoma Prevention with Celecoxib (APC) Trial to determine whether the presence of ACF in the rectum correlated with that of adenomas in the entire large intestine. Participants were randomized to placebo (n=17), celecoxib 200 mg bid (n=15), or celecoxib 400 mg bid (n=13). Magnification chromoendoscopy (MCE) was performed to identify and biopsy ACF within the rectum at baseline and after 8-12 months of medication use. A total of 670 ACF were identified in 45 patients, and 70 of these were examined histologically. All of the ACF examined were non-dysplastic. Analysis showed no differences in ACF number between baseline and post-treatment studies (8.3±1.0 vs. 6.3±1.1) and no modulation by treatment (celecoxib vs placebo; p=0.77). Immunohistochemical studies showed that ACF contained cells exhibiting increased proliferation, but lacked other features of neoplasia such as increased Cox-2 expression and microvascular density, nuclear localization of β-catenin, or decreased expression of the tumor suppressors SMAD4, estrogen receptor (ERα) or MGMT. Of the secondary markers assessed at baseline, only SMAD4 expression correlated with post-treatment adenoma recurrence. Taken together, these data showed that non-dysplastic ACF are not accurate surrogate endpoint biomarkers of colorectal adenoma risk or NSAID chemoprevention response.

Purpose: To analyze incidence of clinically significant upper or lower gastrointestinal adverse events (CSULGIEs) of celecoxib vs placebo, using adjudicated gastrointestinal (GI) data from the Adenoma Prevention with Celecoxib (APC), and Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) studies. Methods: In APC, 2035 subjects were randomized to celecoxib 200 mg BID, 400 mg BID, or placebo for 3 years. In PreSAP, 1561 subjects were randomized to 400 mg QD or placebo for 3 years. Adverse events (AEs), bleeds, perforations, obstructions or ulcers were evaluated up to 30 days last dose by a blinded GI Endpoint Adjudication Committee (GIEAC). Subjects with GI AEs, GI-related deaths, or Hb fall 3 g from baseline were included. Time between first dose and CSULGIE was analyzed by a Cox proportional hazards model, stratified by study, with aspirin as covariate. Age, gender, clinical history were also analyzed. Results: Of total population reporting AEs (N = 3588), 97 subjects met inclusion criteria and were reviewed by the GIEAC. 54 were adjudicated as having CSULGIEs (1.62% for celecoxib; 1.30% for placebo). Incidence of CSULGIEs was higher among aspirin-users in both groups (2.99% vs 1.17% celecoxib; 2.83% vs 0.81% placebo). No significant difference was shown in hazard ratio (HR) or relative risk (RR) of celecoxib vs placebo. HR of celecoxib vs placebo was 1.24 with upper 0.025 CI at 2.21 (rejects non-inferiority). There were no significant differences in RR of CSULGIEs between treatments in either aspirin (RR 1.06, 95% CI 0.48, 2.34, P= 0.894) or non-aspirin users (RR 1.44, 95% CI 0.64, 3.25, P= 0.374). Aspirin and age were significant contributors of toxicity. Conclusion: In this pooled analysis, testing for non-inferiority, incidence of CSULGIEs was equivalent for celecoxib and placebo. Importantly, there were few events and the analysis was underpowered. These findings support celcoxib's long-term GI safety and tolerability, and show long-term aspirin use is associated with significant GI toxicity.Table

BACKGROUND Overexpression of cyclooxygenase 2 (COX-2) has been associated with colorectal adenomatous polyps and cancer, prompting researchers to propose its inhibition as a chemopreventive intervention. METHODS The Prevention of Colorectal Sporadic Adenomatous Polyps trial was a randomized, placebo-controlled, double-blind study of the COX-2 inhibitor celecoxib given daily in a single 400-mg dose. At 107 centers in 32 countries, we randomly assigned 1561 subjects who had had adenomas removed before enrollment to receive celecoxib (933 subjects) or placebo (628 subjects) daily, after stratification according to the use or nonuse of low-dose aspirin. The primary outcome was detection of adenomas at either year 1 or year 3 by colonoscopy and was compared among the groups with the use of the Mantel-Cox test. RESULTS Colonoscopies were performed at year 1 on 88.7 percent of the subjects who had undergone randomization and at year 3 on 79.2 percent. Of the 557 subjects in the placebo group and the 840 subjects in the celecoxib group who were included in the efficacy analysis, 264 and 270, respectively, were found to have at least one adenoma at year 1, at year 3, or both. The cumulative rate of adenomas detected through year 3 was 33.6 percent in the celecoxib group and 49.3 percent in the placebo group (relative risk, 0.64; 95 percent confidence interval, 0.56 to 0.75; P<0.001). The cumulative rate of advanced adenomas detected through year 3 was 5.3 percent in the celecoxib group and 10.4 percent in the placebo group (relative risk, 0.49; 95 percent confidence interval, 0.33 to 0.73; P<0.001). Adjudicated serious cardiovascular events occurred in 2.5 percent of subjects in the celecoxib group and 1.9 percent of those in the placebo group (relative risk, 1.30; 95 percent confidence interval, 0.65 to 2.62). CONCLUSIONS The use of 400 mg of celecoxib once daily significantly reduced the occurrence of colorectal adenomas within three years after polypectomy. (ClinicalTrials.gov number, NCT00141193 [ClinicalTrials.gov].).

BACKGROUNDStudies showing that drugs that inhibit cyclooxygenase-2 (COX-2) reduce the number of colorectal adenomas in animals and patients with familial adenomatous polyposis suggest that COX-2 inhibitors may also prevent sporadic colorectal neoplasia.METHODSWe randomly assigned patients who had adenomas removed before study entry to receive placebo (679 patients) or 200 mg (685 patients) or 400 mg (671 patients) of celecoxib twice daily. Randomization was stratified for the use of low-dose aspirin. Follow-up colonoscopies were performed at one and three years after randomization. The occurrence of newly detected colorectal adenomas was compared among the groups with the life-table extension of the Mantel-Haenszel test.RESULTSFollow-up colonoscopies were completed at year 1 in 89.5 percent of randomized patients, and at year 3 in 75.7 percent. The estimated cumulative incidence of the detection of one or more adenomas by year 3 was 60.7 percent for patients receiving placebo, as compared with 43.2 percent for those receiving 200 mg of celecoxib twice a day (risk ratio, 0.67; 95 percent confidence interval, 0.59 to 0.77; P<0.001) and 37.5 percent for those receiving 400 mg of celecoxib twice a day (risk ratio, 0.55; 95 percent confidence interval, 0.48 to 0.64; P<0.001). Serious adverse events occurred in 18.8 percent of patients in the placebo group, as compared with 20.4 percent of those in the low-dose celecoxib group (risk ratio, 1.1; 95 percent confidence interval, 0.9 to 1.3; P=0.5) and 23.0 percent of those in the high-dose group (risk ratio, 1.2; 95 percent confidence interval, 1.0 to 1.5; P=0.06). As compared with placebo, celecoxib was associated with an increased risk of cardiovascular events (risk ratio for the low dose, 2.6; 95 percent confidence interval, 1.1 to 6.1; and risk ratio for the high dose, 3.4; 95 percent confidence interval, 1.5 to 7.9).CONCLUSIONSThese findings indicate that celecoxib is an effective agent for the prevention of colorectal adenomas but, because of potential cardiovascular events, cannot be routinely recommended for this indication. (ClinicalTrials.gov number, NCT00005094 [ClinicalTrials.gov].).

Objective: Exposure to non-steroidal anti-inflammatory drugs (NSAIDs) is associated wit increased risk of serious gastrointestinal (GI) events compared with non-exposure. We investigated whether that risk is sustained over time.Data sources: Cochrane Controlled Trials Register (to 2002); MEDLINE, EMBASE, Derwent Drug File and Current Contents (1999-2002); manual searching of reviews (1999-2002).Study selection: From 479 search results reviewed and 221 articles retrieved, seven studies of patients exposed to prescription non-selective NSAIDs for more than 6 months and reporting time-dependent serious GI event rates were selected for quantitative data synthesis. These were stratified into two groups by study design.Data extraction: Incidence of GI events and number of patients at specific time points were extracted.Data synthesis: Meta-regression analyses were performed. Change in risk was evaluated by testing whether the slope of the regression line declined over time. Four randomised controlled trials (RCTs) provided evaluable data from five NSAID arms (aspirin, naproxen, two ibuprofen arms, and diclofenac). When the RCT data were combined, a small significant decline in annualised risk was seen: -0.005% (95% Cl, -0.008% to -0.001%) per month. Sensitivity analyses were conducted because there was disparity within the RCT data. The pooled estimate from three cohort studies showed no significant decline in annualised risk over periods up to 2 years: -0.003% (95% Cl, -0.008% to 0.003%) per month.Conclusions: Small decreases in risk over time were observed; these were of negligible clinical importance. For patients who need long-term (> 6 months) treatment, precautionary measures should be considered to reduce the net probability of serious GI events over the anticipated treatment duration. The effect of intermittent versus regular daily therapy on long-term risk needs further investigation.