Inflammation, as measured by the circulating inflammatory marker high-sensitivity C-reactive protein (hsCRP), has been associated with cardiovascular disease. However, data about CRP and risk of colorectal cancer have been conflicting. The Adenoma Prevention with Celecoxib (APC) trial showed that the anti-inflammatory drug celecoxib prevents recurrence of colorectal adenoma but increases risk of cardiovascular events. We examined whether serum hsCRP modified these results. We measured hsCRP from serum specimens provided at study entry by patients enrolled in the APC trial. Patients were stratified according to use of low-dose aspirin, randomized to receive 3 years of treatment with placebo, 200-mg-bid celecoxib, or 400-mg-bid celecoxib, and underwent follow-up colonoscopies at years 1 and 3. Among 1,680 patients, the estimated 3-year cumulative incidence of adenoma was 42% for patients with hsCRP <1 mg/L, compared with 43% [relative risk (RR) = 1.02; 95% CI = 0.85–1.22] for hsCRP 1–3 mg/L, and 41% (RR = 1.10; 95% CI = 0.90–1.34) for hsCRP >3 mg/L. The effect of celecoxib on adenoma recurrence did not vary among patients with high (>3 mg/L) compared with low (≤3 mg/L) hsCRP. However, among patients with high hsCRP, the RR of cardiovascular events compared with placebo was 2.27 (95% CI = 0.72–7.14) for those randomized to celecoxib 200-mg-bid and 3.28 (95% CI = 1.09–9.91) for 400-mg-bid. In contrast, among patients with low hsCRP, the corresponding RRs were 0.99 (95% CI = 0.53–1.83) and 1.11 (95% CI = 0.61–2.02). hsCRP may predict risk of celecoxib-associated cardiovascular toxicity but not adenoma recurrence or celecoxib treatment efficacy. Patients with low hsCRP may be a subgroup with a favorable risk-benefit profile for celecoxib chemoprevention. Cancer Prev Res; 4(8); 1172–80. ©2011 AACR.

See perspective on p. 1145

Aspirin and selective COX-2 inhibitors, such as celecoxib, reduce risk of colorectal adenoma and cancer (1–5). This effect may be mediated through abrogation of inflammation (6–8). High-sensitivity C-reactive protein (hsCRP) is a circulating inflammatory biomarker of chronic conditions including cardiovascular disease (9, 10). However, prospective studies relating hsCRP to risk of colorectal cancer and adenoma have been equivocal (11–29).

In the Adenoma Prevention with Celecoxib (APC) trial, patients who had recently undergone colonoscopic removal of an adenoma were randomly assigned to receive placebo, 200 mg twice daily (200-mg-bid) of celecoxib, or 400 mg twice daily (400-mg-bid) of celecoxib and underwent follow-up colonoscopies at 1 and 3 years. The relative risk (RR) of the detection of 1 or more new adenomas by year 3 compared with placebo was 0.67 (95% CI = 0.59–0.77) for those receiving 200-mg-bid celecoxib and 0.55 (95% CI = 0.48–0.64) for those receiving 400-mg-bid celecoxib (4). Unfortunately, in a separate, adjudicated safety analysis, the APC trial also revealed unexpected dose-related cardiovascular toxicity (30). Because hsCRP may be related to both risk of neoplasia and cardiovascular events and celecoxib has been shown to reduce hsCRP levels (31, 32), we examined baseline hsCRP in relation to (i) risk of recurrent adenoma, (ii) celecoxib-related chemopreventive efficacy, and (iii) celecoxib-related cardiovascular toxicity.

Study population

Jointly sponsored by the National Cancer Institute and Pfizer, Inc., the APC trial was a randomized, placebo-controlled trial which enrolled patients within 6 months of colonoscopic removal of multiple adenomas or a single adenoma larger than 5 mm in diameter (ClinicalTrials.gov NCT00005094; ref. 4). Beginning in November 1999, 2,457 potential participants at 91 clinical sites were entered into a 30-day placebo run-in period during which they were required to have at least 80% adherence to medication use. After the run-in period, 2,035 patients were subsequently randomly assigned to placebo, 200-mg-bid of celecoxib, or 400-mg-bid of celecoxib. Randomization was stratified on the basis of the use or nonuse of low-dose aspirin (≤325 mg every other day or ≤162.5 mg every day) and clinical site. For the duration of the study, patients were required to abstain from long-term use of non–steroidal anti-inflammatory drugs. Patients were excluded if they had a history of familial adenomatous polyposis, hereditary nonpolyposis colon cancer, inflammatory bowel disease, or large-bowel resection other than appendectomy. Other exclusion criteria included a history of a renal or hepatic disorder, a clinically significant bleeding disorder, or treatment for a gastrointestinal ulcer before study entry. Study drug treatment was initially planned for 3 years for all participants. However, at the recommendation of the APC trial Data Safety Monitoring Board (DSMB), treatment was terminated prematurely on December 17, 2004, based on the results of an unscheduled safety analysis conducted by an independent cardiovascular safety committee. At that time 1,762 patients (86.6%) had completed 3 years of treatment and 273 patients had 1 to 3 months of treatment remaining. In addition, 639 patients had begun participation in the extension study in which study medication was continued in a blinded manner for an additional 2 years. The median duration of treatment exposure in the extension study was 3.5 years (33). All patients provided written informed consent and the human subjects committee at each site approved the study. This analysis was approved by the Human Subjects Committee of Partners HealthCare.

hsCRP measurements

At baseline randomization, 1,707 participants provided a serum specimen at baseline randomization which was subsequently stored at −70°C. Personnel blinded to quality control and outcome data assayed for hsCRP using a high-sensitivity, latex-enhanced immunoturbidimetric assay (intra-assay coefficient of variation = 2.9%; Denka Seiken). Among the 1,707 specimens, 27 could not be measured for technical reasons (Fig. 1). Thus, this analysis included 1,680 participants, which were similar according to baseline characteristics to those for whom we did not measure hsCRP (data not shown).

Figure 1.

Flow of patients through the study. Patients who violated study entry criteria were those for whom the presence or absence of adenoma on the baseline colonoscopy could not be confirmed. Adherence to the use of study medication was calculated as duration of use in days, divided by 1,095.

Figure 1.

Flow of patients through the study. Patients who violated study entry criteria were those for whom the presence or absence of adenoma on the baseline colonoscopy could not be confirmed. Adherence to the use of study medication was calculated as duration of use in days, divided by 1,095.

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Outcome ascertainment

A study investigator conducted follow-up colonoscopies with endoscopic removal of polyps at 1 and 3 years after randomization. A central study pathologist examined, in a blinded fashion, all polyps removed during these colonoscopies. Adverse events were reported by investigators and classified according to criteria from the Medical Dictionary for Regulatory Activities (MedDRA), version 8.1 (4, 33).

Statistical analysis

As in prior studies (21), we examined hsCRP levels according to cutoff points proposed in clinical guidelines (<1, 1–3, and >3 mg/L; ref. 34). Consistent with the intent-to-treat principle, we used the detection of an adenoma during a postrandomization colonoscopy, regardless of whether the patient adhered to the treatment regimen, as the primary endpoint. We estimated the cumulative incidence of adenoma at 3 years within different subgroups using Kaplan–Meier method. The effect of hsCRP levels on having a recurrent adenoma at a postrandomization colonoscopy was estimated by RR derived from Cox proportional hazards modeling with ties handled by the exact method, stratified by age (≥65 vs. <65), sex, time, baseline use of low-dose aspirin (≤325 mg/every other day or ≤162.5 mg/d), postmenopausal hormones, and duration of statin use (≤3 vs. >3 y) as a time-dependent variable (35). We used Cox proportional hazards models, adjusted for the same variables as the efficacy analyses, to estimate the RR of an investigator-reported adverse event after the first dose and up to 30 days after the last dose of study medication including events among patients who continued study medication in the 24-month extension study (33, 35). We used the SAS version 9.1 (SAS Institute) for all analyses. All significance tests were 2 sided at a 5% level of significance.

Among the 1,680 participants, the median age was 59 [range = 31–88] years, 92% were white, and 68% were men, and the median hsCRP level was 1.6 mg/L (range = 0.1–2.72 mg/L). Patients with elevated CRP levels (>3 mg/L) more frequently smoked, had a higher body mass index, had a prior history of cardiovascular events, hypertension, and diabetes mellitus, and used low-dose aspirin and statin drugs. Consistent with the known effect of postmenopausal hormones on CRP levels (36), the prevalence of postmenopausal hormone use was higher among women with elevated CRP. The number of adenomas (P = 0.24) or adenoma burden (sum of diameter of all adenomas; P = 0.61) at the baseline qualifying examination did not vary according to hsCRP (Table 1).

Table 1.

Baseline characteristics of the patients according to serum hsCRP levelsa

hSCRP Level
All<1 mg/L1–3 mg/L>3 mg/L
Characteristics (n = 1,680)(n = 563)(n = 603)(n = 514)Pb
CRP, median mg/L, (range) 1.6 (0.1–272) 0.6 (0.1–0.99) 1.7 (1–2.99) 5.5 (3–272) – 
Age, median y, (range) 59 (31–88) 58 (31–82) 59 (35–88) 59.5 (35–87) 0.004 
Women, n (%) 535 (32) 146 (26) 154 (26) 235 (46) <0.001 
Race or ethnic group,cn (%)  
 Non-Hispanic White 1,549 (92) 518 (92) 569 (94) 462 (90) 0.04 
 Non-Hispanic Black 88 (5) 28 (5) 21 (3) 39 (7)  
 Hispanic 29 (2) 11 (2) 9 (2) 9 (2)  
 Asian/Pacific Islander/other 14 (1) 2 (0.3) 4 (0.8) 8 (1.4)  
Current cigarette smoker, n (%) 277 (16) 54 (10) 115 (19) 108 (21) <0.001 
Body mass indexd 28 (15–58) 26 (15–43) 28 (17–43) 31 (19–58) <0.001 
 Men 28 (15–49) 27 (15–43) 29 (17–43) 30 (20–49) <0.001 
 Women 28 (18–58) 24 (18–41) 28 (18–43) 30 (19–58) <0.001 
Colorectal cancer in a parent, n (%) 355 (21) 122 (22) 136 (23) 97 (19) 0.3 
Findings at baseline colonoscopy 
 No. of adenomas 2 (1–17) 2 (1–11) 2 (1–17) 2 (1–10) 0.24 
 At least 1 adenoma ≥1 cm, n (%) 719 (43) 241 (43) 245 (41) 233 (45) 0.29 
 Multiple adenomas, n (%) 932 (55) 310 (55) 341 (57) 281 (55) 0.80 
 Adenoma burden,e cm 1.5 (1.2) 1.4 (1.2) 1.5 (1.3) 1.5 (1.2) 0.61 
History of cardiovascular events,fn (%) 237 (14) 59 (10) 102 (17) 76 (15) 0.006 
History of hypertension, n (%) 677 (40) 175 (31) 261 (43) 241 (47) <0.001 
History of diabetes, n (%) 156 (9) 37 (7) 55 (9) 64 (12) 0.004 
Use of low-dose aspirin,gn (%) 539 (32) 177 (31) 219 (36) 143 (28) 0.009 
Use of postmenopausal hormones,hn (%) 211 (39) 31 (21) 56 (36) 124 (53) <0.001 
Use of statins, n (%) 421 (25) 147 (21) 166 (28) 108 (21) 0.03 
Randomized to placebo, n (%) 563 (34) 192 (34) 209 (35) 162 (32) 0.05 
Randomized to celecoxib, 200-mg-bid, n (%) 558 (33) 175 (31) 212 (35) 171 (33) 0.06 
Randomized to celecoxib, 400-mg-bid, n (%) 559 (34) 196 (35) 182 (30) 181 (35) 0.74 
hSCRP Level
All<1 mg/L1–3 mg/L>3 mg/L
Characteristics (n = 1,680)(n = 563)(n = 603)(n = 514)Pb
CRP, median mg/L, (range) 1.6 (0.1–272) 0.6 (0.1–0.99) 1.7 (1–2.99) 5.5 (3–272) – 
Age, median y, (range) 59 (31–88) 58 (31–82) 59 (35–88) 59.5 (35–87) 0.004 
Women, n (%) 535 (32) 146 (26) 154 (26) 235 (46) <0.001 
Race or ethnic group,cn (%)  
 Non-Hispanic White 1,549 (92) 518 (92) 569 (94) 462 (90) 0.04 
 Non-Hispanic Black 88 (5) 28 (5) 21 (3) 39 (7)  
 Hispanic 29 (2) 11 (2) 9 (2) 9 (2)  
 Asian/Pacific Islander/other 14 (1) 2 (0.3) 4 (0.8) 8 (1.4)  
Current cigarette smoker, n (%) 277 (16) 54 (10) 115 (19) 108 (21) <0.001 
Body mass indexd 28 (15–58) 26 (15–43) 28 (17–43) 31 (19–58) <0.001 
 Men 28 (15–49) 27 (15–43) 29 (17–43) 30 (20–49) <0.001 
 Women 28 (18–58) 24 (18–41) 28 (18–43) 30 (19–58) <0.001 
Colorectal cancer in a parent, n (%) 355 (21) 122 (22) 136 (23) 97 (19) 0.3 
Findings at baseline colonoscopy 
 No. of adenomas 2 (1–17) 2 (1–11) 2 (1–17) 2 (1–10) 0.24 
 At least 1 adenoma ≥1 cm, n (%) 719 (43) 241 (43) 245 (41) 233 (45) 0.29 
 Multiple adenomas, n (%) 932 (55) 310 (55) 341 (57) 281 (55) 0.80 
 Adenoma burden,e cm 1.5 (1.2) 1.4 (1.2) 1.5 (1.3) 1.5 (1.2) 0.61 
History of cardiovascular events,fn (%) 237 (14) 59 (10) 102 (17) 76 (15) 0.006 
History of hypertension, n (%) 677 (40) 175 (31) 261 (43) 241 (47) <0.001 
History of diabetes, n (%) 156 (9) 37 (7) 55 (9) 64 (12) 0.004 
Use of low-dose aspirin,gn (%) 539 (32) 177 (31) 219 (36) 143 (28) 0.009 
Use of postmenopausal hormones,hn (%) 211 (39) 31 (21) 56 (36) 124 (53) <0.001 
Use of statins, n (%) 421 (25) 147 (21) 166 (28) 108 (21) 0.03 
Randomized to placebo, n (%) 563 (34) 192 (34) 209 (35) 162 (32) 0.05 
Randomized to celecoxib, 200-mg-bid, n (%) 558 (33) 175 (31) 212 (35) 171 (33) 0.06 
Randomized to celecoxib, 400-mg-bid, n (%) 559 (34) 196 (35) 182 (30) 181 (35) 0.74 

aData are expressed as mean (SD) unless otherwise indicated.

bTest of difference between hsCRP groups was calculated by ANOVA for continuous variables, χ2 for categorical variables.

cRace or ethnic group was determined by the investigator.

dBody mass index is the weight in kilograms divided by the square of the height in meters.

eThe adenoma burden was defined as the sum of the diameter of all adenomas reported during colonoscopy at baseline.

fCardiovascular events were defined as myocardial infarction, cerebrovascular disease, congestive heart failure, angina, and atherosclerotic heart disease.

gLow-dose aspirin was defined as ≤325 mg every other day or ≤162.5 mg every day.

hPercentage using postmenopausal hormones was calculated among women only.

Baseline hsCRP was not statistically significantly associated with risk of recurrent colorectal adenoma. The RR of adenoma through year 3 associated with a 1 SD increase in log hsCRP was 0.96 (95% CI = 0.89–1.03). The estimated 3-year cumulative incidence of adenoma was 42% for patients with hsCRP <1 mg/L, compared with 43% (RR = 1.02; 95% CI = 0.85–1.22) for hsCRP 1–3 mg/L, and 41% (RR = 1.1; 95% CI = 0.90–1.34) for hsCRP >3 mg/L. These results did not vary according to strata defined by celecoxib assignment, aspirin use, sex, use of postmenopausal hormones, body mass index, or use of statin drugs (Table 2). When we analyzed data according to quartile cutoff points of the distribution of hsCRP, our results were essentially unchanged (data not shown). We also examined hsCRP in relation to risk of advanced adenoma. The estimated 3-year cumulative incidence of advanced adenoma was 8.2% for patients with hsCRP <1 mg/L, compared with 7.5% (RR = 0.90; 95% CI = 0.59–1.38) for hsCRP 1–3 mg/L, and 5.6% (RR = 0.72; 95% CI = 0.44–1.17) for hsCRP >3 mg/L.

Table 2.

Risk of adenoma according to serum hsCRP levels

hsCRP ≤1 mg/LhsCRP 1–3 mg/LhsCRP ≥3 mg/L
All patientsa 
No. at risk 533 529 453 
 Cumulative incidence, 3 y, % ± SE 42 ± 2 43 ± 2 41 ± 2 
 RR (95% CI) 1 (ref) 1.02 (0.85–1.22) 1.10 (0.90–1.34) 
P  0.86 0.36 
By celecoxib treatment    
Patients randomized to placebo, no. at risk 179 177 148 
 Cumulative incidence, 3 y, % ± SE 54 ± 4 53 ± 4 57 ± 4 
 RR (95% CI) 1 (ref) 0.98 (0.74–1.3) 1.22 (0.9–1.64) 
P  0.91 0.20 
Patients randomized to celecoxib 200-mg-bid, no. at risk 163 190 153 
 Cumulative incidence, 3 y, % ± SE 36 ± 4 41 ± 4 37 ± 4 
 RR (95% CI) 1 (ref) 1.18 (0.84–1.64) 1.13 (0.79–1.62) 
P  0.34 0.50 
Patients randomized to celecoxib 400-mg-bid, no. at risk 191 162 152 
 Cumulative incidence, 3 y, % ± SE 35 ± 3 34 ± 4 30 ± 4 
 RR (95% CI) 1 (ref) 0.89 (0.63–1.27) 0.94 (0.64–1.38) 
P  0.52 0.76 
Pinteraction  0.53 0.58 
By low-dose aspirin stratab    
Patients taking aspirin, no. at risk 171 183 129 
 Cumulative incidence, 3 y, % ± SE 40 ± 4 49 ± 4 41 ± 4 
 RR (95% CI) 1 (ref) 1.34 (0.98–1.82) 1.24 (0.87–1.78) 
P  0.07 0.23 
Patients not taking aspirin, no. at risk 362 346 324 
 Cumulative incidence, 3 y, % ± SE 43 ± 3 40 ± 3 41 ± 4 
 RR (95% CI) 1 (ref) 0.89 (0.71–1.11) 1.04 (0.82–1.31) 
P  0.29 0.77 
Pinteraction  0.05 0.80 
By sex    
Men, no. at risk 395 391 249 
 Cumulative incidence, 3 y, % ± SE 45 ± 2 46 ± 2 48 ± 3 
 RR (95% CI) 1 (ref) 1.01 (0.82–1.23) 1.11 (0.88–1.40) 
P  0.95 0.37 
Women, no. at risk 138 138 204 
 Cumulative incidence, 3 y, % ± SE 34 ± 4 34 ± 4 33 ± 3 
 RR (95% CI) 1 (ref) 1.05 (0.70–1.57) 1.03 (0.71–1.50) 
P  0.81 0.86 
Pinteraction  0.89 0.81 
By postmenopausal hormone usec 
Patients taking hormones, no. at risk 29 49 110 
 Cumulative incidence, 3 y, % ± SE 30 ± 8 29 ± 6 35 ± 4 
 RR (95% CI) 1 (ref) 1.02 (0.44–2.37) 1.25 (0.60–2.59) 
P  0.97 0.55 
Patients not taking hormones, no. at risk 109 89 94 
 Cumulative incidence, 3 y, % ± SE 35 ± 5 37 ± 5 30 ± 5 
 RR (95% CI) 1 (ref) 1.12 (0.70–1.79) 0.95 (0.59–1.54) 
P  0.63 0.83 
Pinteraction  0.74 0.56 
By body mass indexd 
Patients with high body mass index, no. at risk 175 279 297 
 Cumulative incidence, 3 y, % ± SE 48 ± 4 41 ± 3 41 ± 3 
 RR (95% CI) 1 (ref) 0.90 (0.68–1.19) 0.98 (0.74–1.30) 
P  0.44 0.91 
Patients with low body mass index, no. at risk 358 250 156 
 Cumulative incidence, 3 y, % ± SE 39 ± 3 45 ± 3 41 ± 4 
 RR (95% CI) 1 (ref) 1.12 (0.87–1.43) 1.16 (0.86–1.56) 
P  0.37 0.33 
Pinteraction  0.24 0.49 
By statin use 
Patients taking statins, no. at risk 142 143 98 
 Cumulative incidence, 3 y, % ± SE 46 ± 4 42 ± 4 51 ± 5 
 RR (95% CI) 1 (ref) 0.96 (0.68–1.36) 1.22 (0.84–1.78) 
P  0.81 0.30 
Patients not taking statins, no. at risk 391 386 355 
 Cumulative incidence, 3 y, % ± SE 41 ± 2 43 ± 2 38 ± 3 
 RR (95% CI) 1 (ref) 1.05 (0.85–1.3) 1.05 (0.83–1.32) 
P  0.66 0.68 
Pinteraction  0.67 0.52 
hsCRP ≤1 mg/LhsCRP 1–3 mg/LhsCRP ≥3 mg/L
All patientsa 
No. at risk 533 529 453 
 Cumulative incidence, 3 y, % ± SE 42 ± 2 43 ± 2 41 ± 2 
 RR (95% CI) 1 (ref) 1.02 (0.85–1.22) 1.10 (0.90–1.34) 
P  0.86 0.36 
By celecoxib treatment    
Patients randomized to placebo, no. at risk 179 177 148 
 Cumulative incidence, 3 y, % ± SE 54 ± 4 53 ± 4 57 ± 4 
 RR (95% CI) 1 (ref) 0.98 (0.74–1.3) 1.22 (0.9–1.64) 
P  0.91 0.20 
Patients randomized to celecoxib 200-mg-bid, no. at risk 163 190 153 
 Cumulative incidence, 3 y, % ± SE 36 ± 4 41 ± 4 37 ± 4 
 RR (95% CI) 1 (ref) 1.18 (0.84–1.64) 1.13 (0.79–1.62) 
P  0.34 0.50 
Patients randomized to celecoxib 400-mg-bid, no. at risk 191 162 152 
 Cumulative incidence, 3 y, % ± SE 35 ± 3 34 ± 4 30 ± 4 
 RR (95% CI) 1 (ref) 0.89 (0.63–1.27) 0.94 (0.64–1.38) 
P  0.52 0.76 
Pinteraction  0.53 0.58 
By low-dose aspirin stratab    
Patients taking aspirin, no. at risk 171 183 129 
 Cumulative incidence, 3 y, % ± SE 40 ± 4 49 ± 4 41 ± 4 
 RR (95% CI) 1 (ref) 1.34 (0.98–1.82) 1.24 (0.87–1.78) 
P  0.07 0.23 
Patients not taking aspirin, no. at risk 362 346 324 
 Cumulative incidence, 3 y, % ± SE 43 ± 3 40 ± 3 41 ± 4 
 RR (95% CI) 1 (ref) 0.89 (0.71–1.11) 1.04 (0.82–1.31) 
P  0.29 0.77 
Pinteraction  0.05 0.80 
By sex    
Men, no. at risk 395 391 249 
 Cumulative incidence, 3 y, % ± SE 45 ± 2 46 ± 2 48 ± 3 
 RR (95% CI) 1 (ref) 1.01 (0.82–1.23) 1.11 (0.88–1.40) 
P  0.95 0.37 
Women, no. at risk 138 138 204 
 Cumulative incidence, 3 y, % ± SE 34 ± 4 34 ± 4 33 ± 3 
 RR (95% CI) 1 (ref) 1.05 (0.70–1.57) 1.03 (0.71–1.50) 
P  0.81 0.86 
Pinteraction  0.89 0.81 
By postmenopausal hormone usec 
Patients taking hormones, no. at risk 29 49 110 
 Cumulative incidence, 3 y, % ± SE 30 ± 8 29 ± 6 35 ± 4 
 RR (95% CI) 1 (ref) 1.02 (0.44–2.37) 1.25 (0.60–2.59) 
P  0.97 0.55 
Patients not taking hormones, no. at risk 109 89 94 
 Cumulative incidence, 3 y, % ± SE 35 ± 5 37 ± 5 30 ± 5 
 RR (95% CI) 1 (ref) 1.12 (0.70–1.79) 0.95 (0.59–1.54) 
P  0.63 0.83 
Pinteraction  0.74 0.56 
By body mass indexd 
Patients with high body mass index, no. at risk 175 279 297 
 Cumulative incidence, 3 y, % ± SE 48 ± 4 41 ± 3 41 ± 3 
 RR (95% CI) 1 (ref) 0.90 (0.68–1.19) 0.98 (0.74–1.30) 
P  0.44 0.91 
Patients with low body mass index, no. at risk 358 250 156 
 Cumulative incidence, 3 y, % ± SE 39 ± 3 45 ± 3 41 ± 4 
 RR (95% CI) 1 (ref) 1.12 (0.87–1.43) 1.16 (0.86–1.56) 
P  0.37 0.33 
Pinteraction  0.24 0.49 
By statin use 
Patients taking statins, no. at risk 142 143 98 
 Cumulative incidence, 3 y, % ± SE 46 ± 4 42 ± 4 51 ± 5 
 RR (95% CI) 1 (ref) 0.96 (0.68–1.36) 1.22 (0.84–1.78) 
P  0.81 0.30 
Patients not taking statins, no. at risk 391 386 355 
 Cumulative incidence, 3 y, % ± SE 41 ± 2 43 ± 2 38 ± 3 
 RR (95% CI) 1 (ref) 1.05 (0.85–1.3) 1.05 (0.83–1.32) 
P  0.66 0.68 
Pinteraction  0.67 0.52 

aNo. at risk includes patients who underwent a follow-up colonoscopy at years 1 and/or 3. A patient with a colonoscopy at year 3 but with no colonoscopy at year 1 was included in the analysis through year 1, with the assumption that the patient had no adenoma at year 1, and was then included in the analysis through year 3 according to the findings of the colonoscopy at year 3. The analyses at year 3 excluded patients with an adenoma at year 1 colonoscopy and patients with no adenoma at year 1 and no colonoscopy at year 3 (4). All RRs are multivariate-adjusted as described in the methods. P values for interaction were assessed by using cross-product terms for each celecoxib treatment group and each risk factor strata.

bAt the time of randomization, patients were stratified according to use of low-dose aspirin, defined as ≤325 mg/every other day or ≤162.5 mg/y.

cAnalyses were restricted to women.

dHigh body mass index defined as ≥ median (28 mg/kg2) and low body mass index defined as < median.

The overall reduction in cumulative incidence of adenoma associated with celecoxib did not appear to vary among patients with high (>3 mg/L) compared with low (≤3 mg/L) hsCRP (Table 3). However, among patients with high hsCRP, the RR of cardiovascular events compared with placebo was 2.27 (95% CI = 0.72–7.14) for those randomized to celecoxib 200-mg-bid and 3.28 (95% CI = 1.09–9.91) for 400-mg-bid. In contrast, among patients with low hsCRP, the corresponding RRs were 0.99 (95% CI = 0.53–1.83) and 1.11 (95% CI = 0.61–2.02; Table 4; Fig. 2). A formal test of interaction between high hsCRP and 400-mg-bid celecoxib approached statistical significance (P = 0.11). We considered the possibility that concurrent aspirin use may modify the interaction between high hsCRP levels and celecoxib-associated cardiovascular events. Among patients with hsCRP >3 mg/L and were not taking low-dose aspirin, the RR for a cardiovascular event compared to those randomized to placebo was 2.74 (95% CI = 0.54–13.70) for those randomized to celecoxib 200-mg-bid and 4.98 (95% CI = 1.10–22.59) for those randomized to celecoxib 400-mg-bid. In contrast, among patients with hsCRP >3 mg/L and were taking low-dose aspirin, the RR for a cardiovascular event compared with those randomized to placebo was 1.72 (95% CI = 0.33–8.96) for those randomized to celecoxib 200-mg-bid, and 1.65 (95% CI = 0.30–9.0) for those randomized to celecoxib 400-mg-bid. Although these results do suggest a possible attenuation of cardiovascular risk associated with low-dose aspirin, a formal test of interaction between celecoxib treatment and use of low-dose aspirin was not statistically significant (P = 0.57). Moreover, because there were limited numbers of events within each aspirin strata (19 events in the group not taking aspirin and 12 events in the group taking low-dose aspirin), these results should be considered exploratory. Finally, among all patients, there did not appear to be an overall dose-related increase in either renal and hypertensive disorders or gastrointestinal ulceration and hemorrhage, consistent with the overall results of the trial (4).

Figure 2.

Relative risk of cardiovascular events according to baseline hsCRP. Error bars correspond to 95% CIs.

Figure 2.

Relative risk of cardiovascular events according to baseline hsCRP. Error bars correspond to 95% CIs.

Close modal
Table 3.

Risk of adenoma according to celecoxib treatment, stratified by hsCRP levela

PlaceboCelecoxib, 200 mg bidCelecoxib, 400 mg bid
All patients, no. at risk 563 558 559 
 Cumulative incidence, 3 y, % ± SE 55 ± 2 30 ± 2 33 ± 2 
 RR (95% CI) 1 (ref) 0.60 (0.50–0.72) 0.49 (0.40–0.59) 
P  <0.001 <0.001 
Patients with hsCRP <3, no. at risk 401 387 378 
 Cumulative incidence, 3 y, % ± SE 53 ± 3 39 ± 3 35 ± 3 
 RR (95% CI) 1 (ref) 0.62 (0.52–0.75) 0.54 (0.44–0.65) 
P  <0.001 <0.001 
Patients with hsCRP ≥3, no. at risk 162 171 181 
 Cumulative incidence, 3 y, % ± SE 57 ± 4 37 ± 4 30 ± 4 
 RR (95% CI) 1 (ref) 0.48 (0.36–0.65) 0.41 (0.30–0.55) 
P  <0.001 <0.001 
Pinteraction  0.50 0.58 
PlaceboCelecoxib, 200 mg bidCelecoxib, 400 mg bid
All patients, no. at risk 563 558 559 
 Cumulative incidence, 3 y, % ± SE 55 ± 2 30 ± 2 33 ± 2 
 RR (95% CI) 1 (ref) 0.60 (0.50–0.72) 0.49 (0.40–0.59) 
P  <0.001 <0.001 
Patients with hsCRP <3, no. at risk 401 387 378 
 Cumulative incidence, 3 y, % ± SE 53 ± 3 39 ± 3 35 ± 3 
 RR (95% CI) 1 (ref) 0.62 (0.52–0.75) 0.54 (0.44–0.65) 
P  <0.001 <0.001 
Patients with hsCRP ≥3, no. at risk 162 171 181 
 Cumulative incidence, 3 y, % ± SE 57 ± 4 37 ± 4 30 ± 4 
 RR (95% CI) 1 (ref) 0.48 (0.36–0.65) 0.41 (0.30–0.55) 
P  <0.001 <0.001 
Pinteraction  0.50 0.58 

aNo. at risk includes patients who underwent a follow-up colonoscopy at years 1 and/or 3. A patient with a colonoscopy at year 3 but with no colonoscopy at year 1 was included in the analysis through year 1, with the assumption that the patient had no adenoma at year 1, and was then included in the analysis through year 3 according to the findings of the colonoscopy at year 3. The analyses at year 3 excluded patients with an adenoma at year 1 colonoscopy and patients with no adenoma at year 1 and no colonoscopy at year 3 (4). All RRs are multivariate-adjusted as described in the methods. P values for interaction were assessed by using cross-product terms for each celecoxib treatment group and each hsCRP strata.

Table 4.

Risk of adverse events according to celecoxib treatment, stratified by hsCRP levela

PlaceboCelecoxib, 200 mg bidCelecoxib, 400 mg bid
Risk of cardiovascular disordersb 
All patients 
 No. with event/no. at risk 23/563 34/558 43/559 
 Cumulative incidence, 3 y, % ± SE 6 ± 1 8 ± 1 9 ± 1 
 RR (95% CI) 1 (ref) 1.19 (0.69–2.03) 1.50 (0.90–2.50) 
P  0.53 0.12 
Patients with hsCRP <3 
 No. with event/no. at risk 19/401 22/387 28/378 
 Cumulative incidence, 3 y, % ± SE 6 ± 2 7 ± 2 8 ± 2 
 RR (95% CI) 1 (ref) 0.99 (0.53–1.83) 1.11 (0.61–2.02) 
P  0.96 0.74 
Patients with hsCRP ≥3 
 No. with event/no. at risk 4/162 12/171 15/181 
 Cumulative incidence, 3 y, % ± SE 5 ± 2 8 ± 2 11 ± 3 
 RR (95% CI) 1 (ref) 2.27 (0.72–7.14) 3.28 (1.09–9.91) 
P  0.16 0.03 
Pinteraction  0.29 0.11 
Risk of renal and hypertensive disordersc 
All patients 
 No. with event/no. at risk 95/563 125/558 100/559 
 Cumulative incidence, 3 y, % ± SE 6 ± 1 8 ± 1 9 ± 1 
 RR (95% CI) 1 (ref) 1.24 (0.94–1.62) 0.87 (0.66–1.16) 
P  0.12 0.35 
Patients with hsCRP <3 
 No. with event/no. at risk 63/401 82/387 60/378 
 Cumulative incidence, 3 y, % ± SE 6 ± 2 7 ± 2 8 ± 2 
 RR (95% CI) 1 (ref) 1.26 (0.90–1.75) 0.78 (0.55–1.12) 
P  0.18 0.18 
Patients with hsCRP ≥3 
 No. with event/no. at risk 32/162 43/171 40/181 
 Cumulative incidence, 3 y, % ± SE 5 ± 2 8 ± 2 11 ± 3 
 RR (95% CI) 1 (ref) 1.13 (0.71–1.80) 1.02 (0.63–1.63) 
P  0.60 0.95 
Pinteraction  0.68 0.46 
Gastrointestinal ulceration/hemorrhaged 
All patients 
 No. with event/no. at risk 57/563 58/558 54/559 
 Cumulative incidence, 3 y, % ± SE 6 ± 1 8 ± 1 9 ± 1 
 RR (95% CI) 1 (ref) 0.87 (0.60–1.25) 0.82 (0.56–1.19) 
P  0.45 0.29 
Patients with hsCRP <3 
 No. with event/no. at risk 36/401 44/387 36/378 
 Cumulative incidence, 3 y, % ± SE 6 ± 2 7 ± 2 8 ± 2 
 RR (95% CI) 1 (ref) 1.06 (0.68–1.65) 0.79 (0.50–1.27) 
P  0.80 0.33 
Patients with hsCRP ≥3 
 No. with event/no. at risk 21/162 14/171 18/181 
 Cumulative incidence, 3 y, % ± SE 5 ± 2 8 ± 2 11 ± 3 
 RR (95% CI) 1 (ref) 0.52 (0.26–1.04) 0.80 (0.42–1.52) 
P  0.06 0.49 
Pinteraction  0.07 0.83 
PlaceboCelecoxib, 200 mg bidCelecoxib, 400 mg bid
Risk of cardiovascular disordersb 
All patients 
 No. with event/no. at risk 23/563 34/558 43/559 
 Cumulative incidence, 3 y, % ± SE 6 ± 1 8 ± 1 9 ± 1 
 RR (95% CI) 1 (ref) 1.19 (0.69–2.03) 1.50 (0.90–2.50) 
P  0.53 0.12 
Patients with hsCRP <3 
 No. with event/no. at risk 19/401 22/387 28/378 
 Cumulative incidence, 3 y, % ± SE 6 ± 2 7 ± 2 8 ± 2 
 RR (95% CI) 1 (ref) 0.99 (0.53–1.83) 1.11 (0.61–2.02) 
P  0.96 0.74 
Patients with hsCRP ≥3 
 No. with event/no. at risk 4/162 12/171 15/181 
 Cumulative incidence, 3 y, % ± SE 5 ± 2 8 ± 2 11 ± 3 
 RR (95% CI) 1 (ref) 2.27 (0.72–7.14) 3.28 (1.09–9.91) 
P  0.16 0.03 
Pinteraction  0.29 0.11 
Risk of renal and hypertensive disordersc 
All patients 
 No. with event/no. at risk 95/563 125/558 100/559 
 Cumulative incidence, 3 y, % ± SE 6 ± 1 8 ± 1 9 ± 1 
 RR (95% CI) 1 (ref) 1.24 (0.94–1.62) 0.87 (0.66–1.16) 
P  0.12 0.35 
Patients with hsCRP <3 
 No. with event/no. at risk 63/401 82/387 60/378 
 Cumulative incidence, 3 y, % ± SE 6 ± 2 7 ± 2 8 ± 2 
 RR (95% CI) 1 (ref) 1.26 (0.90–1.75) 0.78 (0.55–1.12) 
P  0.18 0.18 
Patients with hsCRP ≥3 
 No. with event/no. at risk 32/162 43/171 40/181 
 Cumulative incidence, 3 y, % ± SE 5 ± 2 8 ± 2 11 ± 3 
 RR (95% CI) 1 (ref) 1.13 (0.71–1.80) 1.02 (0.63–1.63) 
P  0.60 0.95 
Pinteraction  0.68 0.46 
Gastrointestinal ulceration/hemorrhaged 
All patients 
 No. with event/no. at risk 57/563 58/558 54/559 
 Cumulative incidence, 3 y, % ± SE 6 ± 1 8 ± 1 9 ± 1 
 RR (95% CI) 1 (ref) 0.87 (0.60–1.25) 0.82 (0.56–1.19) 
P  0.45 0.29 
Patients with hsCRP <3 
 No. with event/no. at risk 36/401 44/387 36/378 
 Cumulative incidence, 3 y, % ± SE 6 ± 2 7 ± 2 8 ± 2 
 RR (95% CI) 1 (ref) 1.06 (0.68–1.65) 0.79 (0.50–1.27) 
P  0.80 0.33 
Patients with hsCRP ≥3 
 No. with event/no. at risk 21/162 14/171 18/181 
 Cumulative incidence, 3 y, % ± SE 5 ± 2 8 ± 2 11 ± 3 
 RR (95% CI) 1 (ref) 0.52 (0.26–1.04) 0.80 (0.42–1.52) 
P  0.06 0.49 
Pinteraction  0.07 0.83 

aNo. at risk includes patients randomized regardless of whether they had a follow-up colonoscopy. All RRs are multivariate-adjusted as described in the methods. P values for interaction were assessed by using cross-product terms for each celecoxib treatment group and each hsCRP strata.

bIncludes investigator-reported cardiovascular disorders, which was a prespecified category encompassing cardiovascular death or circulatory collapse, stroke, myocardial infarction or angina, congestive heart failure, venous thrombosis or thromboembolism, cardiovascular therapeutic procedures, vascular therapeutic procedures, cerebrovascular disease, and vascular disease.

cIncludes investigator-reported renal and hypertensive disorders, which was a prespecified category encompassing elevated creatinine, fluid retention or edema, hypertension, proteinuria, and renal failure.

dIncludes investigator-reported gastrointestinal ulceration and hemorrhage, which was a prespecified category encompassing anemia, gastrointestinal bleeding, gastritis/duodenitis, upper or lower gastrointestinal ulceration, and other hemorrhage.

The divergent results of previous studies relating hsCRP to colorectal adenoma or cancer may be related to the timing at which hsCRP was measured (11–29). Specifically, positive studies may reflect hsCRP elevations associated with occult disease including adenoma (11, 12, 14, 22). In support of this explanation, cross-sectional data measuring hsCRP at the time of colonoscopy have shown a modest association with prevalent adenoma (24, 25), whereas a prospective study of incident adenoma and a cross-sectional study measuring hsCRP several years before diagnosis of adenoma showed inverse or no association (26, 28). In our study, because we examined hsCRP levels among individuals within 6 months of a clearing colonoscopy and endpoints were ascertained at protocol-defined surveillance colonoscopies, our results more closely reflect the association between hsCRP and incident neoplasia. Our findings are largely consistent with those of the similarly designed Aspirin Polyp Prevention Study (PPS; ref. 37). However, the results from both the APC and Aspirin PPS trials do not exclude a potential association between hsCRP and the initial development of adenoma rather than recurrence. A limitation of our study is that we only had a single baseline measure of hsCRP and we could not correlate change in hsCRP with celecoxib treatment. However, celecoxib treatment reduced adenoma recurrence irrespective of baseline levels of hsCRP. Taken together with data from the Aspirin PPS which did measure hsCRP levels at baseline and at year 3, our findings support the conclusion that hsCRP does not mediate the chemopreventive effect of aspirin or celecoxib (37).

Among individuals with high hsCRP levels (>3 mg/L), celecoxib treatment was associated with a 3-fold higher risk of an adverse cardiovascular event; in contrast, among those with low hsCRP (≤3 mg/L), celecoxib treatment was not associated with higher risk. Although a formal test for interaction was not significant, this is likely due to the limited number of adverse cardiovascular events. These findings are consistent with emerging data that individuals can be stratified for celecoxib cardiovascular toxicity according to baseline cardiovascular risk. A prior pooled analysis of 6 placebo-controlled trials of celecoxib observed that patients with high baseline cardiovascular risk scores had the greatest risk of celecoxib-related adverse events (38). Similarly, a 5-year safety analysis of an extension of the APC trial showed a significant interaction between a baseline history of atherosclerotic heart disease and risk of celecoxib-associated cardiovascular events (33). Further studies are needed to determine whether baseline hsCRP alone can be used to identify patients for whom long-term use of celecoxib is relatively safe.

In the APC trial, patients were randomized to either 200-mg-bid or 400-mg-bid doses of celecoxib. Thus, it is unclear if baseline hsCRP may also predict risk of cardiovascular events among patients who take celecoxib once daily. In a parallel randomized, placebo-controlled trial, treatment with 400 mg of daily celecoxib was associated with an overall nonsignificant increase in risk of cardiovascular events (RR = 1.30; 95% CI = 0.65–2.62; ref. 5). Thus, it is possible that use of a once daily dosing of celecoxib among patients with low hsCRP may be a particularly effective strategy to minimize cardiovascular risk.

Finally, in our analysis, we did observe a nonsignificant increase in risk of renal and hypertensive events in the subgroup of patients with low hsCRP randomized to 200-mg-bid. In contrast, there was no association among those randomized to 400-mg-bid. On the basis of this lack of a dose response, it is unlikely that there is a unique biological interaction between celecoxib and low baseline inflammatory state and renal or hypertensive events. Nonetheless, larger studies with a greater number of such endpoints are needed to make definitive conclusions.

In this large, randomized, placebo-controlled trial, baseline hsCRP was not associated with overall risk of adenoma recurrence or celecoxib chemopreventive benefit after 3 years of treatment. However, individuals with high hsCRP appeared to have the greatest risk of celecoxib-related cardiovascular toxicity. Further studies are needed to determine the role of hsCRP in relation to other markers of cardiovascular risk to evaluate the risk-benefit profile of celecoxib treatment for a range of clinical indications.

A.T. Chan is a Damon Runyon Cancer Research Foundation Clinical Investigator and has served as a consultant to Bayer HealthCare. M.M. Bertagnolli is the recipient of research funding from Pfizer Inc. E.T. Hawk has served as a consultant for Pozen Pharmaceutical Development Company. P.M. Ridker is listed as a coinventor on patents held by Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes that have been licensed to Siemens and AstraZeneca. C.S. Sima has no conflicts of interest. The statistical analysis of the entire data sets pertaining to efficacy and safety has been independently confirmed by A.G. Zauber, who is not employed by any corporate entity. The corresponding author had full access to all of the data and takes full responsibility for the veracity of the data and analysis.

The authors thank Dr. Nader Rifai and Mr. Gary Bradwin for technical assistance with the CRP assays.

This work was supported by the National Cancer Institute at the NIH (grant number R01 CA137178 to A.T. Chan and N01 CN95015 to M.M. Bertagnolli).

1.
Chan
AT
,
Ogino
S
,
Fuchs
CS
. 
Aspirin and the risk of colorectal cancer in relation to the expression of COX-2
.
N Engl J Med
2007
;
356
:
2131
42
.
2.
Baron
JA
,
Cole
BF
,
Sandler
RS
,
Haile
RW
,
Ahnen
D
,
Bresalier
R
, et al
A randomized trial of aspirin to prevent colorectal adenomas
.
N Engl J Med
2003
;
348
:
891
9
.
3.
Cole
BF
,
Logan
RF
,
Halabi
S
,
Benamouzig
R
,
Sandler
RS
,
Grainge
MJ
, et al
Aspirin for the chemoprevention of colorectal adenomas: meta-analysis of the randomized trials
.
J Natl Cancer Inst
2009
;
101
:
256
66
.
4.
Bertagnolli
MM
,
Eagle
CJ
,
Zauber
AG
,
Redston
M
,
Solomon
SD
,
Kim
K
, et al
Celecoxib for the prevention of sporadic colorectal adenomas
.
N Engl J Med
2006
;
355
:
873
84
.
5.
Arber
N
,
Eagle
CJ
,
Spicak
J
,
Rácz
I
,
Dite
P
,
Hajer
J
, et al
Celecoxib for the prevention of colorectal adenomatous polyps
.
N Engl J Med
2006
;
355
:
885
95
.
6.
Schottenfeld
D
,
Beebe-Dimmer
J
. 
Chronic inflammation: a common and important factor in the pathogenesis of neoplasia
.
CA Cancer J Clin
2006
;
56
:
69
83
.
7.
Balkwill
F
,
Mantovani
A
. 
Inflammation and cancer: back to Virchow?
Lancet
2001
;
357
:
539
45
.
8.
Shacter
E
,
Weitzman
SA
. 
Chronic inflammation and cancer
.
Oncology
2002
;
16
:
217
26
,
229; discussion 230–2
.
9.
Ridker
PM
,
Cushman
M
,
Stampfer
MJ
,
Tracy
RP
,
Hennekens
CH
. 
Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men
.
N Engl J Med
1997
;
336
:
973
9
.
10.
Ridker
PM
,
Hennekens
CH
,
Buring
JE
,
Rifai
N
. 
C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women
.
N Engl J Med
2000
;
342
:
836
43
.
11.
Erlinger
TP
,
Platz
EA
,
Rifai
N
,
Helzlsouer
KJ
. 
C-reactive protein and the risk of incident colorectal cancer
.
JAMA
2004
;
291
:
585
90
.
12.
Il'yasova
D
,
Colbert
LH
,
Harris
TB
,
Newman
AB
,
Bauer
DC
,
Satterfield
S
, et al
Circulating levels of inflammatory markers and cancer risk in the health aging and body composition cohort
.
Cancer Epidemiol Biomarkers Prev
2005
;
14
:
2413
8
.
13.
Ito
Y
,
Suzuki
K
,
Tamakoshi
K
,
Wakai
K
,
Kojima
M
,
Ozasa
K
, et al
Colorectal cancer and serum C-reactive protein levels: a case-control study nested in the JACC Study
.
J Epidemiol
2005
;
15
Suppl 2
:
S185
9
.
14.
Gunter
MJ
,
Stolzenberg-Solomon
R
,
Cross
AJ
,
Leitzmann
MF
,
Weinstein
S
,
Wood
RJ
, et al
A prospective study of serum C-reactive protein and colorectal cancer risk in men
.
Cancer Res
2006
;
66
:
2483
7
.
15.
Otani
T
,
Iwasaki
M
,
Sasazuki
S
,
Inoue
M
,
Tsugane
S
. 
Plasma C-reactive protein and risk of colorectal cancer in a nested case-control study: Japan Public Health Center-based prospective study
.
Cancer Epidemiol Biomarkers Prev
2006
;
15
:
690
5
.
16.
Trichopoulos
D
,
Psaltopoulou
T
,
Orfanos
P
,
Trichopoulou
A
,
Boffetta
P
. 
Plasma C-reactive protein and risk of cancer: a prospective study from Greece
.
Cancer Epidemiol Biomarkers Prev
2006
;
15
:
381
4
.
17.
Siemes
C
,
Visser
LE
,
Coebergh
JW
,
Splinter
TA
,
Witteman
JC
,
Uitterlinden
AG
, et al
C-reactive protein levels, variation in the C-reactive protein gene, and cancer risk: the Rotterdam Study
.
J Clin Oncol
2006
;
24
:
5216
22
.
18.
Heikkilä
K
,
Harris
R
,
Lowe
G
,
Rumley
A
,
Yarnell
J
,
Gallacher
J
, et al
Associations of circulating C-reactive protein and interleukin-6 with cancer risk: findings from two prospective cohorts and a meta-analysis
.
Cancer Causes Control
2009
;
20
:
15
26
.
19.
Allin
KH
,
Bojesen
SE
,
Nordestgaard
BG
. 
Baseline C-reactive protein is associated with incident cancer and survival in patients with cancer
.
J Clin Oncol
2009
;
27
:
2217
24
.
20.
Allin
KH
,
Nordestgaard
BG
,
Zacho
J
,
Tybjaerg-Hansen
A
,
Bojesen
SE
. 
C-reactive protein and the risk of cancer: a mendelian randomization study
.
J Natl Cancer Inst
2010
;
102
:
202
6
.
21.
Zhang
SM
,
Buring
JE
,
Lee
IM
,
Cook
NR
,
Ridker
PM
. 
C-reactive protein levels are not associated with increased risk for colorectal cancer in women
.
Ann Intern Med
2005
;
142
:
425
32
.
22.
Aleksandrova
K
,
Jenab
M
,
Boeing
H
,
Jansen
E
,
Bueno-de-Mesquita
HB
,
Rinaldi
S
, et al
Circulating C-reactive protein concentrations and risks of colon and rectal cancer: a nested case-control study within the European Prospective Investigation into Cancer and Nutrition
.
Am J Epidemiol
2010
;
172
:
407
18
.
23.
Chan
AT
,
Ogino
S
,
Giovannucci
EL
,
Fuchs
CS
. 
Inflammatory markers are associated with risk of colorectal cancer and chemopreventive response to anti-inflammatory drugs
.
Gastroenterology
2011
;
140
:
799
808
.
24.
Otake
T
,
Uezono
K
,
Takahashi
R
,
Fukumoto
J
,
Tabata
S
,
Abe
H
, et al
C-reactive protein and colorectal adenomas: Self Defense Forces Health Study
.
Cancer Sci
2009
;
100
:
709
14
.
25.
Kim
S
,
Keku
TO
,
Martin
C
,
Galanko
J
,
Woosley
JT
,
Schroeder
JC
, et al
Circulating levels of inflammatory cytokines and risk of colorectal adenomas
.
Cancer Res
2008
;
68
:
323
8
.
26.
Tsilidis
KK
,
Erlinger
TP
,
Rifai
N
,
Hoffman
S
,
Hoffman-Bolton
J
,
Helzlsouer
KJ
, et al
C-reactive protein and colorectal adenoma in the CLUE II cohort
.
Cancer Causes Control
2008
;
19
:
559
67
.
27.
Ognjanovic
S
,
Yamamoto
J
,
Saltzman
B
,
Franke
A
,
Ognjanovic
M
,
Yokochi
L
, et al
Serum CRP and IL-6, genetic variants and risk of colorectal adenoma in a multiethnic population
.
Cancer Causes Control
2010
;
21
:
1131
8
.
28.
Gunter
MJ
,
Cross
AJ
,
Huang
WY
,
Stanczyk
FZ
,
Purdue
M
,
Xue
X
, et al
A prospective evaluation of C-reactive protein levels and colorectal adenoma development
.
Cancer Epidemiol Biomarkers Prev
2011
;
20
:
537
44
.
29.
Prizment
AE
,
Anderson
KE
,
Visvanathan
K
,
Folsom
AR
. 
Association of inflammatory markers with colorectal cancer incidence in the atherosclerosis risk in communities study
.
Cancer Epidemiol Biomarkers Prev
2011
;
20
:
297
307
.
30.
Solomon
SD
,
McMurray
JJ
,
Pfeffer
MA
,
Wittes
J
,
Fowler
R
,
Finn
P
, et al
Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention
.
N Engl J Med
2005
;
352
:
1071
80
.
31.
Chenevard
R
,
Hürlimann
D
,
Béchir
M
,
Enseleit
F
,
Spieker
L
,
Hermann
M
, et al
Selective COX-2 inhibition improves endothelial function in coronary artery disease
.
Circulation
2003
;
107
:
405
9
.
32.
Bogaty
P
,
Brophy
JM
,
Noel
M
,
Boyer
L
,
Simard
S
,
Bertrand
F
, et al
Impact of prolonged cyclooxygenase-2 inhibition on inflammatory markers and endothelial function in patients with ischemic heart disease and raised C-reactive protein: a randomized placebo-controlled study
.
Circulation
2004
;
110
:
934
9
.
33.
Bertagnolli
MM
,
Eagle
CJ
,
Zauber
AG
,
Redston
M
,
Breazna
A
,
Kim
K
, et al
Five-year efficacy and safety analysis of the Adenoma Prevention with Celecoxib Trial
.
Cancer Prev Res
2009
;
2
:
310
21
.
34.
Pearson
TA
,
Mensah
GA
,
Alexander
RW
,
Anderson
JL
,
Cannon
RO
,
Criqui
M
, et al
Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association
.
Circulation
2003
;
107
:
499
511
.
35.
Chan
AT
,
Zauber
AG
,
Hsu
M
,
Breazna
A
,
Hunter
DJ
,
Rosenstein
RB
, et al
Cytochrome P450 2C9 variants influence response to celecoxib for prevention of colorectal adenoma
.
Gastroenterology
2009
;
136
:
2127
36
e1
.
36.
Ridker
PM
,
Hennekens
CH
,
Rifai
N
,
Buring
JE
,
Manson
JE
. 
Hormone replacement therapy and increased plasma concentration of C-reactive protein
.
Circulation
1999
;
100
:
713
6
.
37.
Ho
GY
,
Xue
X
,
Cushman
M
,
McKeown-Eyssen
G
,
Sandler
RS
,
Ahnen
DJ
, et al
Antagonistic effects of aspirin and folic acid on inflammation markers and subsequent risk of recurrent colorectal adenomas
.
J Natl Cancer Inst
2009
;
101
:
1650
4
.
38.
Solomon
SD
,
Wittes
J
,
Finn
PV
,
Fowler
R
,
Viner
J
,
Bertagnolli
MM
, et al
Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross trial safety analysis
.
Circulation
2008
;
117
:
2104
13
.

Supplementary data