C-reactive protein and colorectal cancer risk: A systematic review of prospective studies Konstantinos K. Tsilidis 1 , Casey Branchini 2 , Eliseo Guallar 1,3 , Kathy J. Helzlsouer 1,4,5,6 , Thomas P. Erlinger 7 and Elizabeth A. Platz 1,6 * 1 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 2 Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 3 Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD 4 George W. Comstock Center for Public Health Research and Prevention, Johns Hopkins Bloomberg School of Public Health, Hagerstown, MD 5 Prevention and Research Center, Weinberg Center for Women’s Health and Medicine, Mercy Medical Center, Baltimore, MD 6 The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 7 Department of Internal Medicine, University of Texas Medical Branch, Austin, TX C-reactive protein is a sensitive but nonspecific systemic marker of inflammation. Several prospective studies have investigated the association of prediagnostic circulating C-reactive protein concen- trations with the development of colorectal cancer, but the results have been inconsistent. We performed a systematic review of pro- spective studies of the association between prediagnostic measure- ments of circulating high-sensitivity C-reactive protein and devel- opment of invasive colorectal cancer. Authors of original studies were contacted to acquire uniform data. We combined relative risks (RR) for colorectal cancer associated with a one unit change in natural logarithm-transformed high-sensitivity C-reactive pro- tein using inverse variance weighted random effects models. We identified eight eligible studies, which included 1,159 colorectal cancer cases and 37,986 controls. The summary RR per one unit change in natural log-transformed high-sensitivity C-reactive pro- tein was 1.12 (95% confidence intervals [CI], 1.01–1.25) for colo- rectal cancer, 1.13 (95% CI, 1.00–1.27) for colon cancer, and 1.06 (95% CI, 0.86–1.30) for rectal cancer. The association was stron- ger in men (RR, 1.18; 95% CI, 1.04–1.34) compared to women (RR, 1.09; 95% CI, 0.93–1.27) but this difference was sensitive to the findings from a single study. Prediagnostic high-sensitivity C- reactive protein concentrations were weakly associated with an increased risk for colorectal cancer. More work is needed to understand the extent to which circulating high-sensitivity C-reac- tive protein or other blood inflammatory markers are related to colonic inflammation. ' 2008 Wiley-Liss, Inc. Key words: meta-analysis; C-reactive protein; inflammation; colorectal neoplasms C-reactive protein (CRP) is a sensitive but nonspecific systemic marker of inflammation. 1 CRP is produced mainly in the liver along with other acute-phase proteins in response to cytokines released by phagocytes during infection, trauma, surgery, burns, tissue infarction, advanced cancer and chronic inflammatory con- ditions. 2–4 Several lines of evidence suggest that colorectal neo- plasia may arise from colonic areas with chronic subclinical inflammation. 5 Investigators have hypothesized that CRP may act as a biomarker for chronic low-grade intestinal inflammation and the subsequent development of colorectal cancer. Several retrospective case–control studies have compared CRP concentrations between colorectal cancer patients and healthy controls, and have reported at least 10-fold higher concentrations in the cancer patients. 6–9 These findings may be explained to some extent by reverse causality due to the host inflammatory response to existing advanced cancer among cases. Prospective studies, where CRP is measured long before cancer diagnosis in all partici- pants, are thus required to answer whether CRP is associated with colorectal cancer incidence. Findings from such studies, however, have been inconsistent. The reasons underlying these heterogene- ous findings need to be investigated, but no formal meta-analysis has been published. Therefore, we performed a systematic review and meta-regression analysis to summarize the findings and address the inconsistencies of the CRP and colorectal cancer inci- dence literature. Material and methods Study identification We searched MEDLINE and EMBASE from 1966 through Jan- uary 2007 to identify prospective epidemiologic studies of the association between prediagnostic measurements of circulating CRP and development of invasive colorectal cancer. In addition, we also performed a search of the Cochrane Systematic Review Database, and a manual review of references from relevant origi- nal or review articles. The search strategy used the Medical Sub- ject Heading and text key words ‘‘(C-reactive protein or CRP) and (colorectal or colon or rectal) and (cancer or carcinoma or neopla- sia or tumor or adenoma or neoplasm).’’ No language restrictions were imposed. We excluded articles that had no human or no orig- inal data, that did not have colorectal cancer or adenoma as an out- come, or that did not measure blood CRP concentrations. We also excluded prognostic studies. Our search identified 399 articles potentially relevant for abstract review (Fig. 1). Abstracts were reviewed independently by 2 investigators (K.K.T. and C.B.). Differences were resolved by consensus. There were 37 articles retrieved for full-text review based on information in the abstracts. Of these, 9 studies were identified as relevant and were abstracted. Data abstraction was conducted independently by the same 2 investigators, and discrep- ancies were adjudicated. One study had 2 publications using data from overlapping study populations. 10,11 We only abstracted the results from the more recent publication, leading to 8 relevant studies to summarize. 11–18 An additional search of MEDLINE and EMBASE through December 2007 did not identify more relevant studies. The quality of individual studies was assessed using the STROBE statement guidelines. 19 Study quality was evaluated in- dependently by 2 investigators (K.K.T. and E.A.P.) with disagree- ment resolved by consensus. Statistical analysis Corresponding authors from the 8 eligible studies were con- tacted to acquire uniform findings. We requested maximally *Correspondence to: Johns Hopkins Bloomberg School of Public Health, Department of Epidemiology, 615 N. Wolfe St., Rm. E 6132A, Baltimore, MD 21205, USA. Fax: 11-410-614-2632. E-mail: eplatz@jhsph.edu Received 4 January 2008; Accepted after revision 22 February 2008 DOI 10.1002/ijc.23606 Published online 4 June 2008 in Wiley InterScience (www.interscience. wiley.com). Int. J. Cancer: 123, 1133–1140 (2008) ' 2008 Wiley-Liss, Inc. Publication of the International Union Against Cancer