Journal of Experimental & Clinical Cancer Research 2009, 28:89 http://www.jeccr.com/content/28/1/89 tiple lines of evidence suggest involvement of the IGF pathway across a range of malignancies, including both non-small cell lung cancer (NSCLC) and small cell lung cancer [5,10,11]. Elevated plasma levels of IGF-I have been associated with an increased risk of lung cancer, and high plasma levels of IGFBP-3 associated with a reduced risk [5]. Similarly, IGFBP-3 promoter methylation in tumor cells has been linked to decreased survival in stage I NSCLC patients. These suggest that IGF-I may promote tumor cell growth, while IGFBP-3 acts as a tumor suppres- sor gene [12,13]. At the same time, different results were obtained from other studies. Recently, many large-scale clinical prospective case-control studies on association between circulating levels of IGF-I, IGFBP-3 and the risk of lung cancer were performed [14-19]. However, the results of these studies still remain inconclusive, partially because of the possible relatively small sample size in each of the published studies. Here we performed a systematic meta-analysis of all stud- ies published to date to determine and assess the strength of the association between circulating levels of IGF- I and IGFBP-3 and lung cancer. It may be helpful in the diagno- sis and treatment of lung cancer. Methods Search strategy and study selection PubMed and Embase were searched using the search terms: "insulin-like growth factor-I", "lung neoplasm", "case-control study", "cohort study" and "prospective study" (last search was updated on 1 March 2009). All eli- gible studies were retrieved, and their bibliographies were checked for other relevant publications. Review articles and bibliographies of other relevant studies identified were hand-searched to find additional eligible studies. These searches were restricted to studies in which IGF-I and IGFBP-3 concentration were measured. Two investi- gators independently reviewed all potentially relevant articles. Disagreement or uncertainty between 2 investiga- tors was resolved by discussion. Inclusion was restricted to nested case-control studies and prospective cohort stud- ies published in English. Data extraction Data were independently abstracted in duplicate by 2 investigators using a standard protocol and data-collec- tion form. Characteristics abstracted from the studies included name of the first author, location of the study, year of publication, case definition, control definition, selection criteria, method of IGF-I and IGFBP-3 measure- ment, confounding factors that were controlled for by matching or adjustment and mean and standard devia- tion (SD) of IGF-I and IGFBP-3 in each group, odds ratio (OR) comparing the highest category to the lowest and its 95% confidence interval(CI). For data not provided in tabular form or the main text, the required information were obtained by contacting corresponding authors as possible as we can. Statistical analysis Most of studies provided crude and adjusted OR. We used the adjusted OR comparing the highest category with the Measurement IGF-1 IGFBP3 Table 1: Characteristics of case-control studies for lung cancer and IGF-I and IGFBP-3 Study Year, location Sample size (case/control) OR(95%CI) for IGF-I OR(95%CI) for IGFBP-3 Adjusted factors in the model in original report Lukanova et al.[14] 2001, USA 93/186 RIA RIA 0.54(0.14–2.07) 0.90(0.28–2.85) London et al.[15] Spitz et al.[16] 2002, China 2002, USA 230/740 159/297 RIA IRMA ELISA ELISA 0.86(0.47–1.57) 0.64(0.31–1.33) 0.50(0.25–1.02) 2.35(1.13–4.92) Waikai et al.[17] 2002, Japan 194/9351 IRMA IRMA 1.74(1.08–2.81) Ahn et al.[18] 2006, Finland 200/400 ELISA ELISA 0.76(0.39–1.49) 0.67(0.45–1.01) 0.71(0.35–1.47) Morris et al. [19] 2006, British 167/498 ELISA ELISA 1.21(0.62–2.35) 1.70(0.87–3.30) All are nested case-control studies within cohort study. BMI indicates body mass index. IRMA, immunoradiometric assay; ELISA, enzyme-linked immunoabsorbent assay; RIA, radioimmunoassay assay. Age, date of recruitment in the study, menopausal status, current smoking, time since last meal, cotinine and BMI Smoking Age, sex, race, year of enrollment, and year of blood draw, BMI, smoking status, pack- years of smoking, exposure population Age, area, gender, smoking habits, and BMI Age, intervention arm, BMI, and years of smoking Age, smoking Page 2 of 6 (page number not for citation purposes)