Accumulating evidences indicate cancer-triggered inflammation plays a pivotal role in carcinogenesis. Systematic inflammatory response biomarkers are considered as potential prognostic factors for improving predictive accuracy in colorectal cancer (CRC). Preoperative neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (d-NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte- to-monocyte ratio (LMR) were investigated and compared in 205 surgical CRC patients. ROC curve was applied to determine thresholds for four biomarkers, and their prognostic values were assessed using Kaplan–Meier curve, univariate and multivariate COX regression models. Moreover, a number of risk factors were used to form nomograms for evaluating risk of survival, and Harrell’s concordance index (c-index) was used to evaluate predictive accuracy. Results showed that elevated NLR was significantly associated with diminished recurrent-free survival (RFS), overall survival (OS) and cancer-specific survival (CSS) in surgical CRC patients. Moreover, multivariate COX analysis identified elevated NLR as an independent factor for poor RFS (P < 0.001, HR 2.52, 95 % CI 1.65–3.83), OS (P < 0.001, HR 2.73, 95 % CI 1.74–4.29) and CSS (P < 0.001, HR 2.77, 95 % CI 1.72–4.46). Additionally, predictive nomograms including NLR for RFS, OS and CSS could be more effective in predicting RFS (c-index: 0.810 vs. 0.656), OS (c-index: 0.809 vs. 0.690) and CSS (c-index: 0.802 vs. 0.688) in surgical CRC patients, respectively. These findings indicate that preoperative elevated NLR can be considered as an independent prognostic biomarker for RFS, OS and CSS. Nomograms containing NLR provide improved accuracy for predicting clinical outcomes in surgical CRC patients under surgery resection.
Neutrophil-to-lymphocyte ratio Nomogram Colorectal cancer
This is a preview of subscription content, log in to check access.
This study was supported by National Nature Science Foundation of China (No. 81172141), Nanjing Science and Technology Committee project (No. 201108025), Nanjing Medical Technology Development Project (No. ZKX11025), Nanjing Health Young Talent Project, Jiangsu Provincial Key Medical Talents to S.K.W., Nanjing Medical Science and Technique Development Foundation to Y.Q.P. (No. QRX11255) and B.S.H. (No. QRX11254).
Conflict of interest
The authors have declared no conflict of interests with respect to the authorship and/or publication of this article.
Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F: GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. http://globocan.iarc.fr.
Chen W, Zheng R, Zhang S, Zhao P, Zeng H, Zou X, et al. Annual report on status of cancer in China, 2010. Chin J Cancer Res. 2014;26:48–58.PubMedCentralPubMedGoogle Scholar
Zlobec I, Lugli A. Prognostic and predictive factors in colorectal cancer. J Clin Pathol. 2008;61:561–9.PubMedGoogle Scholar
Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer. 2013;13:759–71.PubMedCrossRefGoogle Scholar
Itzkowitz SH, Yio X. Inflammation and cancer IV Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Liver Physiol. 2004;287:G7–17.PubMedCrossRefGoogle Scholar
Kao SC, Pavlakis N, Harvie R, Vardy JL, Boyer MJ, van Zandwijk N, et al. High blood neutrophil-to-lymphocyte ratio is an indicator of poor prognosis in malignant mesothelioma patients undergoing systemic therapy. Clin Cancer Res. 2010;16:5805–13.PubMedCrossRefGoogle Scholar
Raungkaewmanee S, Tangjitgamol S, Manusirivithaya S, Srijaipracharoen S, Thavaramara T. Platelet to lymphocyte ratio as a prognostic factor for epithelial ovarian cancer. J Gynecol Oncol. 2013;23:265–73.CrossRefGoogle Scholar
Szkandera J, Gerger A, Liegl-Atzwanger B, Absenger G, Stotz M, Friesenbichler J, et al. The lymphocyte/monocyte ratio predicts poor clinical outcome and improves the predictive accuracy in patients with soft tissue sarcomas. Int J Cancer. 2014;135:362–70.PubMedCrossRefGoogle Scholar
Absenger G, Szkandera J, Pichler M, Stotz M, Arminger F, Weissmueller M, et al. A derived neutrophil to lymphocyte ratio predicts clinical outcome in stage II and III colon cancer patients. Br J Cancer. 2013;109:395–400.PubMedCentralPubMedCrossRefGoogle Scholar
Stotz M, Pichler M, Absenger G, Szkandera J, Arminger F, Schaberl-Moser R, et al. The preoperative lymphocyte to monocyte ratio predicts clinical outcome in patients with stage III colon cancer. Br J Cancer. 2014;110:435–40.PubMedCentralPubMedCrossRefGoogle Scholar
Liu H, DU X, Sun P, Xiao C, Xu Y, Li R. Preoperative platelet-lymphocyte ratio is an independent prognostic factor for resectable colorectal cancer. J South Med Univ. 2013;33:70–3.Google Scholar
Walsh SR, Cook EJ, Goulder F, Justin TA, Keeling NJ. Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg Oncol. 2005;91:181–4.PubMedCrossRefGoogle Scholar
Chiang SF, Hung HY, Tang R, Changchien CR, Chen JS, You YT, et al. Can neutrophil-to-lymphocyte ratio predict the survival of colorectal cancer patients who have received curative surgery electively? Int J Colorectal Dis. 2012;27:1347–57.PubMedCrossRefGoogle Scholar
Greiner M, Pfeiffer D, Smith RD. Principles and practical application of thereceiver-operating characteristic analysis for diagnostic tests. Prev Vet Med. 2000;45:23–41.PubMedCrossRefGoogle Scholar
Ulich TR, del Castillo J, Keys M, Granger GA, Ni RX. Kinetics and mechanisms of recombinant human interleukin 1 and tumor necrosisfactor-alpha- induced changes in circulating numbers of neutrophils and lymphocytes. J Immunol. 1987;139:3406–15.PubMedGoogle Scholar
Ulich TR, del Castillo J, Guo KZ. In vivo hematologic effects of recombinant interleukin-6 on hematopoiesis and circulating numbers of RBCs and WBCs. Blood. 1989;73:108–10.PubMedGoogle Scholar
Teramukai S, Kitano T, Kishida Y, Kawahara M, Kubota K, Komuta K, et al. Pretreatment neutrophil count as an independent prognostic factor in advanced non-small-cell lung cancer: an analysis of Japan Multinational Trial Organisation LC00-03. Eur J Cancer. 2009;45:1950–8.PubMedCrossRefGoogle Scholar
Lord BI, Bronchud MH, Owens S, Chang J, Howell A, Souza L, et al. The kinetics of human granulopoiesis following treatment with granulocyte colony-stimulating factor in vivo. Proc Natl Acad Sci USA. 1989;86:9499–503.PubMedCentralPubMedCrossRefGoogle Scholar
Cedrés S, Torrejon D, Martínez A, Martinez P, Navarro A, Zamora E, et al. Neutrophil to lymphocyte ratio (NLR) as an indicator of poor prognosis in stage IV non-small cell lung cancer. Clin Transl Oncol. 2012;14:864–9.PubMedCrossRefGoogle Scholar
Stotz M, Gerger A, Eisner F, Szkandera J, Loibner H, Ress AL, et al. Increased neutrophil-lymphocyte ratio is a poor prognostic factor in patients with primary operable and inoperable pancreatic cancer. Br J Cancer. 2013;109:416–21.PubMedCentralPubMedCrossRefGoogle Scholar
Mano Y, Shirabe K, Yamashita Y, Harimoto N, Tsujita E, Takeishi K, et al. Preoperative neutrophil-to-lymphocyte ratio is a predictor of survival after hepatectomy for hepatocellular carcinoma: a retrospective analysis. Ann Surg. 2013;258:301–5.PubMedCrossRefGoogle Scholar
Shibutani M, Maeda K, Nagahara H, Noda E, Ohtani H, Sugano K, et al. Significance of preoperative neutrophil-to-lymphocyte ratio as a predictor of prognosis in patients with stage IV colorectal cancer. Gan To Kagaku Ryoho. 2013;40:1603–5.PubMedGoogle Scholar
Shibutani M, Maeda K, Nagahara H, Noda E, Ohtani H, Nishiguchi Y, et al. A high preoperative neutrophil-to-lymphocyte ratio is associated with poor survival in patients with colorectal cancer. Anticancer Res. 2013;33:3291–4.PubMedGoogle Scholar
Weitzman SA, Gordon LI. Inflammation and cancer: role of phagocyte-generated oxidants in carcinogenesis. Blood. 1990;76:655–63.PubMedGoogle Scholar
Kusumanto YH, Dam WA, Hospers GA, Meijer C, Mulder NH. Platelets and granulocytes, in particular the neutrophils, form important compartments for circulating vascular endothelial growth factor. Angiogenesis. 2003;6:283–7.PubMedCrossRefGoogle Scholar
Hanrahan V, Currie MJ, Gunningham SP, Morrin HR, Scott PA, Robinson BA, et al. The angiogenic switch for vascular endothelial growth factor (VEGF)-A, VEGF-B, VEGF-C, and VEGF-D in the adenoma-carcinoma sequence during colorectal cancer progression. J Pathol. 2003;200:183–94.PubMedCrossRefGoogle Scholar
Kim SL, Lee ST, Trang KT, Kim SH, Kim IH, Lee SO, et al. Parthenolide exerts inhibitory effects on angiogenesis through the down regulation of VEGF/VEGFRs in colorectal cancer. Int J Mol Med. 2014;33:1261–7.PubMedGoogle Scholar
Kuper H, Adami HO, Trichopoulos D. Infections as a major preventable cause of human cancer. J Intern Med. 2000;248:171–83.PubMedCrossRefGoogle Scholar
Blaser MJ, Chyou PH, Nomura A. Age at establishment of Helicobacter pylori infection and gastric carcinoma, gastric ulcer, and duodenal ulcer risk. Cancer Res. 1995;55:562–5.PubMedGoogle Scholar
Scholl SM, Pallud C, Beuvon F, Hacene K, Stanley ER, et al. Anti-colony-stimulating factor-1 antibody staining in primary breast adenocarcinomas correlates with marked inflammatory cell infiltrates and prognosis. J Natl Cancer Inst. 1994;86:120–6.PubMedCrossRefGoogle Scholar
Shacter E, Weitzman SA. Chronic inflammation and cancer. Oncology. 2002;16:217–26.PubMedGoogle Scholar
Rabinowich H, Cohen R, Bruderman I, Steiner Z, Klajman A. Functional analysis of mononuclear cells infiltrating into tumors: lysis of autologous human tumor cells by cultured infiltrating lymphocytes. Cancer Res. 1987;47:173–7.PubMedGoogle Scholar
Menges T, Engel J, Welters I, Wagner RM, Little S, Ruwoldt R, et al. Changes in blood lymphocyte populations after multiple trauma: association with posttraumatic complications. Crit Care Med. 1999;27:733–40.PubMedCrossRefGoogle Scholar