Prognostic role of a new inflammatory index with neutrophil-to-lymphocyte ratio and lactate dehydrogenase (CII: Colon Inflammatory Index) in patients with metastatic colorectal cancer: results from the randomized Italian Trial in Advanced Colorectal Cancer (ITACa) study

Andrea Casadei-Gardini, Emanuela Scarpi, Paola Ulivi, Maria Angela Palladino, Caterina Accettura, Ilaria Bernardini, Andrea Spallanzani, Fabio Gelsomino, Jody Corbelli, Giorgia Marisi, Silvia Ruscelli, Martina Valgiusti, Giovanni Luca Frassineti, Alessandro Passardi, Andrea Casadei-Gardini, Emanuela Scarpi, Paola Ulivi, Maria Angela Palladino, Caterina Accettura, Ilaria Bernardini, Andrea Spallanzani, Fabio Gelsomino, Jody Corbelli, Giorgia Marisi, Silvia Ruscelli, Martina Valgiusti, Giovanni Luca Frassineti, Alessandro Passardi

Abstract

Aim: The aim of this study was to investigate the role of a new inflammatory index (Colon Inflammatory Index [CII]) as a predictor of prognosis and treatment efficacy in patients with metastatic colorectal cancer (mCRC) enrolled in the prospective multicenter randomized ITACa (Italian Trial in Advanced Colorectal Cancer) trial to receive first-line chemotherapy (CT)+ bevacizumab or CT alone. Patients and methods: Between November 14, 2007 and March 6, 2012, 276 patients diagnosed with CRC were available for baseline neutrophil-to-lymphocyte ratio (NLR) and lactate dehydrogenase (LDH). We divided the population into three groups on basis of the CII index. Results: At baseline in all populations, median PFS and OS was predictive of clinical outcome (p<0.0001). Following adjustment for clinical covariates, multivariate analysis confirmed CII index as an independent prognostic factor. The CII index was also predictive when we evaluated the two distinct arms with (p=0.0009) or without bevacizumab (p=0.0001). When we divided right side versus left side for treatment regimen (CT plus bevacizumab versus only bevacizumab), we found a benefit of bevacizumab versus only CT in the right side in patients treated with bevacizumab and not in patients treated with only chemotherapy. Conversely, we found no difference the left side, but we found a difference in the poor group of 4 months in favor to only chemotherapy. Conclusion: Our results indicate that the CII index is a good prognostic marker for mCRC patients in first line treatment with CT with or without bevacizumab. Trial registration: NCT01878422 ClinicalTrials.gov; date of registration: June 7, 2013.

Keywords: bevacizumab; first-line; lactate dehydrogenase; metastatic colorectal cancer; neutrophil-to-lymphocyte ratio; prognosis.

Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Flowchart of the study. Abbreviation: CII, Colon Inflammatory Index.
Figure 2
Figure 2
Kaplan–Meier curves of progression free survival (PFS) (A) and overall survival (OS) (B) of patients for the Colon Inflammatory Index.
Figure 3
Figure 3
Kaplan–Meier curves of PFS (A) and OS (B) for the Colon Inflammatory Index patients treated with CT +B. Abbreviations: CT, chemotherapy; B, bevacizumab.
Figure 4
Figure 4
Kaplan–Meier curves of progression free survival (PFS) (A) and overall survival (OS) (B) for Colon Inflammatory Index in patients treated with chemotherapy alone.

References

    1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics. CA Cancer J Clin. 2014;64(1):9–29. doi:10.3322/caac.21208
    1. Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015;16(13):1306–1315. doi:10.1016/S1470-2045(15)00122-9
    1. Venook AP, Niedzwiecki D, Lenz HJ, et al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA. 2017;317(23):2392–2401. doi:10.1001/jama.2017.5254
    1. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883–899. doi:10.1016/j.cell.2010.01.025.
    1. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer- related in ammation. Nature. 2008;454:436–444. doi:10.1038/nature07205
    1. Ko E, Jung G. Positive association of long telomeres with the invasive capacity of hepatocellular carcinoma cells. Biochem Biophys Res Commun. 2014;447:358–363. doi:10.1016/j.bbrc.2014.04.022
    1. Casadei Gardini A, Scarpi E, Orlandi E, et al. Prognostic role of aspartate aminotransferase-lymphocyte ratio index in patients with metastatic colorectal cancer: results from the randomized ITACa trial. Onco Targets Ther. 2018;11:5261–5268. doi:10.2147/OTT.S166614
    1. Casadei Gardini A, Foschi FG, Conti F, et al. Immune inflammation indicators and ALBI score to predict liver cancer in HCV-patients treated with direct-acting antivirals. Dig Liver Dis. 2018. pii: S1590–8658(18)30986–1. doi:10.1016/j.dld.2018.09.016
    1. Casadei Gardini A, Conti F, Foschi FG, et al. Imbalance of neutrophils and lymphocyte counts can be predictive of hepatocellular carcinoma occurrence in hepatitis c-related cirrhosis treated with direct-acting antivirals. Gastroenterology. 2018;154(8):2281–2282. doi:10.1053/j.gastro.2017.12.051
    1. Casadei Gardini A, Scarpi E, Faloppi L, et al. Immune inflammation indicators and implication for immune modulation strategies in advanced hepatocellular carcinoma patients receiving sorafenib. Oncotarget. 2016;7(41):67142–67149.
    1. Bruix J 1, Cheng AL 2, Meinhardt G, et al. Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase III studies. J Hepatol. 2017;67(5):999–1008. doi:10.1016/j.jhep.2017.06.026
    1. Lué A, Serrano MT, Bustamante FJ, et al. Neutrophil-to-lymphocyte ratio predicts survival in European patients with hepatocellular carcinoma administered sorafenib. Oncotarget. 2017;8(61):103077–103086. doi:10.18632/oncotarget.21528
    1. Giampieri R, Puzzoni M, Daniele B, et al. First-line FOLFIRI and bevacizumab in patients with advanced colorectal cancer prospectively stratified according to serum LDH: final results of the GISCAD (Italian Group for the Study of Digestive Tract Cancers) CENTRAL (ColorEctalavastiNTRiAlLdh) trial. Br J Cancer. 2017;117(8):1099–1104. doi:10.1038/bjc.2017.234
    1. Fanotto V, Cordio S, Pasquini G, et al. Prognostic factors in 868 advanced gastric cancer patients treated with second-line chemotherapy in the real world. Gastric Cancer. 2017;20(5):825–833. doi:10.1007/s10120-016-0681-6
    1. Faloppi L, Bianconi M, Memeo R, et al. Lactate dehydrogenase in hepatocellular carcinoma: something old, something new. Biomed Res Int. 2016;2016:7196280. doi:10.1155/2016/7196280
    1. Faloppi L, Del Prete M, Casadei Gardini A, et al. The correlation between LDH serum levels and clinical outcome in advanced biliary tract cancer patients treated with first line chemotherapy. Sci Rep. 2016;11(6):24136. doi:10.1038/srep24136
    1. Faloppi L, Bianconi M, Giampieri R, et al. The value of lactate dehydrogenase serum levels as a prognostic and predictive factor for advanced pancreatic cancer patients receiving sorafenib. Oncotarget. 2015;6(33):35087–35094. doi:10.18632/oncotarget.5197
    1. Passardi A, Scarpi E, Tamberi S, et al. Impact of pre-treatment lactate dehydrogenase levels on prognosis and bevacizumab efficacy in patients with metastatic colorectal cancer. PLoS One. 2015;10(8):e0134732. doi:10.1371/journal.pone.0134732
    1. Passardi A, Scarpi E, Cavanna L, et al. Inflammatory indexes as predictors of prognosis and bevacizumab efficacy in patients with metastatic colorectal cancer. Oncotarget. 2016;7(22):33210–33219. doi:10.18632/oncotarget.8901
    1. Kolev Y, Uetake H, Takagi Y, et al. Lactate dehydrogenase-5 (LDH-5) expression in human gastric cancer: association with hypoxia-inducible factor (HIF-1) pathway, angiogenic factors production and poor prognosis. Annals of Surgical Oncology. 2008;15(8):pp. 2336–2344. doi:10.1245/s10434-008-9955-5
    1. Passardi A, Nanni O, Tassinari D, et al. Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: nal results for rst-line treatment from the ITACa randomized clinical trial. Ann Oncol. 2015;26:1201–1207. doi:10.1093/annonc/mdv383
    1. D’Ignazio L, Batie M, Rocha S. Hypoxia and inflammation in cancer, focus on HIF and NF-κB. Biomedicines. 2017;5(2):pii: E21.
    1. Cuomo F, Coppola A, Botti C, et al. Pro-inflammatory cytokines activate hypoxia-inducible factor 3α via epigenetic changes in mesenchymal stromal/stem cells. Sci Rep. 2018;8(1):5842. doi:10.1038/s41598-018-24221-5
    1. Wang S, Liu Z, Wang L, Zhang XN. F-kappaB signaling pathway, inflammation and colorectal cancer. Cell Mol Immunol. 2009;6(5):327–334. doi:10.1038/cmi.2009.33
    1. Ulivi P, Marisi G, Passardi A. Relationship between hypoxia and response to antiangiogenic therapy in metastatic colorectal cancer. Oncotarget. 2016;7(29):46678–46691. doi:10.18632/oncotarget.v7i29
    1. Ulivi P, Scarpi E, Chiadini E, et al. Right- vs. left-sided metastatic colorectal cancer: differences in tumor biology and bevacizumab efficacy. Int J Mol Sci. 2017;18(6). doi:10.3390/ijms18061240
    1. Hashemi Goradel N, Najafi M, Salehi E. Cyclooxygenase-2 in cancer: a review. J Cell Physiol. 2019;234(5):5683–5699.
    1. Song Y, Zhao XP, Song K, Shang Z-J, Lee JW. Ephrin-A1 is up-regulated by hypoxia in cancer cells and promotes angiogenesis of HUVECs through a coordinated cross-talk with eNOS. PLoS One. 2013;8(9):e74464. doi:10.1371/journal.pone.0074464
    1. Narayanan S, Gabriel E 2, Attwood K, Boland P, Nurkin S. Association of clinicopathologic and molecular markers on stage-specific survival of right versus left colon cancer. Clin Colorectal Cancer. 2018;17(4):e671–e678. doi:10.1016/j.clcc.2018.07.001
    1. Wang Y, Vnencak-Jones CL, Cates JM, Shi C. Deciphering elevated microsatellite alterations at selected tetra/pentanucleotide repeats, microsatellite instability, and loss of heterozygosity in colorectal cancers. J Mol Diagn. 2018;20(3):366–372. doi:10.1016/j.jmoldx.2018.02.001
    1. Carethers JM, Koi M, Tseng-Rogenski SS. EMAST is a form of microsatellite instability that is initiated by inflammation and modulates colorectal cancer progression. Genes (Basel). 2015;6(2):185–205.
    1. Koi M, Tseng-Rogenski SS, Carethers JM, et al. Inflammation-associated microsatellite alterations: mechanisms and significance in the prognosis of patients with colorectal cancer. World J Gastrointest Oncol. 2018;10(1):1–14. doi:10.4251/wjgo.v10.i1.1

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅