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Objective: Systemic inflammatory markers have been shown to have prognostic value in many types of cancers. Although the prognostic role of the systemic immune-inflammation index (SII), derived neutrophil-lymphocyte ratio (dNLR) and platelet lymphocyte ratio (PLR) has been shown in hepatocellular cancer (HCC) patients who underwent transplantation, its prognostic value has not been investigated in HCC patients under sorafenib treatment. We investigated the prognostic value of inflammatory indices in patients with HCC under sorafenib treatment.
Materials and Methods: The data of 46 patients with stage III unresectable and stage IV HCC were evaluated retrospectively. SII and dNLR were dichotomized based on receiver operating characteristic (ROC) curve analysis (cut-off values: 355 and 1.8). No cut-off value could be determined for PLR; therefore, the median value was defined as the cut-off for PLR. At the time of diagnosis, values of these three inflammatory markers were analyzed to determine their association with clinicopathologic characteristics and to assess their prognostic values via the Kaplan-Meier method and multivariate Cox regression analysis.
Results: Overall survival (OS) was significantly shorter in patients with a high SII, dNLR, or PLR. In univariate analyses, tumor stage, tumor focus count, and presence of extrahepatic lesions seemed to affect survival. Multivariate analysis revealed SII and the presence of extrahepatic lesions as independent risk factors for survival.
Conclusion: The findings of the present study suggest that a high SII is an independent risk factor for survival in patients with HCC under sorafenib treatment.
2. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86.
3. Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006;66(24):11851–8.
4. Rovesti G, Orsi G, Kalliopi A, Vivaldi C, Marisi G, Faloppi L, et al. Impact of Baseline Characteristics on the Overall Survival of HCC Patients Treated with Sorafenib: Ten Years of Experience. Gastrointest Tumors. 2019;6(3–4):92–107.
5. Reig M, Torres F, Rodriguez-Lope C, Forner A, Llarch N, Rimola J, et al. Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J Hepatol [Internet]. 2014;61(2):318–24. Available from: http://dx.doi.org/10.1016/j.jhep.2014.03.030
6. Bettinger D, Schultheiß M, Knüppel E, Thimme R, Blum HE, Spangenberg HC. Diarrhea predicts a positive response to sorafenib in patients with advanced hepatocellular carcinoma. Hepatology. 2012;56(2):789–90.
7. Llovet JM, Peña CEA, Lathia CD, Shan M, Meinhardt G, Bruix J. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2012;18(8):2290–300.
8. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436–44.
9. Zhong J-H, Huang D-H, Chen Z-Y. Oncotarget 75381 www.impactjournals.com/oncotarget Prognostic role of systemic immune-inflammation index in solid tumors: a systematic review and meta-analysis. Oncotarget [Internet]. 2017;8(43):75381–8. Available from: www.impactjournals.com/oncotarget/
10. Zou ZY, Liu HL, Ning N, Li SY, Du XH, Li R. Clinical significance of pre-operative neutrophil lymphocyte ratio and platelet lymphocyte ratio as prognostic factors for patients with colorectal cancer. Oncol Lett. 2016;11(3):2241–8.
11. Yamada Y, Sakamoto S, Rii J, Yamamoto S, Kamada S, Imamura Y, et al. Prognostic value of an inflammatory index for patients with metastatic castration-resistant prostate cancer. Prostate. 2020;(February).
12. Hu B, Yang XR, Xu Y, Sun YF, Sun C, Guo W, et al. Systemic immune-inflammation index predicts prognosis of patients after curative resection for hepatocellular carcinoma. Clin Cancer Res. 2014;20(23):6212–22.
13. Hong X, Cui B, Wang M, Yang Z, Wang L, Xu Q. Systemic immune-inflammation index, based on platelet counts and neutrophil-lymphocyte ratio, is useful for predicting prognosis in small cell lung cancer. Tohoku J Exp Med. 2015;236(4):297–304.
14. Lolli C, Caffo O, Scarpi E, Aieta M, Conteduca V, Maines F, et al. Systemic immune-inflammation index predicts the clinical outcome in patients with mCRPC treated with abiraterone. Front Pharmacol. 2016;7(OCT):1–7.
15. Shao YY, Lin ZZ, Hsu C, Shen YC, Hsu CH, Cheng AL. Early alpha-fetoprotein response predicts treatment efficacy of antiangiogenic systemic therapy in patients with advanced hepatocellular carcinoma. Cancer. 2010;116(19):4590–6.
16. Ismael MN, Forde J, Milla E, Khan W, Cabrera R. Utility of inflammatory markers in predicting hepatocellular carcinoma survival after liver transplantation. Biomed Res Int. 2019;2019:5–8.
17. Bambace NM, Holmes CE. The platelet contribution to cancer progression. J Thromb Haemost. 2011;9(2):237–49.
18. Jensen HK, Donskov F, Marcussen N, Nordsmark M, Lundbeck F, Von Der Maase H. Presence of intratumoral neutrophils is an independent prognostic factor in localized renal cell carcinoma. J Clin Oncol. 2009;27(28):4709–17.
19. Kuang DM, Zhao Q, Wu Y, Peng C, Wang J, Xu Z, et al. Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J Hepatol [Internet]. 2011;54(5):948–55. Available from: http://dx.doi.org/10.1016/j.jhep.2010.08.041
20. Fossati G, Ricevuti G, Edwards SW, Walker C, Dalton A, Rossi ML. Neutrophil infiltration into human gliomas. Acta Neuropathol. 1999;98(4):349–54.
21. Ferrone C, Dranoff G. Dual roles for immunity in gastrointestinal cancers. J Clin Oncol. 2010;28(26):4045–51.
22. Russo A, Franchina T, Ricciardi GRR, Battaglia A, Scimone A, Berenato R, et al. Baseline neutrophilia, derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), and outcome in non small cell lung cancer (NSCLC) treated with Nivolumab or Docetaxel. J Cell Physiol. 2018;233(10):6337–43.
23. Proctor MJ, McMillan DC, Morrison DS, Fletcher CD, Horgan PG, Clarke SJ. A derived neutrophil to lymphocyte ratio predicts survival in patients with cancer. Br J Cancer [Internet]. 2012;107(4):695–9. Available from: http://dx.doi.org/10.1038/bjc.2012.292
24. Li P, Huang W, Wang F, Ke YF, Gao L, Shi KQ, et al. Nomograms based on inflammatory biomarkers for predicting tumor grade and micro-vascular invasion in stage I/II hepatocellular carcinoma. Vol. 38, Bioscience Reports. 2018.
25. Liu L, Gong Y, Zhang Q, Cai P, Feng L. Prognostic Roles of Blood Inflammatory Markers in Hepatocellular Carcinoma Patients Taking Sorafenib. A Systematic Review and Meta-Analysis. Front Oncol. 2020;9(January):1–10.
26. Kusumanto YH, Dam WA, Hospers GAP, Meijer C, Mulder NH. Platelets and granulocytes, in particular the neutrophils, form important compartments for circulating vascular endothelial growth factor. Angiogenesis. 2003;6(4):283–7.
27. Cools-Lartigue J, Spicer J, McDonald B, Gowing S, Chow S, Giannias B, et al. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J Clin Invest. 2013; 123:3446-58.
28. Gil-Bernabé AM, Ferjančič Š, Tlalka M, Zhao L, Allen PD, Im JH, et al. Recruitment of monocytes/macrophages by tissue factor-mediated coagulation is essential for metastatic cell survival and premetastatic niche establishment in mice. Blood. 2012;119(13):3164–75.
29. Liyanage UK, Moore TT, Joo H-G, Tanaka Y, Herrmann V, Doherty G, et al. Prevalence of Regulatory T Cells Is Increased in Peripheral Blood and Tumor Microenvironment of Patients with Pancreas or Breast Adenocarcinoma. J Immunol. 2002;169(5):2756–61.
30. Clark EJ, Connor S, Taylor MA, Madhavan KK, Garden OJ, Parks RW. Preoperative lymphocyte count as a prognostic factor in resected pancreatic ductal adenocarcinoma. Hpb. 2007;9(6):456–60.
31. Ding PR, An X, Zhang RX, Fang YJ, Li LR, Chen G, et al. Elevated preoperative neutrophil to lymphocyte ratio predicts risk of recurrence following curative resection for stage IIA colon cancer. Int J Colorectal Dis. 2010;25(12):1427–33.
32. Feng JF, Chen S, Yang X. Systemic immune-inflammation index (SII) is a useful prognostic indicator for patients with squamous cell carcinoma of the esophagus. Med (United States). 2017;96(4):0–5.
33. Lolli C, Basso U, Derosa L, Scarpi E, Sava T, Santoni M, Crabb SJ, Massari F, Aieta M, Conteduca V, Maruzzo M, La Russa F, Wheater M, et al. Systemic immune-inflammation index predicts the clinical outcome in patients with metastatic renal cell cancer treated with sunitinib. Oncotarget. 2016; 7:54564-71. https://doi.org/10.18632/ oncotarget.10515.