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Preoperative neutrophil-to-lymphocyte ratio is prognostic for early recurrence after curative intrahepatic cholangiocarcinoma resection

  • Woo Jin Choi (Department of Surgery, University of Toronto) ;
  • Fiorella Murillo Perez (Toronto Center for Liver Disease, University Health Network) ;
  • Annabel Gravely (Toronto Center for Liver Disease, University Health Network) ;
  • Tommy Ivanics (HPB Surgical Oncology, University Health Network) ;
  • Marco P. A. W. Claasen (HPB Surgical Oncology, University Health Network) ;
  • Liza Abraham (Department of Surgery, University of Toronto) ;
  • Phillipe Abreu (HPB Surgical Oncology, University Health Network) ;
  • Robin Visser (HPB Surgical Oncology, University Health Network) ;
  • Steven Gallinger (Department of Surgery, University of Toronto) ;
  • Bettina E. Hansen (Toronto Center for Liver Disease, University Health Network) ;
  • Gonzalo Sapisochin (Department of Surgery, University of Toronto)
  • Received : 2022.11.14
  • Accepted : 2022.12.27
  • Published : 2023.05.31

Abstract

Backgrounds/Aims: Within two years of surgery, 70% of resected intrahepatic cholangiocarcinoma (iCCA) recur. Better biomarkers are needed to identify those at risk of "early recurrence" (ER). In this study, we defined ER and investigated whether preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic-inflammatory index were prognostic of both overall relapse and ER after curative hepatectomy for iCCA. Methods: A retrospective cohort of patients who underwent curative-intent hepatectomy for iCCA between 2005 and 2017 were created. The cut-off timepoint for the ER of iCCA was estimated using a piecewise linear regression model. Univariable analyses of recurrence were conducted for the overall, early, and late recurrence periods. For the early and late recurrence periods, multivariable Cox regression with time-varying regression coefficient analysis was used. Results: A total of 113 patients were included in this study. ER was defined as recurrence within 12 months of a curative resection. Among the included patients, 38.1% experienced ER. In the univariable model, a higher preoperative NLR (> 4.3) was significantly associated with an increased risk of recurrence overall and in the first 12 months after curative surgery. In the multivariable model, a higher NLR was associated with a higher recurrence rate overall and in the ER period (≤ 12 months), but not in the late recurrence period. Conclusions: Preoperative NLR was prognostic of both overall recurrence and ER after curative iCCA resection. NLR is easily obtained before and after surgery and should be integrated into ER prediction tools to guide preoperative treatments and intensify postoperative follow-up.

Keywords

Acknowledgement

Woo Jin Choi has been supported by the Canadian Institutes of Health Research (CIHR) (FRN: 181365, 2022) for his PhD studies.

References

  1. Forner A, Vidili G, Rengo M, Bujanda L, Ponz-Sarvise M, Lamarca A. Clinical presentation, diagnosis and staging of cholangiocarcinoma. Liver Int 2019;39 Suppl 1:98-107.
  2. Todua F, Gagua R, Maglakelidze M, Maglakelidze D. Cancer incidence and mortality - major patterns in GLOBOCAN 2012, Worldwide and Georgia. Bull Georgian Natl Acad Sci 2015;9:168-173.
  3. Shaib YH, Davila JA, McGlynn K, El-Serag HB. Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? J Hepatol 2004;40:472-477.
  4. Flemming JA, Zhang-Salomons J, Nanji S, Booth CM. Increased incidence but improved median overall survival for biliary tract cancers diagnosed in Ontario from 1994 through 2012: a population-based study. Cancer 2016;122:2534-2543.
  5. Ali H, Tedder B, Waqar SH, Mohamed R, Cate EL, Ali E. Changing incidence and survival of intrahepatic cholangiocarcinoma based on Surveillance, Epidemiology, and End Results Database (2000-2017). Ann Hepatobiliary Pancreat Surg 2022;26:235-243.
  6. Javle M, Lee S, Azad NS, Borad MJ, Kate Kelley R, Sivaraman S, et al. Temporal changes in cholangiocarcinoma incidence and mortality in the United States from 2001 to 2017. Oncologist 2022;27:874-883.
  7. Waseem D, Tushar P. Intrahepatic, perihilar and distal cholangiocarcinoma: management and outcomes. Ann Hepatol 2017;16:133-139.
  8. Scott AJ, Shroff RT. Moving the needle forward with locoregional treatment in unresectable cholangiocarcinoma-the jury is still out. JAMA Oncol 2020;6:29-31.
  9. Hu LS, Zhang XF, Weiss M, Popescu I, Marques HP, Aldrighetti L, et al. Recurrence patterns and timing courses following curative-intent resection for intrahepatic cholangiocarcinoma. Ann Surg Oncol 2019;26:2549-2557.
  10. Bridgewater J, Galle PR, Khan SA, Llovet JM, Park JW, Patel T, et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol 2014;60:1268-1289.
  11. Tsilimigras DI, Sahara K, Wu L, Moris D, Bagante F, Guglielmi A, et al. Very early recurrence after liver resection for intrahepatic cholangiocarcinoma: considering alternative treatment approaches. JAMA Surg 2020;155:823-831.
  12. Yang H, Wang J, Li Z, Yang Y, Yang L, Zhang Y, et al. Risk factors and outcomes of early relapse after curative resection of intrahepatic cholangiocarcinoma. Front Oncol 2019;9:854.
  13. Zhang Y, Shi SM, Yang H, Yang LX, Wang Z, Li XD, et al. Systemic inflammation score predicts survival in patients with intrahepatic cholangiocarcinoma undergoing curative resection. J Cancer 2019;10:494-503.
  14. Wang C, Pang S, Si-Ma H, Yang N, Zhang H, Fu Y, et al. Specific risk factors contributing to early and late recurrences of intrahepatic cholangiocarcinoma after curative resection. World J Surg Oncol 2019;17:2.
  15. Yadav S, Xie H, Bin-Riaz I, Sharma P, Durani U, Goyal G, et al. Neoadjuvant vs. adjuvant chemotherapy for cholangiocarcinoma: a propensity score matched analysis. Eur J Surg Oncol 2019;45:1432-1438.
  16. Hu HJ, Jin YW, Shrestha A, Ma WJ, Wang JK, Liu F, et al. Predictive factors of early recurrence after R0 resection of hilar cholangiocarcinoma: a single institution experience in China. Cancer Med 2019;8:1567-1575.
  17. Shimoda M, Maruyama T, Suzuki K, Tago T, Nishida K, Shimazaki J, et al. Risk factors for recurrence of hepatocellular carcinoma after curative resection. Surg Gastroenterol Oncol 2018;23:314-319.
  18. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008;454:436-444.
  19. Sellers CM, Uhlig J, Ludwig JM, Stein SM, Kim HS. Inflammatory markers in intrahepatic cholangiocarcinoma: effects of advanced liver disease. Cancer Med 2019;8:5916-5929.
  20. Chen Q, Yang LX, Li XD, Yin D, Shi SM, Chen EB, et al. The elevated preoperative neutrophil-to-lymphocyte ratio predicts poor prognosis in intrahepatic cholangiocarcinoma patients undergoing hepatectomy. Tumour Biol 2015;36:5283-5289.
  21. Lin G, Liu Y, Li S, Mao Y, Wang J, Shuang Z, et al. Elevated neutrophil-to-lymphocyte ratio is an independent poor prognostic factor in patients with intrahepatic cholangiocarcinoma. Oncotarget 2016;7:50963-50971.
  22. Ohira M, Yoshizumi T, Yugawa K, Kosai-Fujimoto Y, Inokuchi S, Motomura T, et al. Association of inflammatory biomarkers with long-term outcomes after curative surgery for mass-forming intrahepatic cholangiocarcinoma. Surg Today 2020;50:379-388.
  23. Buettner S, Galjart B, van Vugt JLA, Bagante F, Alexandrescu S, Marques HP, et al. Performance of prognostic scores and staging systems in predicting long-term survival outcomes after surgery for intrahepatic cholangiocarcinoma. J Surg Oncol 2017;116:1085-1095.
  24. Tan DW, Fu Y, Su Q, Guan MJ, Kong P, Wang SQ, et al. Prognostic significance of neutrophil to lymphocyte ratio in oncologic outcomes of cholangiocarcinoma: a meta-analysis. Sci Rep 2016;6:33789.
  25. Tsilimigras DI, Moris D, Mehta R, Paredes AZ, Sahara K, Guglielmi A, et al. The systemic immune-inflammation index predicts prognosis in intrahepatic cholangiocarcinoma: an international multi-institutional analysis. HPB (Oxford) 2020;22:1667-1674.
  26. Zhang Z, Zhou Y, Hu K, Huang Y. Investigating effects of preoperative inflammatory biomarkers on predicting survival outcomes of intrahepatic cholangiocarcinoma after curative resection. World J Surg Oncol 2020;18:272.
  27. Yoh T, Seo S, Hatano E, Taura K, Fuji H, Ikeno Y, et al. A novel biomarker-based preoperative prognostic grading system for predicting survival after surgery for intrahepatic cholangiocarcinoma. Ann Surg Oncol 2017;24:1351-1357.
  28. Tsilimigras DI, Hyer JM, Paredes AZ, Diaz A, Moris D, Guglielmi A, et al. A novel classification of intrahepatic cholangiocarcinoma phenotypes using machine learning techniques: an international multi-institutional analysis. Ann Surg Oncol 2020;27:5224-5232.
  29. Sasaki K, Margonis GA, Andreatos N, Bagante F, Weiss M, Barbon C, et al. Preoperative risk score and prediction of long-term outcomes after hepatectomy for intrahepatic cholangiocarcinoma. J Am Coll Surg 2018;226:393-403.
  30. Tsilimigras DI, Mehta R, Aldrighetti L, Poultsides GA, Maithel SK, Martel G, et al. Development and validation of a laboratory risk score (LabScore) to predict outcomes after resection for intrahepatic cholangiocarcinoma. J Am Coll Surg 2020;230:381-391.e2.
  31. Bartsch F, Hahn F, Muller L, Baumgart J, Hoppe-Lotichius M, Kloeckner R, et al. Intrahepatic cholangiocarcinoma: introducing the preoperative prediction score based on preoperative imaging. Hepatobiliary Pancreat Dis Int 2021;20:262-270.
  32. Choi WJ, Cleghorn MC, Jiang H, Jackson TD, Okrainec A, Quereshy FA. Preoperative neutrophil-to-lymphocyte ratio is a better prognostic serum biomarker than platelet-to-lymphocyte ratio in patients undergoing resection for nonmetastatic colorectal cancer. Ann Surg Oncol 2015;22 Suppl 3:S603-S613.
  33. Kitano Y, Yamashita YI, Yamamura K, Arima K, Kaida T, Miyata T, et al. Effects of preoperative neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios on survival in patients with extrahepatic cholangiocarcinoma. Anticancer Res 2017;37:3229-3237.
  34. Lausen B, Hothorn T, Bretz F, Schumacher M. Assessment of optimal selected prognostic factors. Biom J 2004;46:364-374.
  35. Hothorn T, Lausen B. On the exact distribution of maximally selected rank statistics. Comput Stat Data Anal 2003;43:121-137.
  36. R Core Team. A language and environment for statistical computing [Internet]. Vienna: R Foundation for Statistical Computing 2016 [cited 2022 Dec 16]. Available from: https://www.R-project.org/.
  37. Zhang XF, Beal EW, Bagante F, Chakedis J, Weiss M, Popescu I, et al. Early versus late recurrence of intrahepatic cholangiocarcinoma after resection with curative intent. Br J Surg 2018;105:848-856.
  38. Jung SM, Kim JM, Choi GS, Kwon CHD, Yi NJ, Lee KW, et al. Characteristics of early recurrence after curative liver resection for solitary hepatocellular carcinoma. J Gastrointest Surg 2019;23:304-311.
  39. Imamura H, Matsuyama Y, Tanaka E, Ohkubo T, Hasegawa K, Miyagawa S, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol 2003;38:200-207.
  40. Sahara K, Tsilimigras DI, Toyoda J, Miyake K, Ethun CG, Maithel SK, et al. Defining the risk of early recurrence following curative-intent resection for distal cholangiocarcinoma. Ann Surg Oncol 2021;28:4205-4213.
  41. Akateh C, Ejaz AM, Pawlik TM, Cloyd JM. Neoadjuvant treatment strategies for intrahepatic cholangiocarcinoma. World J Hepatol 2020;12:693-708.
  42. Howard R, Kanetsky PA, Egan KM. Exploring the prognostic value of the neutrophil-to-lymphocyte ratio in cancer. Sci Rep 2019;9:19673.
  43. Park HM, Yun SP, Lee EC, Lee SD, Han SS, Kim SH, et al. Outcomes for patients with recurrent intrahepatic cholangiocarcinoma after surgery. Ann Surg Oncol 2016;23:4392-4400.
  44. Saiura A, Yamamoto J, Kokudo N, Koga R, Seki M, Hiki N, et al. Intrahepatic cholangiocarcinoma: analysis of 44 consecutive resected cases including 5 cases with repeat resections. Am J Surg 2011;201:203-208.
  45. Bartolini I, Risaliti M, Fortuna L, Agostini C, Ringressi MN, Taddei A, et al. Current management of intrahepatic cholangiocarcinoma: from resection to palliative treatments. Radiol Oncol 2020;54:263-271.
  46. Mavros MN, Economopoulos KP, Alexiou VG, Pawlik TM. Treatment and prognosis for patients with intrahepatic cholangiocarcinoma: systematic review and meta-analysis. JAMA Surg 2014;149:565-574.
  47. Zhang XF, Xue F, Dong DH, Weiss M, Popescu I, Marques HP, et al. Number and station of lymph node metastasis after curative-intent resection of intrahepatic cholangiocarcinoma impact prognosis. Ann Surg 2021;274:e1187-e1195.