Prognostic Value of the Systemic Immune-Inflammation Index (SII) After Neoadjuvant Therapy for Patients with Resected Pancreatic Cancer

  • Pranav Murthy
  • Mazen S. Zenati
  • Amr I. Al Abbas
  • Caroline J. Rieser
  • Nathan Bahary
  • Michael T. Lotze
  • Herbert J. ZehIII
  • Amer H. Zureikat
  • Brian A. BooneEmail author
Pancreatic Tumors



The systemic immune-inflammation index (SII), calculated using absolute platelet, neutrophil, and lymphocyte counts, has recently emerged as a predictor of survival for patients with pancreatic ductal adenocarcinoma (PDAC) when assessed at diagnosis. Neoadjuvant therapy (NAT) is increasingly used in the treatment of PDAC. However, biomarkers of response are lacking. This study aimed to determine the prognostic significance of SII before and after NAT and its association with the pancreatic tumor biomarker carbohydrate-antigen 19-9 (CA 19-9).


This study retrospectively analyzed all PDAC patients treated with NAT before pancreatic resection at a single institution between 2007 and 2017. Pre- and post-NAT lab values were collected to calculate SII. Absolute pre-NAT, post-NAT, and change in SII after NAT were evaluated for their association with clinical outcomes.


The study analyzed 419 patients and found no significant correlation between pre-NAT SII and clinical outcomes. Elevated post-NAT SII was an independent, negative predictor of overall survival (OS) when assessed as a continuous variable (hazard ratio [HR], 1.0001; 95% confidence interval [CI] 1.00003–1.00014; p = 0.006). Patients with a post-NAT SII greater than 900 had a shorter median OS (31.9 vs 26.1 months; p = 0.050), and a post-NAT SII greater than 900 also was an independent negative predictor of OS (HR, 1.369; 95% CI 1.019–1.838; p = 0.037). An 80% reduction in SII independently predicted a CA 19-9 response after NAT (HR, 4.22; 95% CI 1.209–14.750; p = 0.024).


Post-treatment SII may be a useful prognostic marker in PDAC patients receiving NAT.



Dr. Nathan Bahary has held Advisory Roles/Boards for BioLIneRx, AstraZeneca, Exelixis, BMS, and Thermo Fisher. The remaining authors declare no conflict of interests.

Supplementary material

10434_2019_8094_MOESM1_ESM.docx (38 kb)
Supplementary material 1 (DOCX 39 kb)


  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.PubMedCrossRefGoogle Scholar
  2. 2.
    Aier I, Semwal R, Sharma A, Varadwaj PK. A systematic assessment of statistics, risk factors, and underlying features involved in pancreatic cancer. Cancer Epidemiol. 2018;58:104–10.PubMedCrossRefGoogle Scholar
  3. 3.
    Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913–21.PubMedCrossRefGoogle Scholar
  4. 4.
    Yamamoto T, Yagi S, Kinoshita H, et al. Long-term survival after resection of pancreatic cancer: a single-center retrospective analysis. World J Gastroenterol. 2015;21:262–8.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Lopez NE, Prendergast C, Lowy AM. Borderline resectable pancreatic cancer: definitions and management. World J Gastroenterol. 2014;20:10740–51.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Ferrone CR, Marchegiani G, Hong TS, et al. Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer. Ann Surg. 2015;261:12–7.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Yeung RS, Weese JL, Hoffman JP, et al. Neoadjuvant chemoradiation in pancreatic and duodenal carcinoma: a Phase II study. Cancer. 1993;72:2124–33.PubMedCrossRefGoogle Scholar
  8. 8.
    Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas. J Clin Oncol. 1997;15:928–37.PubMedCrossRefGoogle Scholar
  9. 9.
    Mokdad AA, Minter RM, Zhu H, et al. Neoadjuvant therapy followed by resection versus upfront resection for resectable pancreatic cancer: a propensity score-matched analysis. J Clin Oncol. 2017;35:515–22.PubMedCrossRefGoogle Scholar
  10. 10.
    Katz MH, Fleming JB, Bhosale P, et al. Response of borderline resectable pancreatic cancer to neoadjuvant therapy is not reflected by radiographic indicators. Cancer. 2012;118:5749–56.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Christians KK, Tsai S, Mahmoud A, et al. Neoadjuvant FOLFIRINOX for borderline resectable pancreas cancer: a new treatment paradigm? Oncologist. 2014;19:266–74.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Wagner M, Antunes C, Pietrasz D, et al. CT evaluation after neoadjuvant FOLFIRINOX chemotherapy for borderline and locally advanced pancreatic adenocarcinoma. Eur Radiol. 2017;27:3104–16.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Kluger MD, Rashid MF, Rosario VL, et al. Resection of locally advanced pancreatic cancer without regression of arterial encasement after modern-era neoadjuvant therapy. J Gastrointest Surg. 2018;22:235–41.PubMedCrossRefGoogle Scholar
  14. 14.
    Cassinotto C, Sa-Cunha A, Trillaud H. Radiological evaluation of response to neoadjuvant treatment in pancreatic cancer. Diagn Interv Imaging. 2016;97:1225–32.PubMedCrossRefGoogle Scholar
  15. 15.
    Boone BA, Steve J, Zenati MS, et al. Serum CA 19-9 response to neoadjuvant therapy is associated with outcome in pancreatic adenocarcinoma. Ann Surg Oncol. 2014;21:4351–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Tzeng CW, Balachandran A, Ahmad M, et al. Serum carbohydrate antigen 19-9 represents a marker of response to neoadjuvant therapy in patients with borderline resectable pancreatic cancer. HPB Oxford. 2014;16:430–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Ballehaninna UK, Chamberlain RS. Serum CA 19-9 as a biomarker for pancreatic cancer: a comprehensive review. Indian J Surg Oncol. 2011;2:88–100.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Poruk KE, Gay DZ, Brown K, et al. The clinical utility of CA 19-9 in pancreatic adenocarcinoma: diagnostic and prognostic updates. Curr Mol Med. 2013;13:340–51.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Nishihara S, Yazawa S, Iwasaki H, et al. Alpha (1,3/1,4)fucosyltransferase (FucT-III) gene is inactivated by a single amino acid substitution in Lewis histo-blood-type-negative individuals. Biochem Biophys Res Commun. 1993;196:624–31.PubMedCrossRefGoogle Scholar
  20. 20.
    Haab BB, Huang Y, Balasenthil S, et al. Definitive characterization of CA 19-9 in resectable pancreatic cancer using a reference set of serum and plasma specimens. PLoS One. 2015;10:e0139049.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.PubMedCrossRefGoogle Scholar
  22. 22.
    Hausmann S, Kong B, Michalski C, Erkan M, Friess H. The role of inflammation in pancreatic cancer. Adv Exp Med Biol. 2014;816:129–51.PubMedCrossRefGoogle Scholar
  23. 23.
    Hu B, Yang XR, Xu Y, et al. Systemic immune-inflammation index predicts prognosis of patients after curative resection for hepatocellular carcinoma. Clin Cancer Res. 2014;20:6212–22.PubMedCrossRefGoogle Scholar
  24. 24.
    Aziz MH, Sideras K, Aziz NA, et al. The systemic-immune-inflammation index independently predicts survival and recurrence in resectable pancreatic cancer and its prognostic value depends on bilirubin levels: a retrospective multicenter cohort study. Ann Surg. 2018;270:139–46.CrossRefGoogle Scholar
  25. 25.
    Jomrich G, Gruber ES, Winkler D, et al. Systemic Immune-Inflammation Index (SII) predicts poor survival in pancreatic cancer patients undergoing resection. J Gastrointest Surg. 2019. Scholar
  26. 26.
    Rieser CJ, Zenati M, Hamad A, et al. CA19-9 on postoperative surveillance in pancreatic ductal adenocarcinoma: predicting recurrence and changing prognosis over time. Ann Surg Oncol. 2018;25:3483–91.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Belli C, Cereda S, Anand S, Reni M. Neoadjuvant therapy in resectable pancreatic cancer: a critical review. Cancer Treat Rev. 2013;39:518–24.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Zhan HX, Xu JW, Wu D, et al. Neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of prospective studies. Cancer Med. 2017;6:1201–19.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Epelboym I, Zenati MS, Hamad A, et al. Analysis of perioperative chemotherapy in resected pancreatic cancer: identifying the number and sequence of chemotherapy cycles needed to optimize survival. Ann Surg Oncol. 2017;24:2744–51.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Zhang Y, Lin S, Yang X, Wang R, Luo L. Prognostic value of pretreatment systemic immune-inflammation index in patients with gastrointestinal cancers. J Cell Physiol. 2019;234:5555–63.PubMedCrossRefGoogle Scholar
  31. 31.
    Zhong JH, Huang DH, Chen ZY. Prognostic role of systemic immune-inflammation index in solid tumors: a systematic review and meta-analysis. Oncotarget. 2017;8:75381–8.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Zhang K, Hua YQ, Wang D, et al. Systemic immune-inflammation index predicts prognosis of patients with advanced pancreatic cancer. J Transl Med. 2019;17:30.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Dhir M, Zenati MS, Hamad A, et al. FOLFIRINOX versus gemcitabine/nab-paclitaxel for neoadjuvant treatment of resectable and borderline resectable pancreatic head adenocarcinoma. Ann Surg Oncol. 2018;25:1896–903.PubMedCrossRefGoogle Scholar
  34. 34.
    Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018;379:2395–406.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    McKay CJ, Glen P, McMillan DC. Chronic inflammation and pancreatic cancer. Best Pract Res Clin Gastroenterol. 2008;22:65–73.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Guerra C, Collado M, Navas C, et al. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell. 2011;19:728–39.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Guerra C, Schuhmacher AJ, Canamero M, et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell. 2007;11:291–302.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Kirkegard J, Mortensen FV, Cronin-Fenton D. Chronic pancreatitis and pancreatic cancer risk: a systematic review and meta-analysis. Am J Gastroenterol. 2017;112:1366–72.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Coffelt SB, Wellenstein MD, de Visser KE. Neutrophils in cancer: neutral no more. Nat Rev Cancer. 2016;16:431–46.PubMedCrossRefGoogle Scholar
  40. 40.
    Di Mitri D, Toso A, Chen JJ, et al. Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer. Nature. 2014;515:134–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol. 2011;11:519–31.PubMedCrossRefGoogle Scholar
  42. 42.
    Murthy P, Singhi AD, Ross MA, et al. Enhanced neutrophil extracellular trap formation in acute pancreatitis contributes to disease severity and is reduced by chloroquine. Frontiers Immunol. 2019;10:28.CrossRefGoogle Scholar
  43. 43.
    Merza M, Hartman H, Rahman M, et al. Neutrophil extracellular traps induce trypsin activation, inflammation, and tissue damage in mice with severe acute pancreatitis. Gastroenterology. 2015;149:1920–31.PubMedCrossRefGoogle Scholar
  44. 44.
    Boone BA, Orlichenko L, Schapiro NE, et al. The receptor for advanced glycation end products (RAGE) enhances autophagy and neutrophil extracellular traps in pancreatic cancer. Cancer Gene Ther. 2015;22:326–34.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Boone BA, Murthy P, Miller-Ocuin J, et al. Chloroquine reduces hypercoagulability in pancreatic cancer through inhibition of neutrophil extracellular traps. BMC Cancer. 2018;18:678.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Cools-Lartigue J, Spicer J, McDonald B, et al. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J Clin Investig. 2013;123:3446–58.CrossRefGoogle Scholar
  47. 47.
    Bald T, Quast T, Landsberg J, et al. Ultraviolet radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature. 2014;507:109–13.PubMedCrossRefGoogle Scholar
  48. 48.
    Lee W, Ko SY, Mohamed MS, Kenny HA, Lengyel E, Naora H. Neutrophils facilitate ovarian cancer premetastatic niche formation in the omentum. J Exp Med. 2019;216:176–94.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Gaida MM, Gunther F, Wagner C, et al. Expression of the CXCR6 on polymorphonuclear neutrophils in pancreatic carcinoma and in acute, localized bacterial infections. Clin Exp Immunol. 2008;154:216–23.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Chao T, Furth EE, Vonderheide RH. CXCR2-dependent accumulation of tumor-associated neutrophils regulates T-cell immunity in pancreatic ductal adenocarcinoma. Cancer Immunol Res. 2016;4:968–82.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Khorana AA, Fine RL. Pancreatic cancer and thromboembolic disease. Lancet Oncol. 2004;5:655–63.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Boone BA, Zenati MS, Rieser C, et al. Risk of venous thromboembolism for patients with pancreatic ductal adenocarcinoma undergoing preoperative chemotherapy followed by surgical resection. Ann Surg Oncol. 2019;26:1503–11.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Ansari D, Ansari D, Andersson R, Andren-Sandberg A. Pancreatic cancer and thromboembolic disease 150 years after Trousseau. Hepatobiliary Surg Nutr. 2015;4:325–35.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Meikle CK, Kelly CA, Garg P, Wuescher LM, Ali RA, Worth RG. Cancer and thrombosis: the platelet perspective. Front Cell Dev Biol. 2016;4:147.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Coupland LA, Chong BH, Parish CR. Platelets and P-selectin control tumor cell metastasis in an organ-specific manner and independently of NK cells. Cancer Res. 2012;72:4662–71.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Varon D, Hayon Y, Dashevsky O, Shai E. Involvement of platelet-derived microparticles in tumor metastasis and tissue regeneration. Thromb Res. 2012;130(Suppl 1):S98–99.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Dashevsky O, Varon D, Brill A. Platelet-derived microparticles promote invasiveness of prostate cancer cells via upregulation of MMP-2 production. Int J Cancer. 2009;124:1773–7.PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2019

Authors and Affiliations

  • Pranav Murthy
    • 1
  • Mazen S. Zenati
    • 1
    • 2
  • Amr I. Al Abbas
    • 1
  • Caroline J. Rieser
    • 1
  • Nathan Bahary
    • 3
    • 4
  • Michael T. Lotze
    • 1
    • 5
    • 6
  • Herbert J. ZehIII
    • 7
  • Amer H. Zureikat
    • 1
  • Brian A. Boone
    • 8
    Email author
  1. 1.Department of SurgeryUniversity of PittsburghPittsburghUSA
  2. 2.Department of EpidemiologyUniversity of PittsburghPittsburghUSA
  3. 3.Department of Internal MedicineUniversity of PittsburghPittsburghUSA
  4. 4.Department of Molecular Genetics and BiochemistryUniversity of PittsburghPittsburghUSA
  5. 5.Department of ImmunologyUniversity of PittsburghPittsburghUSA
  6. 6.Department of BioengineeringUniversity of PittsburghPittsburghUSA
  7. 7.Department of SurgeryUniversity of Texas SouthwesternDallasUSA
  8. 8.Department of SurgeryWest Virginia UniversityMorgantownUSA

Personalised recommendations