Skip to main content
SpringerLink
Log in

Predictive Impact of Peripheral Blood Markers and C-Reactive Protein in Nivolumab Therapy for Metastatic Renal Cell Carcinoma

  • Original Research Article
  • Published:
Targeted Oncology Aims and scope Submit manuscript

Abstract

Background

Predictive factors that can be routinely used in clinical practice are critically needed for immune checkpoint inhibitor therapy in metastatic renal cell carcinoma (mRCC).

Objective

To comprehensively analyze the predictive impact of peripheral blood markers and C-reactive protein (CRP) in nivolumab therapy for mRCC.

Methods

Fifty-eight patients were retrospectively evaluated. We evaluated neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), absolute eosinophil count (AEC), and absolute monocyte count (AMC) as peripheral blood markers as well as serum CRP levels. The primary endpoints were progression-free survival (PFS) and overall survival (OS) after nivolumab initiation.

Results

Median PFS was significantly shorter in patients with high NLR (≥ 3) versus low NLR (p = 0.0356), high MLR (≥ 0.3) versus low MLR (p = 0.0013), or high PLR (≥ 160) versus low PLR (p = 0.0073), and median OS was significantly shorter in patients with high NLR versus low NLR (p = 0.0025), high MLR versus low MLR (p = 0.0025), high PLR versus low PLR (p = 0.0256), or high CRP (≥ 1.0 mg/dl) versus low CRP (p = 0.0006). Multivariate analyses showed that MLR (HR 2.65, p = 0.0068) was an independent factor for PFS and that NLR (HR 3.34, p = 0.0218), MLR (HR 3.42, p = 0.0381), and CRP (HR 4.98, p = 0.0108) were independent factors for OS.

Conclusions

The systemic inflammatory factors NLR, MLR, and CRP were predictive factors in nivolumab therapy for mRCC. These easily monitored factors can contribute to effective treatment and follow-up.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Ljungberg B, Albiges L, Abu-Ghanem Y, Bensalah K, Dabestani S, Montes SF, et al. European Association of Urology guidelines on renal cell carcinoma: the 2019 update. Eur Urol. 2019. https://doi.org/10.1016/j.eururo.2019.02.011.

    Article  PubMed  Google Scholar 

  2. George S, Rini BI, Hammers HJ. Emerging role of combination immunotherapy in the first-line treatment of advanced renal cell carcinoma: a review. JAMA Oncol. 2018. https://doi.org/10.1001/jamaoncol.2018.4604.

    Article  PubMed  Google Scholar 

  3. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–13. https://doi.org/10.1056/NEJMoa1510665.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277–90. https://doi.org/10.1056/NEJMoa1712126.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. De Giorgi U, Carteni G, Giannarelli D, Basso U, Galli L, Cortesi E, et al. Safety and efficacy of nivolumab for metastatic renal cell carcinoma: real-world results from an expanded access programme. BJU Int. 2018. https://doi.org/10.1111/bju.14461.

    Article  PubMed  Google Scholar 

  6. Zahoor H, Barata PC, Jia X, Martin A, Allman KD, Wood LS, et al. Patterns, predictors and subsequent outcomes of disease progression in metastatic renal cell carcinoma patients treated with nivolumab. J Immunother Cancer. 2018;6(1):107. https://doi.org/10.1186/s40425-018-0425-8.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Ishihara H, Takagi T, Kondo T, Tachibana H, Fukuda H, Yoshida K, et al. Correlation between the magnitude of best tumor response and patient survival in nivolumab therapy for metastatic renal cell carcinoma. Med Oncol (Northwood, London, England). 2019;36(4):35. https://doi.org/10.1007/s12032-019-1261-5.

    Article  Google Scholar 

  8. Champiat S, Dercle L, Ammari S, Massard C, Hollebecque A, Postel-Vinay S, et al. Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1. Clin Cancer Res. 2017;23(8):1920–8. https://doi.org/10.1158/1078-0432.ccr-16-1741.

    Article  CAS  PubMed  Google Scholar 

  9. Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res. 2017;23(15):4242–50. https://doi.org/10.1158/1078-0432.ccr-16-3133.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Ishihara H, Kondo T, Takagi T, Tachibana H, Fukuda H, Yoshida K, et al. Immediate progressive disease in patients with metastatic renal cell carcinoma treated with nivolumab: a multi-institution retrospective study. Target Oncol. 2018;13(5):611–9. https://doi.org/10.1007/s11523-018-0591-0.

    Article  PubMed  Google Scholar 

  11. Verma V, Sprave T, Haque W, Simone CB 2nd, Chang JY, Welsh JW, et al. A systematic review of the cost and cost-effectiveness studies of immune checkpoint inhibitors. J Immunother Cancer. 2018;6(1):128. https://doi.org/10.1186/s40425-018-0442-7.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Tanaka N, Mizuno R, Yasumizu Y, Ito K, Shirotake S, Masunaga A, et al. Prognostic value of neutrophil-to-lymphocyte ratio in patients with metastatic renal cell carcinoma treated with first-line and subsequent second-line targeted therapy: a proposal of the modified-IMDC risk model. Urol Oncol. 2017;35(2):39.e19–28. https://doi.org/10.1016/j.urolonc.2016.10.001.

    Article  Google Scholar 

  13. Teishima J, Kobatake K, Kitano H, Nagamatsu H, Sadahide K, Hieda K, et al. The impact of change in serum C-reactive protein level on the prediction of effects of molecular targeted therapy in patients with metastatic renal cell carcinoma. BJU Int. 2016;117(6b):E67–74. https://doi.org/10.1111/bju.13260.

    Article  CAS  PubMed  Google Scholar 

  14. Beuselinck B, Vano YA, Oudard S, Wolter P, De Smet R, Depoorter L, et al. Prognostic impact of baseline serum C-reactive protein in patients with metastatic renal cell carcinoma (RCC) treated with sunitinib. BJU Int. 2014;114(1):81–9. https://doi.org/10.1111/bju.12494.

    Article  CAS  PubMed  Google Scholar 

  15. Santoni M, De Giorgi U, Iacovelli R, Conti A, Burattini L, Rossi L, et al. Pre-treatment neutrophil-to-lymphocyte ratio may be associated with the outcome in patients treated with everolimus for metastatic renal cell carcinoma. Br J Cancer. 2013;109(7):1755–9. https://doi.org/10.1038/bjc.2013.522.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Keizman D, Ish-Shalom M, Huang P, Eisenberger MA, Pili R, Hammers H, et al. The association of pre-treatment neutrophil to lymphocyte ratio with response rate, progression free survival and overall survival of patients treated with sunitinib for metastatic renal cell carcinoma. Eur J Cancer (Oxford, England 1990). 2012;48(2):202–8. https://doi.org/10.1016/j.ejca.2011.09.001.

    Article  CAS  Google Scholar 

  17. Na N, Yao J, Cheng C, Huang Z, Hong L, Li H, et al. Meta-analysis of the efficacy of the pretreatment neutrophil-to-lymphocyte ratio as a predictor of prognosis in renal carcinoma patients receiving tyrosine kinase inhibitors. Oncotarget. 2016;7(28):44039–46. https://doi.org/10.18632/oncotarget.9836.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Ishihara H, Kondo T, Yoshida K, Omae K, Takagi T, Iizuka J, et al. Effect of systemic inflammation on survival in patients with metastatic renal cell carcinoma receiving second-line molecular-targeted therapy. Clin Genitourin Cancer. 2017;15(4):495–501. https://doi.org/10.1016/j.clgc.2017.01.018.

    Article  PubMed  Google Scholar 

  19. Ishihara H, Kondo T, Omae K, Takagi T, Iizuka J, Kobayashi H, et al. Sarcopenia and the modified glasgow prognostic score are significant predictors of survival among patients with metastatic renal cell carcinoma who are receiving first-line sunitinib treatment. Target Oncol. 2016;11(5):605–17. https://doi.org/10.1007/s11523-016-0430-0.

    Article  PubMed  Google Scholar 

  20. Nunno VD, Mollica V, Gatto L, Santoni M, Cosmai L, Porta C, et al. Prognostic impact of neutrophil-to-lymphocyte ratio in renal cell carcinoma: a systematic review and meta-analysis. Immunotherapy. 2019;11(7):631–43. https://doi.org/10.2217/imt-2018-0175.

    Article  CAS  PubMed  Google Scholar 

  21. Capone M, Giannarelli D, Mallardo D, Madonna G, Festino L, Grimaldi AM, et al. Baseline neutrophil-to-lymphocyte ratio (NLR) and derived NLR could predict overall survival in patients with advanced melanoma treated with nivolumab. J Immunother Cancer. 2018;6(1):74. https://doi.org/10.1186/s40425-018-0383-1.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Nakamura Y, Tanaka R, Maruyama H, Ishitsuka Y, Okiyama N, Watanabe R, et al. Correlation between blood cell count and outcome of melanoma patients treated with anti-PD-1 antibodies. Jpn J Clin Oncol. 2019. https://doi.org/10.1093/jjco/hyy201.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Bagley SJ, Kothari S, Aggarwal C, Bauml JM, Alley EW, Evans TL, et al. Pretreatment neutrophil-to-lymphocyte ratio as a marker of outcomes in nivolumab-treated patients with advanced non-small-cell lung cancer. Lung Cancer (Amsterdam, Netherlands). 2017;106:1–7. https://doi.org/10.1016/j.lungcan.2017.01.013.

    Article  Google Scholar 

  24. Oya Y, Yoshida T, Kuroda H, Mikubo M, Kondo C, Shimizu J, et al. Predictive clinical parameters for the response of nivolumab in pretreated advanced non-small-cell lung cancer. Oncotarget. 2017;8(61):103117–28. https://doi.org/10.18632/oncotarget.21602.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Martens A, Wistuba-Hamprecht K, Geukes Foppen M, Yuan J, Postow MA, Wong P, et al. Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin Cancer Res. 2016;22(12):2908–18. https://doi.org/10.1158/1078-0432.ccr-15-2412.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Weide B, Martens A, Hassel JC, Berking C, Postow MA, Bisschop K, et al. Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab. Clin Cancer Res. 2016;22(22):5487–96. https://doi.org/10.1158/1078-0432.ccr-16-0127.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Heppt MV, Heinzerling L, Kahler KC, Forschner A, Kirchberger MC, Loquai C, et al. Prognostic factors and outcomes in metastatic uveal melanoma treated with programmed cell death-1 or combined PD-1/cytotoxic T-lymphocyte antigen-4 inhibition. Eur J Cancer (Oxford, England: 1990). 2017;82:56–65. https://doi.org/10.1016/j.ejca.2017.05.038.

    Article  CAS  Google Scholar 

  28. Soyano AE, Dholaria B, Marin-Acevedo JA, Diehl N, Hodge D, Luo Y, et al. Peripheral blood biomarkers correlate with outcomes in advanced non-small cell lung cancer patients treated with anti-PD-1 antibodies. J Immunother Cancer. 2018;6(1):129. https://doi.org/10.1186/s40425-018-0447-2.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer (Oxford, England: 1990). 2009;45(2):228–47. https://doi.org/10.1016/j.ejca.2008.10.026.

    Article  CAS  Google Scholar 

  30. Ishihara H, Kondo T, Yoshida K, Omae K, Takagi T, Iizuka J, et al. Time to progression after first-line tyrosine kinase inhibitor predicts survival in patients with metastatic renal cell carcinoma receiving second-line molecular-targeted therapy. Urol Oncol. 2017;35(9):542. https://doi.org/10.1016/j.urolonc.2017.05.014.

    Article  CAS  PubMed  Google Scholar 

  31. Ishihara H, Takagi T, Kondo T, Tachibana H, Yoshida K, Omae K, et al. Efficacy and safety of third-line molecular-targeted therapy in metastatic renal cell carcinoma resistant to first-line vascular endothelial growth factor receptor tyrosine kinase inhibitor and second-line therapy. Int J Clin Oncol. 2018;23(3):559–67. https://doi.org/10.1007/s10147-018-1241-3.

    Article  CAS  PubMed  Google Scholar 

  32. Boissier R, Campagna J, Branger N, Karsenty G, Lechevallier E. The prognostic value of the neutrophil-lymphocyte ratio in renal oncology: a review. Urol Oncol. 2017;35(4):135–41. https://doi.org/10.1016/j.urolonc.2017.01.016.

    Article  PubMed  Google Scholar 

  33. Chen Z, Shao Y, Yao H, Zhuang Q, Wang K, Xing Z, et al. Preoperative albumin to globulin ratio predicts survival in clear cell renal cell carcinoma patients. Oncotarget. 2017;8(29):48291–302. https://doi.org/10.18632/oncotarget.15162.

    Article  PubMed Central  PubMed  Google Scholar 

  34. Chen Z, Wang K, Lu H, Xue D, Fan M, Zhuang Q, et al. Systemic inflammation response index predicts prognosis in patients with clear cell renal cell carcinoma: a propensity score-matched analysis. Cancer Manag Res. 2019;11:909–19. https://doi.org/10.2147/cmar.s186976.

    Article  PubMed Central  PubMed  Google Scholar 

  35. Wang X, Su S, Guo Y. The clinical use of the platelet to lymphocyte ratio and lymphocyte to monocyte ratio as prognostic factors in renal cell carcinoma: a systematic review and meta-analysis. Oncotarget. 2017;8(48):84506–14. https://doi.org/10.18632/oncotarget.21108.

    Article  PubMed Central  PubMed  Google Scholar 

  36. 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. https://doi.org/10.1002/jcp.26609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ramsey S, Lamb GW, Aitchison M, Graham J, McMillan DC. Evaluation of an inflammation-based prognostic score in patients with metastatic renal cancer. Cancer. 2007;109(2):205–12. https://doi.org/10.1002/cncr.22400.

    Article  PubMed  Google Scholar 

  38. Naito S, Kinoshita H, Kondo T, Shinohara N, Kasahara T, Saito K, et al. Prognostic factors of patients with metastatic renal cell carcinoma with removed metastases: a multicenter study of 556 patients. Urology. 2013;82(4):846–51. https://doi.org/10.1016/j.urology.2013.06.035.

    Article  PubMed  Google Scholar 

  39. Ko JJ, Xie W, Kroeger N, Lee JL, Rini BI, Knox JJ, et al. The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a population-based study. Lancet Oncol. 2015;16(3):293–300. https://doi.org/10.1016/s1470-2045(14)71222-7.

    Article  PubMed  Google Scholar 

  40. Bilen MA, Dutcher GMA, Liu Y, Ravindranathan D, Kissick HT, Carthon BC, et al. Association between pretreatment neutrophil-to-lymphocyte ratio and outcome of patients with metastatic renal-cell carcinoma treated with nivolumab. Clin Genitourin Cancer. 2018;16(3):e563–75. https://doi.org/10.1016/j.clgc.2017.12.015.

    Article  PubMed Central  PubMed  Google Scholar 

  41. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860–7. https://doi.org/10.1038/nature01322.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Balkwill FR, Mantovani A. Cancer-related inflammation: common themes and therapeutic opportunities. Semin Cancer Biol. 2012;22(1):33–40. https://doi.org/10.1016/j.semcancer.2011.12.005.

    Article  CAS  PubMed  Google Scholar 

  43. Klinger MH, Jelkmann W. Role of blood platelets in infection and inflammation. Journal Interferon Cytokine Res. 2002;22(9):913–22. https://doi.org/10.1089/10799900260286623.

    Article  CAS  Google Scholar 

  44. Diem S, Schmid S, Krapf M, Flatz L, Born D, Jochum W, et al. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. Lung Cancer (Amsterdam, Netherlands). 2017;111:176–81. https://doi.org/10.1016/j.lungcan.2017.07.024.

    Article  Google Scholar 

  45. Murray PJ. Immune regulation by monocytes. Semin Immunol. 2018;35:12–8. https://doi.org/10.1016/j.smim.2017.12.005.

    Article  CAS  PubMed  Google Scholar 

  46. Bilen MA, Martini DJ, Liu Y, Lewis C, Collins HH, Shabto JM, et al. The prognostic and predictive impact of inflammatory biomarkers in patients who have advanced-stage cancer treated with immunotherapy. Cancer. 2019;125(1):127–34. https://doi.org/10.1002/cncr.31778.

    Article  PubMed  Google Scholar 

  47. De Giorgi U, Procopio G, Giannarelli D, Sabbatini R, Bearz A, Buti S, et al. Association of systemic inflammation index and body mass index with survival in patients with renal cell cancer treated with nivolumab. Clin Cancer Res. 2019. https://doi.org/10.1158/1078-0432.ccr-18-3661.

    Article  PubMed  Google Scholar 

  48. Simson L, Ellyard JI, Dent LA, Matthaei KI, Rothenberg ME, Foster PS, et al. Regulation of carcinogenesis by IL-5 and CCL11: a potential role for eosinophils in tumor immune surveillance. J Immunol (Baltimore, Md: 1950). 2007;178(7):4222–9.

    Article  CAS  Google Scholar 

  49. Carretero R, Sektioglu IM, Garbi N, Salgado OC, Beckhove P, Hammerling GJ. Eosinophils orchestrate cancer rejection by normalizing tumor vessels and enhancing infiltration of CD8(+) T cells. Nat Immunol. 2015;16(6):609–17. https://doi.org/10.1038/ni.3159.

    Article  CAS  PubMed  Google Scholar 

  50. Sasaki A, Nakamura Y, Mishima S, Kawazoe A, Kuboki Y, Bando H, et al. Predictive factors for hyperprogressive disease during nivolumab as anti-PD1 treatment in patients with advanced gastric cancer. Gastric Cancer. 2019. https://doi.org/10.1007/s10120-018-00922-8.

    Article  PubMed  Google Scholar 

  51. Weber JS, Tang H, Hippeli L, Qian M, Wind-Rotolo M, Larkin JMG, et al. Serum IL-6 and CRP as prognostic factors in melanoma patients receiving single agent and combination checkpoint inhibition. J Clin Oncol. 2019;37(15_suppl):100. https://doi.org/10.1200/jco.2019.37.15_suppl.100.

    Article  Google Scholar 

Download references

Acknowledgements

The authors thank Ms. Nobuko Hata (Department of Urology, Tokyo Women’s Medical University and Department of Urology) for secretarial work.

Author information

Authors and Affiliations

  1. Department of Urology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan

    Hiroki Ishihara, Toshio Takagi, Hironori Fukuda, Kazuhiko Yoshida, Junpei Iizuka, Masayoshi Okumi, Hideki Ishida & Kazunari Tanabe

  2. Department of Urology, Tokyo Women’s Medical University Medical Center East, 2-1-10 Nishiogu, Arakawa-ku, Tokyo, 116-8567, Japan

    Hidekazu Tachibana, Tsunenori Kondo & Hirohito Kobayashi

Authors
  1. Hiroki Ishihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hidekazu Tachibana
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Toshio Takagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tsunenori Kondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hironori Fukuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kazuhiko Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Junpei Iizuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hirohito Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Masayoshi Okumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hideki Ishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kazunari Tanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tsunenori Kondo.

Ethics declarations

Conflict of interest

Tsunenori Kondo received honoraria from Ono Pharmaceutical. Hiroki Ishihara, Hidekazu Tachibana, Toshio Takagi, Hironori Fukuda, Kazuhiko Yoshida, Junpei Iizuka, Hirohito Kobayashi, Masayoshi Okumi, Hideki Ishida, and Kazunari Tanabe have no conflicts of interest to declare.

Funding

This study did not receive any funding.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ishihara, H., Tachibana, H., Takagi, T. et al. Predictive Impact of Peripheral Blood Markers and C-Reactive Protein in Nivolumab Therapy for Metastatic Renal Cell Carcinoma. Targ Oncol 14, 453–463 (2019). https://doi.org/10.1007/s11523-019-00660-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-019-00660-6

Search

Navigation