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C-reactive protein and the neutrophil-to-lymphocyte ratio are prognostic biomarkers in metastatic renal cell carcinoma patients treated with nivolumab

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Abstract

Background

Association between systemic inflammation and clinical outcome of immune checkpoint inhibitors (ICIs) has received focus. Our objective was to evaluate the utility of the neutrophil-to-lymphocyte ratio (NLR) in metastatic renal cell carcinoma (mRCC) patients treated with nivolumab as well as the prognostic impact of the C-reactive protein (CRP) level.

Materials and methods

Sixty-five mRCC patients treated with nivolumab were enrolled. We retrospectively investigated several factors, including the NLR and the CRP level, for their association with progression-free survival (PFS) and overall survival (OS). In addition, we evaluated their impact on the objective response.

Results

The CRP level was confirmed to be positively correlated with the NLR in a correlation analysis. An NLR ≥ 5 was significantly associated with a worse PFS (hazard ratio [HR]: 4.54, 95% confidence interval [CI] 1.93–10.7; p < 0.001), and an NLR ≥ 5 and a CRP ≥ 2.1 mg/dL were identified as a significant factors predicting worse OS with HRs of 4.88 (95% CI 1.35–17.7; p < 0.016) and 3.89 (95% CI 1.01–15.0; p = 0.049), respectively. In addition, patients with a ≥ 25% decrease in the NLR and CRP level showed a significantly better response to nivolumab than those without a ≥ 25% decrease in the NLR and CRP level, with odds ratios of 9.54 (95% CI 2.09–49.8, p = 0.001) and 4.36 (95% CI 1.03–18.9, p = 0.032), respectively.

Conclusion

Both the NLR and CRP levels were significantly associated with the clinical outcome of nivolumab in mRCC patients. The potential prognostic impact of those markers needs to be further prospectively investigated.

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Abbreviations

AE:

Adverse event

CI:

Confidence interval

CRP:

C-reactive protein

CTLA-4:

Anti-cytotoxic T-lymphocyte antigen-4

HR:

Hazard ratio

ICI:

Immune checkpoint inhibitor

IMDC:

International metastatic renal cell carcinoma Database Consortium

irAE:

Immune-related adverse event

KPS:

Karnofsky performance status

mRCC:

Metastatic renal cell carcinoma

NLR:

Neutrophil-to-lymphocyte ratio

ORR:

Objective response rate

OS:

Overall survival

PD-1:

Anti-programmed death-1

PFS:

Progression-free survival

PD-L1:

Anti-programmed death-ligand 1

TKI:

Multitargeted receptor tyrosine kinase inhibitor

References

  1. Motzer RJ, Escudier B, McDermott DF et al (2015) Nivolumab versus everolimus in advanced renal-cell carcinoma. New Engl J Med 373(19):1803–1813

    Article  CAS  PubMed  Google Scholar 

  2. Salgia NJ, Dara Y, Bergerot P et al (2019) The changing landscape of management of metastatic renal cell carcinoma: current treatment options and future directions. Curr Treat Options Oncol 20(5):41

    Article  PubMed  Google Scholar 

  3. Motzer RJ, Tannir NM, McDermott DF et al (2018) Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. New Engl J Med 378(14):1277–1290

    Article  CAS  PubMed  Google Scholar 

  4. Rini BI, Plimack ER, Stus V et al (2019) Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. New Engl J Med 380(12):1116–1127

    Article  CAS  PubMed  Google Scholar 

  5. Motzer RJ, Penkov K, Haanen J et al (2019) Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. New Engl J Med 380(12):1103–1115

    Article  CAS  PubMed  Google Scholar 

  6. Topalian SL, Hodi FS, Brahmer JR et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. New Engl J Med 366(26):2443–2454

    Article  CAS  PubMed  Google Scholar 

  7. Herbst RS, Baas P, Kim DW et al (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet (Lond, Engl) 387(10027):1540–1550

    Article  CAS  Google Scholar 

  8. Zhang T, Xie J, Arai S et al (2016) The efficacy and safety of anti-PD-1/PD-L1 antibodies for treatment of advanced or refractory cancers: a meta-analysis. Oncotarget 7(45):73068–73079

    Article  PubMed  PubMed Central  Google Scholar 

  9. Weide B, Martens A, Hassel JC et al (2016) Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab. Clin Cancer Res 22(22):5487–5496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kluger HM, Zito CR, Turcu G et al (2017) PD-L1 studies across tumor types, its differential expression and predictive value in patients treated with immune checkpoint inhibitors. Clin Cancer Res 23(15):4270–4279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70

    Article  CAS  PubMed  Google Scholar 

  12. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    Article  CAS  PubMed  Google Scholar 

  13. Lino-Silva LS, Salcedo-Hernandez RA, Garcia-Perez L et al (2017) Basal neutrophil-to-lymphocyte ratio is associated with overall survival in melanoma. Melanoma Res 27(2):140–144

    Article  PubMed  Google Scholar 

  14. Diem S, Schmid S, Krapf M et al (2017) 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) 111:176–181

    Article  Google Scholar 

  15. Nakaya A, Kurata T, Yoshioka H et al (2018) Neutrophil-to-lymphocyte ratio as an early marker of outcomes in patients with advanced non-small-cell lung cancer treated with nivolumab. Int J Clin Oncol 23(4):634–640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bilen MA, Dutcher GMA, Liu Y et al (2018) Association between pretreatment neutrophil-to-lymphocyte ratio and outcome of patients with metastatic renal-cell carcinoma treated with nivolumab. Clin Genitourin Cancer 16(3):e563–e575

    Article  PubMed  PubMed Central  Google Scholar 

  17. Oya Y, Yoshida T, Kuroda H et al (2017) Predictive clinical parameters for the response of nivolumab in pretreated advanced non-small-cell lung cancer. Oncotarget 8(61):103117–103128

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ozawa Y, Amano Y, Kanata K et al (2019) Impact of early inflammatory cytokine elevation after commencement of PD-1 inhibitors to predict efficacy in patients with non-small cell lung cancer. Med Oncol (Northwood, Lond, Engl) 36(4):33

    Article  CAS  Google Scholar 

  19. Okuhira H, Yamamoto Y, Inaba Y et al (2018) Prognostic factors of daily blood examination for advanced melanoma patients treated with nivolumab. Biosci Trends 12(4):412–418

    Article  CAS  PubMed  Google Scholar 

  20. Heng DYC, Xie W, Regan MM et al (2013) External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol 14(2):141–148

    Article  PubMed  PubMed Central  Google Scholar 

  21. Guthrie GJ, Charles KA, Roxburgh CS et al (2013) The systemic inflammation-based neutrophil-lymphocyte ratio: experience in patients with cancer. Crit Rev Oncol Hematol 88(1):218–230

    Article  PubMed  Google Scholar 

  22. Kanda Y (2013) Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 48(3):452–458

    Article  CAS  PubMed  Google Scholar 

  23. Templeton AJ, Knox JJ, Lin X et al (2016) Change in neutrophil-to-lymphocyte ratio in response to targeted therapy for metastatic renal cell carcinoma as a prognosticator and biomarker of efficacy. Eur Urol 70(2):358–364

    Article  PubMed  Google Scholar 

  24. Teishima J, Kobatake K, Kitano H et al (2016) 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 117(6B):E67–74

    Article  CAS  PubMed  Google Scholar 

  25. Schmidt H, Bastholt L, Geertsen P et al (2005) Elevated neutrophil and monocyte counts in peripheral blood are associated with poor survival in patients with metastatic melanoma: a prognostic model. Br J Cancer 93(3):273–278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Atzpodien J, Royston P, Wandert T et al (2003) Metastatic renal carcinoma comprehensive prognostic system. Br J Cancer 88(3):348–353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Teramukai S, Kitano T, Kishida Y et al (2009) Pretreatment neutrophil count as an independent prognostic factor in advanced non-small-cell lung cancer: an analysis of Japan Multinational Trial Organisation LC00-03. Eur J Cancer 45(11):1950–1958

    Article  PubMed  Google Scholar 

  28. De Larco JE, Wuertz BR, Furcht LT (2004) The potential role of neutrophils in promoting the metastatic phenotype of tumors releasing interleukin-8. Clin Cancer Res 10(15):4895–4900

    Article  PubMed  Google Scholar 

  29. Gooden MJ, de Bock GH, Leffers N et al (2011) The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer 105(1):93–103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Niederhuber JE (1997) Cancer vaccines: the molecular basis for t cell killing of tumor cells. Oncologist 2(5):280–283

    Article  CAS  PubMed  Google Scholar 

  31. Fogar P, Sperti C, Basso D et al (2006) Decreased total lymphocyte counts in pancreatic cancer: an index of adverse outcome. Pancreas 32(1):22–28

    Article  PubMed  Google Scholar 

  32. Clemente CG, Mihm MC Jr, Bufalino R et al (1996) Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 77(7):1303–1310

    Article  CAS  PubMed  Google Scholar 

  33. Galon J, Costes A, Sanchez-Cabo F et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science (New York, NY) 313(5795):1960–1964

    Article  CAS  Google Scholar 

  34. Zhang L, Conejo-Garcia JR, Katsaros D et al (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. New Engl J Med 348(3):203–213

    Article  CAS  PubMed  Google Scholar 

  35. Azab B, Bhatt VR, Phookan J et al (2012) Usefulness of the neutrophil-to-lymphocyte ratio in predicting short- and long-term mortality in breast cancer patients. Ann Surg Oncol 19(1):217–224

    Article  PubMed  Google Scholar 

  36. Casamassima A, Picciariello M, Quaranta M et al (2005) C-reactive protein: a biomarker of survival in patients with metastatic renal cell carcinoma treated with subcutaneous interleukin-2 based immunotherapy. J Urol 173(1):52–55

    Article  CAS  PubMed  Google Scholar 

  37. Beuselinck B, Vano YA, Oudard S et al (2014) Prognostic impact of baseline serum C-reactive protein in patients with metastatic renal cell carcinoma (RCC) treated with sunitinib. BJU Int 114(1):81–89

    Article  CAS  PubMed  Google Scholar 

  38. Nagasaki T, Hara M, Nakanishi H et al (2014) Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis: anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour-stroma interaction. Br J Cancer 110(2):469–478

    Article  CAS  PubMed  Google Scholar 

  39. Gado K, Domjan G, Hegyesi H et al (2000) Role of INTERLEUKIN-6 in the pathogenesis of multiple myeloma. Cell Biol Int 24(4):195–209

    Article  CAS  PubMed  Google Scholar 

  40. Lalani AA, Xie W, Martini DJ et al (2018) Change in Neutrophil-to-lymphocyte ratio (NLR) in response to immune checkpoint blockade for metastatic renal cell carcinoma. J Immunother Cancer 6(1):5

    Article  PubMed  PubMed Central  Google Scholar 

  41. Walsh SR, Cook EJ, Goulder F et al (2005) Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg Oncol 91(3):181–184

    Article  CAS  PubMed  Google Scholar 

  42. Slinker BK, Glantz SA (1985) Multiple regression for physiological data analysis: the problem of multicollinearity. The American journal of physiology 249(1 Pt 2):R1–12

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

Authors

Contributions

KS, TT and KH designed the study. KS, TT, JF, KH acquired and analyzed the data. KS, TT and KH drafted the manuscript, and JF, NH, YN and MF revised it critically for important intellectual content. All authors gave final approval of the version to be published.

Corresponding author

Correspondence to Tomoaki Terakawa.

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Conflict of interest

The authors declare no conflict of interest.

Ethical approval

The study design was approved by the Research Ethics Committee of our institution (No. B190059), which was conducted in accordance with the Declaration of Helsinki. Informed consent to participate in the present study was obtained from all patients.

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Suzuki, K., Terakawa, T., Furukawa, J. et al. C-reactive protein and the neutrophil-to-lymphocyte ratio are prognostic biomarkers in metastatic renal cell carcinoma patients treated with nivolumab. Int J Clin Oncol 25, 135–144 (2020). https://doi.org/10.1007/s10147-019-01528-5

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  • DOI: https://doi.org/10.1007/s10147-019-01528-5

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