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International Journal of Clinical Oncology

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01-01-2020 | Kidney Cancer | Original Article

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

Authors: Kotaro Suzuki, Tomoaki Terakawa, Junya Furukawa, Kenichi Harada, Nobuyuki Hinata, Yuzo Nakano, Masato Fujisawa

Published in: International Journal of Clinical Oncology | Issue 1/2020

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.

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

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):41PubMedCrossRef

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):1277–1290PubMedCrossRef

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):1116–1127PubMedCrossRef

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):1103–1115PubMedCrossRef

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):2443–2454PubMedCrossRef

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):1540–1550CrossRef

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):73068–73079PubMedPubMedCentralCrossRef

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

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):4270–4279PubMedPubMedCentralCrossRef

11.

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

12.

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

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):140–144PubMedCrossRef

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) 111:176–181CrossRef

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):634–640PubMedPubMedCentralCrossRef

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–e575PubMedPubMedCentralCrossRef

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):103117–103128PubMedPubMedCentralCrossRef

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):33CrossRef

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):412–418PubMedCrossRef

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):141–148PubMedPubMedCentralCrossRef

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):218–230PubMedCrossRef

22.

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

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):358–364PubMedCrossRef

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):E67–74PubMedCrossRef

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):273–278PubMedPubMedCentralCrossRef

26.

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

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):1950–1958PubMedCrossRef

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):4895–4900PubMedCrossRef

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):93–103PubMedPubMedCentralCrossRef

30.

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

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):22–28PubMedCrossRef

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):1303–1310PubMedCrossRef

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):1960–1964CrossRef

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):203–213PubMedCrossRef

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):217–224PubMedCrossRef

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):52–55PubMedCrossRef

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):81–89PubMedCrossRef

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):469–478PubMedCrossRef

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):195–209PubMedCrossRef

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):5PubMedPubMedCentralCrossRef

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):181–184PubMedCrossRef

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):R1–12PubMed

Title: C-reactive protein and the neutrophil-to-lymphocyte ratio are prognostic biomarkers in metastatic renal cell carcinoma patients treated with nivolumab
Authors: Kotaro Suzuki
Tomoaki Terakawa
Junya Furukawa
Kenichi Harada
Nobuyuki Hinata
Yuzo Nakano
Masato Fujisawa
Publication date: 01-01-2020
Publisher: Springer Singapore
Keywords: Kidney Cancer
Kidney Cancer
Tyrosine Kinase Inhibitors
Kidney Cancer
Tyrosine Kinase Inhibitors
Checkpoint Inhibitors
Biomarkers
Published in: International Journal of Clinical Oncology / Issue 1/2020
Print ISSN: 1341-9625
Electronic ISSN: 1437-7772
DOI: https://doi.org/10.1007/s10147-019-01528-5

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