Original Study| Volume 15, ISSUE 6, P678-684.e1, December 2017

Neutrophil to Lymphocyte Ratio in Castration-Resistant Prostate Cancer Patients Treated With Daily Oral Corticosteroids



      The neutrophil to lymphocyte ratio (NLR) has been shown to be highly prognostic across many tumor types, and predictive of treatment outcome in advanced prostate cancer, and has been postulated to be an indirect measure of tumor inflammation. We evaluated the effect of low-dose steroids on NLR in men suffering from castration-resistant prostate cancer (CRPC).

      Patients and Methods

      The NLR was evaluated in a prospective randomized phase II trial that compared prednisolone 5 mg twice daily and dexamethasone 0.5 mg daily administered to 75 chemotherapy and abiraterone/enzalutamide-naive CRPC patients. NLR was examined at baseline (BL), after 6 and 12 weeks of corticosteroid treatment; associations with >50% prostate-specific antigen (PSA) response, duration of response (PSA progression-free interval), and overall survival (OS) were tested using logistic regression and Cox regression analysis.


      The median NLR for all evaluable patients was 2.6 at BL; 2.9 at 6 weeks; and 4.0 at 12 weeks. After low-dose corticosteroid initiation, 46 patients had a decline in PSA with 24 confirmed responders. BL NLR (log10) associated with a PSA response (odds ratio, .029, 95% confidence interval [CI], .002-.493; P = .014), and with the extent of the PSA decline (P = .009). A favorable BL NLR (less than median) associated with a 5.5-fold higher odds of a PSA >50% response (95% CI, 1.3-23.9; P = .02). Higher BL NLR (log10) associated with a shorter time to PSA progression (hazard ratio [HR], 9.5; 95% CI, 2.3-39.9; P = .002). In multivariate analysis BL NLR as a discrete variable was independently associated with PSA progression (HR, 3.5; 95% CI, 1.5-8.1; P = .003). NLR at 6 weeks was also associated with duration of benefit; in the favorable NLR category time to PSA progression was 10.8 months, for those who converted to an unfavorable (greater than median) category 4.5 months, and for those remaining in a unfavorable category only 1.5 months (95% CI, 0.5-2.5; P = .003). OS was 33.1 months (95% CI, 24.2-42.0) and 21.9 months (95% CI, 19.3-24.4) for those with an favorable and unfavorable BL NLR, respectively.


      Treatment-naive CRPC patients with a high BL or during-treatment NLR appear not to benefit from low-dose corticosteroids. The immunological implications of an unfavorable NLR, and whether corticosteroids might drive prostate cancer progression in patients harboring a high NLR, warrant further study.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Genitourinary Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Montgomery B.
        • Kheoh T.
        • Molina A.
        • et al.
        Impact of baseline corticosteroids on survival and steroid androgens in metastatic castration-resistant prostate cancer: exploratory analysis from COU-AA-301.
        Eur Urol. 2015; 67: 866-873
        • Khandwala H.M.
        • Vassilopoulou-Sellin R.
        • Logethetis C.J.
        • Friend K.E.
        Corticosteroid-induced inhibition of adrenal androgen production in selected patients with prostate cancer.
        Endocr Pract. 2001; 7: 11-15
        • Venkitaraman R.
        • Lorente D.
        • Murthy V.
        • et al.
        A randomised phase 2 trial of dexamethasone versus prednisolone in castration-resistant prostate cancer.
        Eur Urol. 2015; 67: 673-679
        • Lorente D.
        • Olmos D.
        • Mateo J.
        • et al.
        Decline in circulating tumor cell count and treatment outcome in advanced prostate cancer.
        Eur Urol. 2016; 70: 985-992
        • de Bono J.S.
        • Logothetis C.J.
        • Molina A.
        • et al.
        Abiraterone and increased survival in metastatic prostate cancer.
        N Engl J Med. 2011; 364: 1995-2005
        • Ryan C.J.
        • Smith M.R.
        • de Bono J.S.
        • et al.
        Abiraterone in metastatic prostate cancer without previous chemotherapy.
        N Engl J Med. 2013; 368: 138-148
        • Rhen T.
        • Cidlowski J.A.
        Anti-inflammatory action of glucocorticoids–new mechanisms for old drugs.
        N Engl J Med. 2005; 353: 1711-1723
        • Coutinho A.E.
        • Chapman K.E.
        The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights.
        Mol Cell Endocrinol. 2011; 335: 2-13
        • Geynisman D.M.
        • Szmulewitz R.Z.
        • Plimack E.R.
        Corticosteroids and prostate cancer: friend or foe?.
        Eur Urol. 2015; 67: 874-875
        • Parker C.
        • De Bono J.
        Reply from authors re: Camillo Porta, Sergio Bracarda, Romano Danesi. Steroids in prostate cancer: the jury is still out… and even more confused. Eur Urol 2015;67:680-1.
        Eur Urol. 2015; 67: 681-682
        • Ehrchen J.
        • Steinmüller L.
        • Barczyk K.
        • et al.
        Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes.
        Blood. 2007; 109: 1265-1274
        • Varga G.
        • Ehrchen J.
        • Tsianakas A.
        • et al.
        Glucocorticoids induce an activated, anti-inflammatory monocyte subset in mice that resembles myeloid-derived suppressor cells.
        J Leukoc Biol. 2008; 84: 644-650
        • Di Mitri D.
        • Toso A.
        • Chen J.J.
        • et al.
        Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer.
        Nature. 2014; 515: 134-137
        • Vetsika E.K.
        • Koinis F.
        • Gioulbasani M.
        • et al.
        A circulating subpopulation of monocytic myeloid-derived suppressor cells as an independent prognostic/predictive factor in untreated non-small lung cancer patients.
        J Immunol Res. 2014; 2014: 1-12
        • Idorn M.
        • Køllgaard T.
        • Kongsted P.
        • Sengeløv L.
        • Thor Straten P.
        Correlation between frequencies of blood monocytic myeloid-derived suppressor cells, regulatory T cells and negative prognostic markers in patients with castration-resistant metastatic prostate cancer.
        Cancer Immunol Immunother. 2014; 63: 1177-1187
        • Templeton A.J.
        • McNamara M.G.
        • Šeruga B.
        • et al.
        Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis.
        J Natl Cancer Inst. 2014; 106: dju124
        • Leibowitz-Amit R.
        • Templeton A.J.
        • Omlin A.
        • et al.
        Clinical variables associated with PSA response to abiraterone acetate in patients with metastatic castration-resistant prostate cancer.
        Ann Oncol. 2014; 25: 657-662
        • Conteduca V.
        • Crabb S.
        • Jones R.
        • et al.
        Persistent Neutrophil to Lymphocyte Ratio >3 during Treatment with Enzalutamide and Clinical Outcome in Patients with Castration-Resistant Prostate Cancer.
        PLoS One. 2016; 11: e0158952
        • Lorente D.
        • Mateo J.
        • Templeton A.J.
        • et al.
        Baseline neutrophil-lymphocyte ratio (NLR) is associated with survival and response to treatment with second-line chemotherapy for advanced prostate cancer independent of baseline steroid use.
        Ann Oncol. 2015; 26: 750-755
        • Ohki S.
        • Shibata M.
        • Gonda K.
        • et al.
        Circulating myeloid-derived suppressor cells are increased and correlate to immune suppression, inflammation and hypoproteinemia in patients with cancer.
        Oncol Rep. 2012; 28: 453-458
        • Mehra N.
        • Morilla R.
        • Sharp A.
        • et al.
        High neutrophil-lymphocyte ratio, myeloid-derived suppressor cells and resistance to corticosteroid therapy in castration-resistant prostate cancer.
        J Clin Oncol. 2016; 34 (suppl; abstr 5076)
        • Scher H.I.
        • Jia X.
        • de Bono J.S.
        • et al.
        Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data.
        Lancet Oncol. 2009; 10: 233-239
        • Savino W.
        • Mendes-da-Cruz D.A.
        • Lepletier A.
        • Dardenne M.
        Hormonal control of T-cell development in health and disease.
        Nat Rev Endocrinol. 2016; 12: 77-89
        • Liu B.
        • Dhanda A.
        • Hirani S.
        • et al.
        CD14++CD16+ monocytes are enriched by glucocorticoid treatment and are functionally attenuated in driving effector T cell responses.
        J Immunol. 2015; 194: 5150-5160
        • Rea D.
        • van Kooten C.
        • van Meijgaarden K.E.
        • Ottenhoff T.H.
        • Melief C.J.
        • Offringa R.
        Glucocorticoids transform CD40-triggering of dendritic cells into an alternative activation pathway resulting in antigen-presenting cells that secrete IL-10.
        Blood. 2000; 95: 3162-3167
        • Rutella S.
        • Lemoli R.M.
        Regulatory T cells and tolerogenic dendritic cells: from basic biology to clinical applications.
        Immunol Lett. 2004; 94: 11-26
        • Xing K.
        • Gu B.
        • Zhang P.
        • Wu X.
        Dexamethasone enhances programmed cell death 1 (programmed cell death 1-1) expression during T cell activation: an insight into the optimum application of glucocorticoids in anti-cancer therapy.
        BMC Immunol. 2015; 16: 39
        • Mehra N.
        • Seed G.
        • Lambros M.
        • et al.
        Myeloid-derived suppressor cells (MDSCs) in metastatic castration-resistant prostate cancer (CRPC) patients (PTS) (abstract 757P).
        Ann Oncol. 2016; 27
      1. Mehra N, Lambros M, Seed G, et al. Myeloid-derived suppressor cells (MDSCs) in metastatic castration-resistant prostate cancer (CRPC) patients (abstract). Poster presentation, October 27, 2016, 23rd Annual PCF Scientific Retreat.

        • Scher H.I.
        • Fizazi K.
        • Saad F.
        • et al.
        Association of baseline corticosteroid with outcomes in a multivariate analysis of the Phase 3 AFFIRM study of enzalutamide (ENZA), an androgen receptor signaling inhibitor (abstract 899PD).
        Ann Oncol. 2012; 23
        • Scher H.I.
        • Fizazi K.
        • Saad F.
        • et al.
        Impact of on-study corticosteroid use on efficacy and safety in the phase III AFFIRM study of enzalutamide (ENZA), an androgen receptor inhibitor (abstract 6).
        J Clin Oncol. 2013; 31
        • Arora V.K.
        • Schenkein E.
        • Murali R.
        • et al.
        Glucocorticoid receptor confers resistance to anti-androgens by bypassing androgen receptor blockade.
        Cell. 2013; 155: 1309-1322
        • Carreira S.
        • Romanel A.
        • Goodall J.
        • et al.
        Tumor clone dynamics in lethal prostate cancer.
        Sci Transl Med. 2014; 6: 254ra125
        • Richards J.
        • Lim A.C.
        • Hay C.W.
        • et al.
        Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100.
        Cancer Res. 2012; 72: 2176-2182
        • Lorente D.
        • Omlin A.
        • Ferraldeschi R.
        • et al.
        Tumour responses following a steroid switch from prednisone to dexamethasone in castration-resistant prostate cancer patients progressing on abiraterone.
        Br J Cancer. 2014; 111: 2248-2253