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Pretreatment neutrophil‐to‐lymphocyte ratio as a potential prognostic biomarker for newly diagnosed patients with metastatic castration‐sensitive prostate cancer

Pretreatment neutrophil‐to‐lymphocyte ratio as a potential prognostic biomarker for newly... INTRODUCTIONProstate cancer is the most common malignancy and the second cause of cancer‐related death among men.1,2 According to the American cancer society estimations, 191 930 new cases will be diagnosed and 33 330 will die of the disease in 2020.1 Although 5% of prostate cancer patients present with stage IV disease in the USA, one‐fifth of men with prostate cancer present with metastatic disease in the Middle East.2The treatment algorithm of newly diagnosed metastatic castrate‐sensitive prostate cancer (mCSPC) has changed.3‐6 Early introduction of novel therapies such as docetaxel, abiraterone, and enzalutamide in the treatment regimen for mCSPC has resulted in significant improvement in overall survival (OS), particularly for the groups with poor prognostic factors.7,8 The survival of the CHAARTED‐trial defined high‐volume group is significantly improved with upfront docetaxel. No such benefit was observed for patients with low volume disease.7 Similar survival benefit has been reported with upfront use of abiraterone and prednisone plus androgen deprivation therapy (ADT) compared to ADT alone for the LATITUDE‐trial defined high‐risk group.8 Several poor prognostic factors in mCSPC have been described such as disease volume, visceral metastasis, Gleason score (GS) ≥8, high serum alkaline phosphatase (ALP), and poor Eastern Cooperative Oncology Group performance status (ECOG PS).9‐13Inflammation is a hallmark of cancer development and progression.14 Preclinical studies have pointed out that inflammation is involved in various cancer development stages, including initiation, promotion, malignant conversion, invasion, and metastasis.15 The neutrophil‐to‐lymphocyte ratio (NLR) is an inflammatory parameter that has been evaluated as a potential prognostic factor in various malignancies, including prostate cancer.16 Several reports showed an association between high NLR and poor survival outcomes for many cancers.16‐18 Yin et al conducted a meta‐analysis and found that elevated NLR predicted poor OS (HR  =  1.57; 95% CI 1.41‐1.74; P  <  .001) and progression‐free survival (HR  =  1.97; 95% CI 1.28‐3.04; P  =  .002) of patients with metastatic castration‐resistant prostate cancer (mCRPC). On the contrary, NLR was not associated with oncological outcomes in patients with localized disease.19Although the impact of NLR on OS has been well studied in metastatic castration‐resistant disease, it is not explored in newly diagnosed patients with mCSPC.19‐23The CHAARTED and LATITUDE trials highlighted the importance of prognostic stratification on initial therapy selection.7,8 Identifying all prognostic factors at the time of diagnosis of metastatic disease is a pre‐requisite to better risk‐stratify patients enrolled in future trials and may improve therapy selection. In this study, we assessed the prognostic role of pre‐treatment (baseline) NLR in newly diagnosed patients with mCSPC.METHODSAim and objectivesThis study aims to examine the prognostic role of NLR on the oncological outcomes of patients with newly diagnosed mCSPC. Study primary endpoints are to assess the impact of high NLR on time to prostatic‐specific antigen (PSA) progression and OS.Patients populationAfter Institutional Review Board approval, we identified all patients with metastatic prostate cancer who were referred to our center between June 2007 and June 2019. All patients were required to have pathologically confirmed prostatic adenocarcinoma and to have a metastatic disease detected on conventional imaging studies (computed tomography (CT) scan, magnetic resonance imaging, and bone scan). Patients with metastasis detected only on prostate‐specific membrane antigen scan without being detected on conventional imaging studies were excluded. Patients who develop a metastatic disease while being treated with ADT for biochemical relapse following definitive primary radiotherapy or radical prostatectomy or those presenting with castration‐resistant metastatic disease were also excluded.Variables: age at presentation, date of diagnosis of metastatic disease, sites of metastasis, number of metastatic bone lesions, GS, ECOG PS, and date of initiation of ADT, defined as the date of the first injection in patients treated with medical castration (GnRH agonists) or the date of orchidectomy for patients treated with surgical castration were abstracted. Concurrent administration of docetaxel and abiraterone was noted. Finally, pre‐treatment laboratory values, including blood counts, serum PSA, ALP, and serum calcium, were extracted. The pretreatment neutrophil‐to‐lymphocyte ratio was calculated for every patient by dividing the absolute neutrophil over the absolute lymphocyte count from the CBC before commencing ADT treatment.Also, we extracted data on the time of first PSA progression after starting ADT. PSA progression was defined according to the prostate cancer working group criteria (PCWG3).24 As such, time to PSA progression was defined as the time from start of ADT to the first PSA increase that is ≥25% and ≥2 ng/mL above the nadir, which is confirmed by a second value ≥3 weeks later. We also gathered data on dates of last follow‐up or death for all patients. OS was defined as time from diagnosis of the metastatic disease until the last follow‐up or death date.Metastatic burden was stratified into high volume and low volume disease based on the definition from CHAARTED trial. Accordingly, high volume disease was defined as the presence of more than three metastatic bone lesions with at least one lesion outside the spine and pelvis or the presence of visceral metastasis,7 while the LATITUDE trial defined risk status was used to classify patients into high‐risk/low‐risk disease, where high‐risk disease is defined as having at least two of the following: GS ≥8, at least three bone lesions, visceral metastasis.8Statistical analysisDescriptive statistics were interpreted as means, medians, SDs, and proportions. Time to PSA progression and OS were assessed by the Kaplan‐Meier method. Survival comparisons were carried out by the Log‐rank test.As the cutoff value for high vs low NLR is not well defined in literature, we opted to assess the correlation of NLR (< vs ≥ the median value) on the median time to PSA progression. In addition, we utilized cutoffs of 3 and 4 utilized and compared in the literature.25 We assessed the correlation of NLR at each of these cutoff points on time to PSA progression. In addition, we assessed the correlation of other‐disease related factors with time to PSA progression in univariate analysis, and then underwent a multivariate analysis for the significant factors (P < .05), utilizing the backward stepwise cox‐regression method.We priori planned to utilize the cutoff value of NLR significantly associated with time to PSA progression in OS analysis. Univariate analysis to assess the possible impact of factors other than the NLR on OS, including: GS, age, serum PSA, visceral vs non‐visceral metastasis, ECOG PS, serum alkaline phosphatase, serum calcium, serum Hb, volume status, and risk status was conducted. All factors with P < .05 in the univariate analysis were forced into a multivariate analysis for OS utilizing the backward stepwise cox‐regression method. All P‐values <.05 were considered statistically significant. All statistical analyses were performed using SPSS version 21 (SPSS Inc, Chicago, Illinois).RESULTSEligible patientsWe identified a total of 280 patients with metastatic prostate cancer. Forty‐three (15%) were excluded because they presented as new cases of mCRPC. Seventeen (6%) were excluded because they came for a second opinion and continued treatment at other centers or lost follow up, 9 (3%) because the pathology did not confirm prostatic adenocarcinoma, 4 (1%) because of diagnosis of a concurrent second malignancy, and 4 (1%) because the metastasis was not detected on conventional imaging studies. In addition, 14 (5%) were excluded for missing data on complete blood counts prior to starting ADT. Thus, a total of 189 patients were included in the final analysis. Patients' characteristics are summarized in Table 1. The median age at presentation was 69 years (range: 40‐89), median serum PSA: 155 ng/mL (range: 1.1‐30 000), and median GS: 9 (range: 6‐10).1TABLEDisease characteristics at initial presentation of included patientsPatients characteristicsN (%) or median (range)De novo metastatic181 (96%)Prior local therapy8 (4%)Median age69 (40–89)Median baseline serum PSA155 ng/mL (1.1–30 000)Median GS9 (6‐10)Bone metastasis174 (92%)No bone metastasis15 (8%)One organ metastasis104 (55%)≥2 organ metastases85 (45%)Visceral metastasis41 (22%)Non‐visceral metastasis148 (78%)ECOG PS 082 (43%)ECOG PS ≥183 (44%)Missing24 (13%)Hb < 12 g/dL50 (26%)Hb ≥12 g/dL139 (74%)NLR < 4150 (79%)NLR ≥439 (21%)High‐volume diseasea146 (77%)Low‐volume disease41 (22%)Not assessable2 (1%)High‐risk diseaseb144 (76%)Low‐risk disease44 (23%)Not assessable1 (<1%)Abbreviations: ECOG PS, Eastern Cooperative Oncology Group Performance Status; GS, Gleason Score; NLR, neutrophil‐to‐lymphocyte ratio; PSA, prostatic‐specific antigen.aCHAARTED trial definition.bLATITUDE trial definition.More than 90% (174/189) of patients had bone metastasis. Of 174 patients with bone metastasis, 37 (21%) had fewer than three bone lesions, and 135 (78%) had ≥3 bone lesions, whereas the number of lesions was not documented in 2 (1%). Approximately three‐quarters of patients had CHAARTED‐trial defined, and LATITUDE‐trial defined high‐volume and high‐risk status. Initial therapy administered was ADT alone for 134 patients (72%), ADT plus docetaxel (preplanned 6 cycles; CHAARTED protocol) for 48 (24%), and ADT plus abiraterone and prednisone for 7 (4%).The median NLR was 2.7, mean NLR 3.2 (sd: 2.37; range: 0.5‐22). A total of 39 patients (21%) had NLR ≥4.NLR and time to PSA progressionThe median time to PSA progression for the entire cohort was 15.6 months. Patients with NLR ≥4 had a shorter time to PSA progression compared to patients with NLR < 4; 11.3 and.18.3 months, respectively (P = .015) (Figure 1). We did not find any statistically significant difference of NLR on the median time to PSA progression using cutoff value of 3 (15.2 months for NLR ≥3 and 16.1 months for NLR < 3, P = .55). There was no impact of NLR ≥ median vs < median on time to PSA progression (15.5 and 16.1 months, respectively, P = .86).1FIGUREKaplan‐Meier estimation of time to PSA progression according to NLROn univariate analysis, ECOG PS≥1, serum ALP > ULN, Hb < 12 g/dL, high volume disease, and high‐risk status were also identified as significant factors predicting time to PSA progression (Table 2). We did not find any association of age, GS, the number of organ metastasis, visceral metastasis, serum calcium, and upfront docetaxel or abiraterone with time to PSA progression. In multivariate analysis, NLR ≥4 did not significantly predict time to PSA progression. However, ECOG PS ≥1, serum ALP > upper limit of normal, and Hb < 12 g/dL were identified as independent factors for shorter time to PSA progression (Table 3).2TABLEFactors significantly predicting time to PSA progression in the univariate analysisFactorMedian time to PSA progression (months)P‐valueECOG PS 028.2<.001ECOG PS ≥19.4ALP > ULN9.4<.001ALP ≤ ULN20.2Hb <12 g/dL9.3<.001Hb ≥12 g/dL18.4NLR ≥411.3.015NLR <418.3High volume diseasea12.1.002Low volume disease26.3High risk diseaseb12.0.001Low risk disease28.2Abbreviations: ALP, Alkaline Phosphatase; ECOG PS, Eastern Cooperative Oncology Group Performance status; Hb, Hemoglobin; NLR, neutrophil‐to‐lymphocyte ratio; ULN, Upper Limit of Normal.aCHAARTED trial definition.bLATITUDE trial definition.3TABLEMultivariate analysis for factors affecting time to PSA progressionFactorHR (95% CI)P‐valueECOG PS ≥13.33 (2.18‐5.08)<.001ALP ≥ ULN1.90 (1.30‐2.85).001Hb < 12 g/dL1.67 (1.10‐2.53).019High volume diseasea1.14 (0.60‐2.19).67High risk diseaseb1.31 (0.69‐2.48).15NLR ≥41.056 (0.65‐1.73).83Abbreviations: ALP, Alkaline Phosphatase; ECOG PS, Eastern Cooperative Oncology Group Performance Status; Hb, hemoglobin; ULN, upper limit of normal.aCHAARTED trial definition.bLATITUDE trial definition.NLR and OSAt a median follow‐up of 26 months, the median OS for the entire cohort was 47.1 months. Median OS was inferior in patients with NLR ≥4 compared to patients with NLR < 4 [23.9 vs 49.5 months, P = .001] (Figure 2). We did not identify a significant difference of NLR on OS by median NLR or at cutoff 3 (P‐values were not significant).2FIGUREKaplan‐Meier overall survival estimation according to NLROther factors that predicted OS in the univariate analysis included ECOG PS, volume status, risk status, serum ALP level, Hemoglobin level, and initial therapy administered (Table 4). Age, GS, serum calcium, visceral metastasis, prior local therapy, and the number of organ metastasis were not significant predictors of OS (P‐values were not statistically significant).4TABLEFactors significantly predicting overall survival in the univariate analysisFactorMedian OS (months)P‐valueNLR ≥423.90.001NLR <449.5ECOG PS ≥135.4<.001ECOG PS = 081.3High volume diseasea36.7<.001Low volume disease61.5High risk diseaseb37.7.002Low risk disease81.6ALP > ULN26.2<.001ALP ≤ ULN58.5Hb <12 g/dL20.5<.001Hb ≥12 g/dL55.9ADT alone40.4.040ADT plus docetaxel or abirateroneUnreachedAbbreviations: ADT, androgen deprivation therapy; ALP, alkaline phosphatase; ECOG PS, Eastern Cooperative Oncology Group Performance status; Hb, hemoglobin; NLR, neutrophil‐to‐lymphocyte ratio; OS, overall survival; ULN, upper limit of normal.aCHAARTED trial definition.bLATITUDE trial definition.NLR≥4 remains an independent factor for inferior OS on multivariate analysis and was associated with three‐fold increased risk of death (Table 5).5TABLEMultivariate analysis for factors affecting overall survivalFactorHR (95% CI)P‐valueECOG PS ≥19.90 (4.0‐24.5)<.001ALP > ULN1.39 (0.61‐3.17).43Hb < 12 g/dL5.75 (2.62‐14.29)<.001NLR ≥42.75 (1.01‐7.87).047High‐volume diseasea4.83 (1.53‐15.27).005High‐risk diseaseb3.04 (0.98‐9.43).065ADT alone1.55 (0.50‐4.76).43Abbreviations: ADT, androgen deprivation therapy; ALP, Alkaline Phosphatase; ECOG PS, Eastern Cooperative Oncology Group Performance Status; Hb, hemoglobin; ULN, upper limit of normal.aCHAARTED trial definition.bLATITUDE trial definition.DISCUSSIONThe importance of identifying pre‐treatment factors in patients with mCSPC that correlate with poor oncological outcomes stems from the fact that these patients might benefit from early treatment intensification. In this study, we assessed the impact of pre‐treatment NLR on oncological outcomes of patients with mCSPC and found that an elevated ratio was associated with inferior OS. Notably, after controlling for other patients and disease factors, elevated NLR remains an independent factor predicting inferior OS.The role of several inflammatory markers such as platelet‐to‐lymphocyte ratio (PLR), CRP, albumin, and NLR have been extensively studied in the context of various malignancies, as these markers might reflect the interaction between the immune system and tumor microenvironment.16‐18,26,27 For instance, the neutrophil count plays a major role in the tumor‐promoting activity, including cancer cell growth, and metastasis. While lymphocytes are suppressors of cancer progression.26,27 Sejima et al emphasized the concept of “Fas ligand tumor counter‐attack,” where FasL in tumor cells induce apoptosis of cytotoxic T lymphocytes in the tumor microenvironment, thus higher NLR. Indeed, FasL is overexpressed in high‐grade prostate cancer and is associated with worse OS.28Previous reports have assessed the prognostic value of NLR in the castration‐resistant stage of metastatic prostate cancer or those with non‐metastatic disease. In the meta‐analysis conducted by Yin et al, elevated NLR predicted poor OS (HR  =  1.57; 95% CI 1.41‐1.74; P   <  .001) and progression‐free survival (HR  =  1.97; 95% CI 1.28‐3.04; p   =  .002) of patients with mCRPC. On the contrary, NLR was not associated with oncological outcomes in patients with localized disease.19 Many other studies assessed the impact of NLR on treatment response to various treatment lines in mCRPC. For instance, elevated NLR (>2.14) was found to be associated with inferior OS in patients treated with enzalutamide.29 Other data showed a correlation between elevated NLR (> median value of 3.5) and inferior OS in patients treated with docetaxel in the first‐line setting.20 Mehra et al found a correlation between baseline NLR and clinical outcomes of patients with mCRPC treated with corticosteroids. In their study, a lower NLR was associated with superior PSA responses, and a higher NLR (log10) was associated with a shorter time to PSA progression (hazard ratio [HR], 9.5; 95% CI, 2.3‐39.9; P = .002).30 Moreover, baseline NLR ≥3.5 was predictive of lower PSA and radiologic responses to second‐line chemotherapy in mCRPC regardless of the use of corticosteroids.31 Most recently, a subanalysis of the CARD trial in mCRPC identified high baseline NLR (> median value of 3.38) as a predictor of a better response to cabazitaxel compared to Abiraterone/Enzulatamide.32Identifying NLR as a prognostic factor in mCRPC has led to incorporating it in prognostic models and nomograms alongside other prognostic factors.16,23 Such prognostic models may provide better insights on outcomes compared to the utilization of individual prognostic factors. Nevertheless, there is no data in the literature on the association of NLR with outcomes of patients with castration‐sensitive disease, and whether it could be useful to include the NLR in prognostic models. Therefore, we studied patients with castration‐sensitive metastatic disease and assessed the baseline NLR before the commencement of ADT. Importantly, we found a significant correlation of high NLR with OS. If these findings are externally validated in other cohorts, then the construction of prognostic models that include the NLR might give better insights on the outcomes of patients with mCSPC. In addition, such prognostic information may help investigate personalized risk‐adapted approaches of initial therapy selection.Although our study is the first to identify a prognostic role of NLR in patients with mCSPC, there are many limitations that we acknowledge. First, the small sample size and the retrospective design of the study are recognized limitations. Second, the study includes patients treated over 12 years, in which disease presentation and management have evolved. Third, to date, there is still no consensus on the optimal NLR cutoff value. Nevertheless, the cutoff of 4 was selected as a potential significant cutoff according to our statistical plan and was not assessed as an exploratory analysis. This cutoff value selection was based on sensitivity analysis for selecting a cutoff of 3 vs 4 in a prospective cohort study in patients with solid metastatic tumors.25 According to the sensitivity analysis, HR value for OS was non‐significant at a cut‐off of 3.0 (HR: 1.34, 95% CI: 0.99‐1.32), but significant when the cutoff was 4.0 (HR: 1.53, 95% CI: 1.11‐2.10). Interestingly, we selected both cutoffs in our preplanned analysis, and our data were supportive of the sensitivity analysis data.In conclusion, our data identified NLR ≥4 as an independent factor of inferior OS. However, NLR was not predictive of time to PSA progression. As such, if these findings are validated in other cohorts, elevated NLR may be used as a biomarker to predict OS in newly patients with mCSPC.CONFLICT OF INTERESTThe authors declare no potential conflict of interest.AUTHOR CONTRIBUTIONSConceptualization; data curation; formal analysis; methodology; supervision; validation; writing‐original draft; writing‐review, and editing, S.S.; Data curation; formal analysis; validation; writing‐review and editing, R. A.‐H.; Conceptualization; data curation; formal analysis; writing‐review and editing, F.A.; Data curation; formal analysis; writing‐review and editing, F.T. and A.A.‐T.; Conceptualization; formal analysis; methodology; writing‐original draft; writing‐review and editing, M.S.ETHICAL STATEMENTThis retrospective study was approved by the Institutional Review Board at King Hussein Cancer Center, Amman‐Jordan (approval of proposal no. 20 KHCC 96).DATA AVAILABILITY STATEMENTThe data used during the current study are available from the corresponding author on reasonable request.REFERENCESSiegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7‐30. https://doi.org/10.3322/caac.21590.Mukherji D, El Massih S, Daher M, et al. Prostate cancer stage at diagnosis: first data from a Middle‐Eastern cohort. J Clin Oncol. 2017;35(6_suppl):e552. https://doi.org/10.1200/JCO.2017.35.6_suppl.e552.de Bono JS, Logothetis CJ, Molina A, et al; COU‐AA‐301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995‐2005.Beltran H, Beer TM, Carducci MA, et al. New therapies for castration‐resistant prostate cancer: efficacy and safety. Eur Urol. 2011;60:279‐290.Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187‐1197.Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel‐T immunotherapy for castration‐resistant prostate cancer. N Engl J Med. 2010;363:411‐422.Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone‐sensitive prostate cancer: long‐term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018;36:1080‐1087. https://doi.org/10.1200/JCO.2017.75.3657.Fizazi K, Tran N, Fein L, et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high‐risk metastatic castration‐sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double‐blind, phase 3 trial. Lancet Oncol. 2019;20:686‐700. https://doi.org/10.1016/S1470-2045(19)30082-8.Gandaglia G, Abdollah F, Schiffmann J, et al. Distribution of metastatic sites in patients with prostate cancer: a population‐based analysis. Prostate. 2014;74:210‐216. https://doi.org/10.1002/pros.22742.Zhao F, Wang J, Chen M, et al. Sites of synchronous distant metastases and prognosis in prostate cancer patients with bone metastases at initial diagnosis: a population‐based study of 16,643 patients. Clin Transl Med. 2019;8:30. https://doi.org/10.1186/s40169-019-0247-4.Shou J, Zhang Q, Wang S, Zhang D. The prognosis of different distant metastases pattern in prostate cancer: a population based retrospective study. Prostate. 2018;78:491‐497. https://doi.org/10.1002/pros.23492.Alhanafy AM, Zanaty F, Ibrahem R, Omar S. Prognostic factors for hormone sensitive metastatic prostate cancer: impact of disease volume. Asian Pac J Cancer Prev. 2018;19:1113‐1118.Cui PF, Cong XF, Gao F, et al. Prognostic factors for overall survival in prostate cancer patients with different site‐specific visceral metastases: a study of 1358 patients. World J Clin Cases. 2020;8:54‐67. https://doi.org/10.12998/wjcc.v8.i1.54.Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646‐674.Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883‐899.Templeton AJ, Pezaro C, Omlin A, et al. Simple prognostic score for metastatic castration‐resistant prostate cancer with incorporation of neutrophil‐to‐lymphocyte ratio. Cancer. 2014;120:3346‐3352.Templeton AJ, McNamara MG, Seruga 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. https://doi.org/10.1093/jnci/dju124.Liu X, Qu JK, Zhang J, et al. Prognostic role of pretreatment neutrophil to lymphocyte ratio in breast cancer patients: a meta‐analysis. Medicine (Baltimore). 2017;96:e8101. https://doi.org/10.1097/MD.0000000000008101. Erratum in: Medicine (Baltimore). 2017; 96:e9526. PMID: 29137007; PMCID: PMC5690700.Yin X, Xiao Y, Li F, Qi S, Yin Z, Gao J. Prognostic role of neutrophil‐to‐lymphocyte ratio in prostate cancer: a systematic review and meta‐analysis. Medicine (Baltimore). 2016;95:e2544. https://doi.org/10.1097/MD.0000000000002544.Yao A, Sejima T, Iwamoto H, et al. High neutrophil‐to‐lymphocyte ratio predicts poor clinical outcome in patients with castration‐resistant prostate cancer treated with docetaxel chemotherapy. Int J Urol. 2015;22:827‐833.Sonpavde G, Pond GR, Armstrong AJ, et al. Prognostic impact of the neutrophil‐to‐lymphocyte ratio in men with metastatic castration‐resistant prostate cancer. Clin Genitourin Cancer. 2014;12:317‐324.Poyet C, Adank JP, Keller E, et al. Pretreatment systemic inflammatory response parameters do not predict the outcome in men with prostate cancer undergoing radical prostatectomy. J Urol. 2015;193:e817.Keizman D, Gottfried M, Ish‐Shalom M, et al. Pretreatment neutrophil‐to‐lymphocyte ratio in metastatic castration‐resistant prostate cancer patients treated with ketoconazole: association with outcome and predictive nomogram. Oncologist. 2012;17:1508‐1514.Scher HI, Morris MJ, Stadler WM, et al. Trial design and objectives for castration‐resistant prostate cancer: updated recommendations from the prostate cancer clinical trials working group 3. J Clin Oncol. 2016;34:1402‐1418. https://doi.org/10.1200/JCO.2015.64.2702.Vano YA, Oudard S, By MA, et al. Optimal cut‐off for neutrophil‐to‐lymphocyte ratio: fact or fantasy? A prospective cohort study in metastatic cancer patients. PLoS One. 2018;13:e0195042. https://doi.org/10.1371/journal.pone.0195042.Mantovani A, Allavena P, Sica A, Balkwill F. Cancer‐related inflammation. Nature. 2008;454:436‐444.Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW. The prognostic influence of tumour‐infiltrating lymphocytes in cancer: a systematic review with meta‐analysis. Br J Cancer. 2011;105:93‐103.Sejima T, Iwamoto H, Morizane S, et al. The significant immunological characteristics of peripheral blood neutrophil‐to‐lymphocyte ratio and Fas ligand expression incidence in nephrectomized tumor in late recurrence from renal cell carcinoma. Urol Oncol. 2013;31:1343‐1349.Kumano Y, Hasegawa Y, Kawahara T, et al. Pretreatment neutrophil to lymphocyte ratio (NLR) predicts prognosis for castration resistant prostate cancer patients underwent Enzalutamide. Biomed Res Int. 2019;20:9450838. https://doi.org/10.1155/2019/9450838.Mehra N, Sharp A, Lorente D, et al. Neutrophil to lymphocyte ratio in castration‐resistant prostate cancer patients treated with daily Oral corticosteroids. Clin Genitourin Cancer. 2017;15:678‐684.e1. https://doi.org/10.1016/j.clgc.2017.05.012.Lorente D, Mateo J, Templeton AJ, 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. https://doi.org/10.1093/annonc/mdu587.de Wit R, Wülfing C, Gauna DC, et al. 629P Neutrophil‐lymphocyte ratio (NLR) as a prognostic and predictive biomarker in patients with metastatic castration‐resistant prostate cancer (mCRPC) treated with cabazitaxel (CBZ) vs abiraterone or enzalutamide in the CARD study. Ann Oncol. 2020;31:S519‐S520. https://doi.org/10.1016/j.annonc.2020.08.888. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cancer Reports Wiley

Pretreatment neutrophil‐to‐lymphocyte ratio as a potential prognostic biomarker for newly diagnosed patients with metastatic castration‐sensitive prostate cancer

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Abstract

INTRODUCTIONProstate cancer is the most common malignancy and the second cause of cancer‐related death among men.1,2 According to the American cancer society estimations, 191 930 new cases will be diagnosed and 33 330 will die of the disease in 2020.1 Although 5% of prostate cancer patients present with stage IV disease in the USA, one‐fifth of men with prostate cancer present with metastatic disease in the Middle East.2The treatment algorithm of newly diagnosed metastatic castrate‐sensitive prostate cancer (mCSPC) has changed.3‐6 Early introduction of novel therapies such as docetaxel, abiraterone, and enzalutamide in the treatment regimen for mCSPC has resulted in significant improvement in overall survival (OS), particularly for the groups with poor prognostic factors.7,8 The survival of the CHAARTED‐trial defined high‐volume group is significantly improved with upfront docetaxel. No such benefit was observed for patients with low volume disease.7 Similar survival benefit has been reported with upfront use of abiraterone and prednisone plus androgen deprivation therapy (ADT) compared to ADT alone for the LATITUDE‐trial defined high‐risk group.8 Several poor prognostic factors in mCSPC have been described such as disease volume, visceral metastasis, Gleason score (GS) ≥8, high serum alkaline phosphatase (ALP), and poor Eastern Cooperative Oncology Group performance status (ECOG PS).9‐13Inflammation is a hallmark of cancer development and progression.14 Preclinical studies have pointed out that inflammation is involved in various cancer development stages, including initiation, promotion, malignant conversion, invasion, and metastasis.15 The neutrophil‐to‐lymphocyte ratio (NLR) is an inflammatory parameter that has been evaluated as a potential prognostic factor in various malignancies, including prostate cancer.16 Several reports showed an association between high NLR and poor survival outcomes for many cancers.16‐18 Yin et al conducted a meta‐analysis and found that elevated NLR predicted poor OS (HR  =  1.57; 95% CI 1.41‐1.74; P  <  .001) and progression‐free survival (HR  =  1.97; 95% CI 1.28‐3.04; P  =  .002) of patients with metastatic castration‐resistant prostate cancer (mCRPC). On the contrary, NLR was not associated with oncological outcomes in patients with localized disease.19Although the impact of NLR on OS has been well studied in metastatic castration‐resistant disease, it is not explored in newly diagnosed patients with mCSPC.19‐23The CHAARTED and LATITUDE trials highlighted the importance of prognostic stratification on initial therapy selection.7,8 Identifying all prognostic factors at the time of diagnosis of metastatic disease is a pre‐requisite to better risk‐stratify patients enrolled in future trials and may improve therapy selection. In this study, we assessed the prognostic role of pre‐treatment (baseline) NLR in newly diagnosed patients with mCSPC.METHODSAim and objectivesThis study aims to examine the prognostic role of NLR on the oncological outcomes of patients with newly diagnosed mCSPC. Study primary endpoints are to assess the impact of high NLR on time to prostatic‐specific antigen (PSA) progression and OS.Patients populationAfter Institutional Review Board approval, we identified all patients with metastatic prostate cancer who were referred to our center between June 2007 and June 2019. All patients were required to have pathologically confirmed prostatic adenocarcinoma and to have a metastatic disease detected on conventional imaging studies (computed tomography (CT) scan, magnetic resonance imaging, and bone scan). Patients with metastasis detected only on prostate‐specific membrane antigen scan without being detected on conventional imaging studies were excluded. Patients who develop a metastatic disease while being treated with ADT for biochemical relapse following definitive primary radiotherapy or radical prostatectomy or those presenting with castration‐resistant metastatic disease were also excluded.Variables: age at presentation, date of diagnosis of metastatic disease, sites of metastasis, number of metastatic bone lesions, GS, ECOG PS, and date of initiation of ADT, defined as the date of the first injection in patients treated with medical castration (GnRH agonists) or the date of orchidectomy for patients treated with surgical castration were abstracted. Concurrent administration of docetaxel and abiraterone was noted. Finally, pre‐treatment laboratory values, including blood counts, serum PSA, ALP, and serum calcium, were extracted. The pretreatment neutrophil‐to‐lymphocyte ratio was calculated for every patient by dividing the absolute neutrophil over the absolute lymphocyte count from the CBC before commencing ADT treatment.Also, we extracted data on the time of first PSA progression after starting ADT. PSA progression was defined according to the prostate cancer working group criteria (PCWG3).24 As such, time to PSA progression was defined as the time from start of ADT to the first PSA increase that is ≥25% and ≥2 ng/mL above the nadir, which is confirmed by a second value ≥3 weeks later. We also gathered data on dates of last follow‐up or death for all patients. OS was defined as time from diagnosis of the metastatic disease until the last follow‐up or death date.Metastatic burden was stratified into high volume and low volume disease based on the definition from CHAARTED trial. Accordingly, high volume disease was defined as the presence of more than three metastatic bone lesions with at least one lesion outside the spine and pelvis or the presence of visceral metastasis,7 while the LATITUDE trial defined risk status was used to classify patients into high‐risk/low‐risk disease, where high‐risk disease is defined as having at least two of the following: GS ≥8, at least three bone lesions, visceral metastasis.8Statistical analysisDescriptive statistics were interpreted as means, medians, SDs, and proportions. Time to PSA progression and OS were assessed by the Kaplan‐Meier method. Survival comparisons were carried out by the Log‐rank test.As the cutoff value for high vs low NLR is not well defined in literature, we opted to assess the correlation of NLR (< vs ≥ the median value) on the median time to PSA progression. In addition, we utilized cutoffs of 3 and 4 utilized and compared in the literature.25 We assessed the correlation of NLR at each of these cutoff points on time to PSA progression. In addition, we assessed the correlation of other‐disease related factors with time to PSA progression in univariate analysis, and then underwent a multivariate analysis for the significant factors (P < .05), utilizing the backward stepwise cox‐regression method.We priori planned to utilize the cutoff value of NLR significantly associated with time to PSA progression in OS analysis. Univariate analysis to assess the possible impact of factors other than the NLR on OS, including: GS, age, serum PSA, visceral vs non‐visceral metastasis, ECOG PS, serum alkaline phosphatase, serum calcium, serum Hb, volume status, and risk status was conducted. All factors with P < .05 in the univariate analysis were forced into a multivariate analysis for OS utilizing the backward stepwise cox‐regression method. All P‐values <.05 were considered statistically significant. All statistical analyses were performed using SPSS version 21 (SPSS Inc, Chicago, Illinois).RESULTSEligible patientsWe identified a total of 280 patients with metastatic prostate cancer. Forty‐three (15%) were excluded because they presented as new cases of mCRPC. Seventeen (6%) were excluded because they came for a second opinion and continued treatment at other centers or lost follow up, 9 (3%) because the pathology did not confirm prostatic adenocarcinoma, 4 (1%) because of diagnosis of a concurrent second malignancy, and 4 (1%) because the metastasis was not detected on conventional imaging studies. In addition, 14 (5%) were excluded for missing data on complete blood counts prior to starting ADT. Thus, a total of 189 patients were included in the final analysis. Patients' characteristics are summarized in Table 1. The median age at presentation was 69 years (range: 40‐89), median serum PSA: 155 ng/mL (range: 1.1‐30 000), and median GS: 9 (range: 6‐10).1TABLEDisease characteristics at initial presentation of included patientsPatients characteristicsN (%) or median (range)De novo metastatic181 (96%)Prior local therapy8 (4%)Median age69 (40–89)Median baseline serum PSA155 ng/mL (1.1–30 000)Median GS9 (6‐10)Bone metastasis174 (92%)No bone metastasis15 (8%)One organ metastasis104 (55%)≥2 organ metastases85 (45%)Visceral metastasis41 (22%)Non‐visceral metastasis148 (78%)ECOG PS 082 (43%)ECOG PS ≥183 (44%)Missing24 (13%)Hb < 12 g/dL50 (26%)Hb ≥12 g/dL139 (74%)NLR < 4150 (79%)NLR ≥439 (21%)High‐volume diseasea146 (77%)Low‐volume disease41 (22%)Not assessable2 (1%)High‐risk diseaseb144 (76%)Low‐risk disease44 (23%)Not assessable1 (<1%)Abbreviations: ECOG PS, Eastern Cooperative Oncology Group Performance Status; GS, Gleason Score; NLR, neutrophil‐to‐lymphocyte ratio; PSA, prostatic‐specific antigen.aCHAARTED trial definition.bLATITUDE trial definition.More than 90% (174/189) of patients had bone metastasis. Of 174 patients with bone metastasis, 37 (21%) had fewer than three bone lesions, and 135 (78%) had ≥3 bone lesions, whereas the number of lesions was not documented in 2 (1%). Approximately three‐quarters of patients had CHAARTED‐trial defined, and LATITUDE‐trial defined high‐volume and high‐risk status. Initial therapy administered was ADT alone for 134 patients (72%), ADT plus docetaxel (preplanned 6 cycles; CHAARTED protocol) for 48 (24%), and ADT plus abiraterone and prednisone for 7 (4%).The median NLR was 2.7, mean NLR 3.2 (sd: 2.37; range: 0.5‐22). A total of 39 patients (21%) had NLR ≥4.NLR and time to PSA progressionThe median time to PSA progression for the entire cohort was 15.6 months. Patients with NLR ≥4 had a shorter time to PSA progression compared to patients with NLR < 4; 11.3 and.18.3 months, respectively (P = .015) (Figure 1). We did not find any statistically significant difference of NLR on the median time to PSA progression using cutoff value of 3 (15.2 months for NLR ≥3 and 16.1 months for NLR < 3, P = .55). There was no impact of NLR ≥ median vs < median on time to PSA progression (15.5 and 16.1 months, respectively, P = .86).1FIGUREKaplan‐Meier estimation of time to PSA progression according to NLROn univariate analysis, ECOG PS≥1, serum ALP > ULN, Hb < 12 g/dL, high volume disease, and high‐risk status were also identified as significant factors predicting time to PSA progression (Table 2). We did not find any association of age, GS, the number of organ metastasis, visceral metastasis, serum calcium, and upfront docetaxel or abiraterone with time to PSA progression. In multivariate analysis, NLR ≥4 did not significantly predict time to PSA progression. However, ECOG PS ≥1, serum ALP > upper limit of normal, and Hb < 12 g/dL were identified as independent factors for shorter time to PSA progression (Table 3).2TABLEFactors significantly predicting time to PSA progression in the univariate analysisFactorMedian time to PSA progression (months)P‐valueECOG PS 028.2<.001ECOG PS ≥19.4ALP > ULN9.4<.001ALP ≤ ULN20.2Hb <12 g/dL9.3<.001Hb ≥12 g/dL18.4NLR ≥411.3.015NLR <418.3High volume diseasea12.1.002Low volume disease26.3High risk diseaseb12.0.001Low risk disease28.2Abbreviations: ALP, Alkaline Phosphatase; ECOG PS, Eastern Cooperative Oncology Group Performance status; Hb, Hemoglobin; NLR, neutrophil‐to‐lymphocyte ratio; ULN, Upper Limit of Normal.aCHAARTED trial definition.bLATITUDE trial definition.3TABLEMultivariate analysis for factors affecting time to PSA progressionFactorHR (95% CI)P‐valueECOG PS ≥13.33 (2.18‐5.08)<.001ALP ≥ ULN1.90 (1.30‐2.85).001Hb < 12 g/dL1.67 (1.10‐2.53).019High volume diseasea1.14 (0.60‐2.19).67High risk diseaseb1.31 (0.69‐2.48).15NLR ≥41.056 (0.65‐1.73).83Abbreviations: ALP, Alkaline Phosphatase; ECOG PS, Eastern Cooperative Oncology Group Performance Status; Hb, hemoglobin; ULN, upper limit of normal.aCHAARTED trial definition.bLATITUDE trial definition.NLR and OSAt a median follow‐up of 26 months, the median OS for the entire cohort was 47.1 months. Median OS was inferior in patients with NLR ≥4 compared to patients with NLR < 4 [23.9 vs 49.5 months, P = .001] (Figure 2). We did not identify a significant difference of NLR on OS by median NLR or at cutoff 3 (P‐values were not significant).2FIGUREKaplan‐Meier overall survival estimation according to NLROther factors that predicted OS in the univariate analysis included ECOG PS, volume status, risk status, serum ALP level, Hemoglobin level, and initial therapy administered (Table 4). Age, GS, serum calcium, visceral metastasis, prior local therapy, and the number of organ metastasis were not significant predictors of OS (P‐values were not statistically significant).4TABLEFactors significantly predicting overall survival in the univariate analysisFactorMedian OS (months)P‐valueNLR ≥423.90.001NLR <449.5ECOG PS ≥135.4<.001ECOG PS = 081.3High volume diseasea36.7<.001Low volume disease61.5High risk diseaseb37.7.002Low risk disease81.6ALP > ULN26.2<.001ALP ≤ ULN58.5Hb <12 g/dL20.5<.001Hb ≥12 g/dL55.9ADT alone40.4.040ADT plus docetaxel or abirateroneUnreachedAbbreviations: ADT, androgen deprivation therapy; ALP, alkaline phosphatase; ECOG PS, Eastern Cooperative Oncology Group Performance status; Hb, hemoglobin; NLR, neutrophil‐to‐lymphocyte ratio; OS, overall survival; ULN, upper limit of normal.aCHAARTED trial definition.bLATITUDE trial definition.NLR≥4 remains an independent factor for inferior OS on multivariate analysis and was associated with three‐fold increased risk of death (Table 5).5TABLEMultivariate analysis for factors affecting overall survivalFactorHR (95% CI)P‐valueECOG PS ≥19.90 (4.0‐24.5)<.001ALP > ULN1.39 (0.61‐3.17).43Hb < 12 g/dL5.75 (2.62‐14.29)<.001NLR ≥42.75 (1.01‐7.87).047High‐volume diseasea4.83 (1.53‐15.27).005High‐risk diseaseb3.04 (0.98‐9.43).065ADT alone1.55 (0.50‐4.76).43Abbreviations: ADT, androgen deprivation therapy; ALP, Alkaline Phosphatase; ECOG PS, Eastern Cooperative Oncology Group Performance Status; Hb, hemoglobin; ULN, upper limit of normal.aCHAARTED trial definition.bLATITUDE trial definition.DISCUSSIONThe importance of identifying pre‐treatment factors in patients with mCSPC that correlate with poor oncological outcomes stems from the fact that these patients might benefit from early treatment intensification. In this study, we assessed the impact of pre‐treatment NLR on oncological outcomes of patients with mCSPC and found that an elevated ratio was associated with inferior OS. Notably, after controlling for other patients and disease factors, elevated NLR remains an independent factor predicting inferior OS.The role of several inflammatory markers such as platelet‐to‐lymphocyte ratio (PLR), CRP, albumin, and NLR have been extensively studied in the context of various malignancies, as these markers might reflect the interaction between the immune system and tumor microenvironment.16‐18,26,27 For instance, the neutrophil count plays a major role in the tumor‐promoting activity, including cancer cell growth, and metastasis. While lymphocytes are suppressors of cancer progression.26,27 Sejima et al emphasized the concept of “Fas ligand tumor counter‐attack,” where FasL in tumor cells induce apoptosis of cytotoxic T lymphocytes in the tumor microenvironment, thus higher NLR. Indeed, FasL is overexpressed in high‐grade prostate cancer and is associated with worse OS.28Previous reports have assessed the prognostic value of NLR in the castration‐resistant stage of metastatic prostate cancer or those with non‐metastatic disease. In the meta‐analysis conducted by Yin et al, elevated NLR predicted poor OS (HR  =  1.57; 95% CI 1.41‐1.74; P   <  .001) and progression‐free survival (HR  =  1.97; 95% CI 1.28‐3.04; p   =  .002) of patients with mCRPC. On the contrary, NLR was not associated with oncological outcomes in patients with localized disease.19 Many other studies assessed the impact of NLR on treatment response to various treatment lines in mCRPC. For instance, elevated NLR (>2.14) was found to be associated with inferior OS in patients treated with enzalutamide.29 Other data showed a correlation between elevated NLR (> median value of 3.5) and inferior OS in patients treated with docetaxel in the first‐line setting.20 Mehra et al found a correlation between baseline NLR and clinical outcomes of patients with mCRPC treated with corticosteroids. In their study, a lower NLR was associated with superior PSA responses, and a higher NLR (log10) was associated with a shorter time to PSA progression (hazard ratio [HR], 9.5; 95% CI, 2.3‐39.9; P = .002).30 Moreover, baseline NLR ≥3.5 was predictive of lower PSA and radiologic responses to second‐line chemotherapy in mCRPC regardless of the use of corticosteroids.31 Most recently, a subanalysis of the CARD trial in mCRPC identified high baseline NLR (> median value of 3.38) as a predictor of a better response to cabazitaxel compared to Abiraterone/Enzulatamide.32Identifying NLR as a prognostic factor in mCRPC has led to incorporating it in prognostic models and nomograms alongside other prognostic factors.16,23 Such prognostic models may provide better insights on outcomes compared to the utilization of individual prognostic factors. Nevertheless, there is no data in the literature on the association of NLR with outcomes of patients with castration‐sensitive disease, and whether it could be useful to include the NLR in prognostic models. Therefore, we studied patients with castration‐sensitive metastatic disease and assessed the baseline NLR before the commencement of ADT. Importantly, we found a significant correlation of high NLR with OS. If these findings are externally validated in other cohorts, then the construction of prognostic models that include the NLR might give better insights on the outcomes of patients with mCSPC. In addition, such prognostic information may help investigate personalized risk‐adapted approaches of initial therapy selection.Although our study is the first to identify a prognostic role of NLR in patients with mCSPC, there are many limitations that we acknowledge. First, the small sample size and the retrospective design of the study are recognized limitations. Second, the study includes patients treated over 12 years, in which disease presentation and management have evolved. Third, to date, there is still no consensus on the optimal NLR cutoff value. Nevertheless, the cutoff of 4 was selected as a potential significant cutoff according to our statistical plan and was not assessed as an exploratory analysis. This cutoff value selection was based on sensitivity analysis for selecting a cutoff of 3 vs 4 in a prospective cohort study in patients with solid metastatic tumors.25 According to the sensitivity analysis, HR value for OS was non‐significant at a cut‐off of 3.0 (HR: 1.34, 95% CI: 0.99‐1.32), but significant when the cutoff was 4.0 (HR: 1.53, 95% CI: 1.11‐2.10). Interestingly, we selected both cutoffs in our preplanned analysis, and our data were supportive of the sensitivity analysis data.In conclusion, our data identified NLR ≥4 as an independent factor of inferior OS. However, NLR was not predictive of time to PSA progression. As such, if these findings are validated in other cohorts, elevated NLR may be used as a biomarker to predict OS in newly patients with mCSPC.CONFLICT OF INTERESTThe authors declare no potential conflict of interest.AUTHOR CONTRIBUTIONSConceptualization; data curation; formal analysis; methodology; supervision; validation; writing‐original draft; writing‐review, and editing, S.S.; Data curation; formal analysis; validation; writing‐review and editing, R. A.‐H.; Conceptualization; data curation; formal analysis; writing‐review and editing, F.A.; Data curation; formal analysis; writing‐review and editing, F.T. and A.A.‐T.; Conceptualization; formal analysis; methodology; writing‐original draft; writing‐review and editing, M.S.ETHICAL STATEMENTThis retrospective study was approved by the Institutional Review Board at King Hussein Cancer Center, Amman‐Jordan (approval of proposal no. 20 KHCC 96).DATA AVAILABILITY STATEMENTThe data used during the current study are available from the corresponding author on reasonable request.REFERENCESSiegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7‐30. https://doi.org/10.3322/caac.21590.Mukherji D, El Massih S, Daher M, et al. Prostate cancer stage at diagnosis: first data from a Middle‐Eastern cohort. J Clin Oncol. 2017;35(6_suppl):e552. https://doi.org/10.1200/JCO.2017.35.6_suppl.e552.de Bono JS, Logothetis CJ, Molina A, et al; COU‐AA‐301 Investigators. 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Journal

Cancer ReportsWiley

Published: Oct 1, 2021

Keywords: biomarkers; metastasis; prognosis; prostate cancer; survival

References