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| A novel preoperative inflammatory marker prognostic score in patients with localized |
R. Sekar Rishia,Patil Dattatrayaa,Baum Yorama,Pearl Jeffreya,Bausum Annaa,A. Bilen Mehmetb,Kucuk Omerbc,B. Harris Waynebcd,C. Carthon Bradleybc,Alemozaffar Mehrdadac,P. Filson Christopherabd,G. Pattaras Johna,T. Nieh Petera,Ogan Kennetha,A. Master Virajac*( )
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a Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
b Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
c Winship Cancer Institute of Emory University, Emory University School of Medicine, Atlanta, GA, USA
d The Atlanta VA Medical Center, Emory University School of Medicine, Atlanta, GA, USA |
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Abstract Objective: Several inflammatory markers have been studied as potential biomarkers in renal cell carcinoma (RCC), however few reports have analyzed their prognostic value in aggregate and in non-clear cell histologies. We hypothesize that a combination of specific inflammatory markers into an RCC Inflammatory Score (RISK) could serve as a rigorous prognostic indicator of overall survival (OS) in patients with clear cell and non-clear cell RCC.Methods: Combination of preoperative C-reactive protein (CRP), albumin, erythrocyte sedimentation rate (ESR), corrected calcium, and aspartate transaminase to alanine transaminase (AST/ALT) ratio was used to develop RISK. RISK was developed using grid-search methodology, receiver-operating-characteristic (ROC) analysis, and sensitivity-specificity trade-off analysis. Prognostic value of RISK was analyzed using the Kaplan-Meier method and Cox proportional regression models. Predictive accuracy was compared with RISK to Size, Size, Grade, and Necrosis (SSIGN) score, University of California-LOS Angeles (UCLA) Integrated Staging System (UISS), and Leibovich Prognosis Score (LPS).Results: Among 391 RCC patients treated with nephrectomy, area under the curve (AUC) for RISK was 0.783, which was comparable to SSIGN (AUC 0.776, p = 0.82) and UISS (AUC 0.809, p = 0.317). Among patients with localized disease, AUC for RISK and LPS was 0.742 and 0.706, respectively (p= 0.456). On multivariate analysis, we observed a step-wise statistically significant inverse relationship between increasing RISK group and OS (all p < 0.001).Conclusion: RISK is an independent and significant predictor of OS for patients treated with nephrectomy for clear cell and non-clear cell RCC, with accuracy comparable to other histopathological prognostic tools.
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Published: 26 October 2017
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Corresponding Authors:
A. Master Viraj
E-mail: vmaster@emory.edu
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Inclusion and exclusion criteria for the study. ALT, alanine transaminase; AST, aspartate transaminase; RCC, renal cell carcinoma.
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| Laboratory value | Collection time before surgerya | Assay method and kit information | | Albumin (g/dL) | Within 21 days | Beckman Coulter Synchron System | | C-reactive protein (mg/L) | Within 14 days | Beckman Coulter Synchron System | | Erythrocyte sedimentation rate (mm/h) | Within 30 days | ALCOR Scientific iSED Automated Sedimentation Rate Analyzer | | AST (U/L) | Within 7 days | Beckman Coulter Synchron System | | ALT (U/L) | Within 7 days | Beckman Coulter Synchron System | | Calcium (mg/dL) | Within 30 days | Beckman Coulter Synchron System |
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RISK biomarker assay methods, collection, and kit information.
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| Parameter | Biomarker Score | | 0 | 1 | 2 | | Albumin (g/dL) | >3.5 | 2.5–3.5 | <2.5 | | CRP (mg/L) | <10 | 10–25 | >25 | | ESR (mm/h) | | | | | Male | <22 | 22–45 | >45 | | Female | <29 | 29–55 | >55 | | AST/ALT ratio | | | | | Male | <1.10 | 1.1–1.54 | >1.54 | | Female | <1.23 | 1.23–1.54 | >1.54 | | Corrected calcium (mg/dL) | <9.7 | 9.7–10.1 | >10.1 |
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RISK calculation based on biomarker thresholds.
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| Feature | Overallcohort*(n=391) | Clearcellsub-cohort*(n=280) | | Primarytumor(1997Tstage)a | | | | T1 | 207(55.95) | 146(54.48) | | T2 | 38(10.27) | 23(8.58) | | T3 | 114(30.81) | 94(35.07) | | T4 | 11(2.97) | 5(1.87) | | Regionallymphnodes(Nstage)a | | | | N0 | 328(84.10) | 234(83.47) | | N1 | 57(14.62) | 45(16.17) | | N2 | 5(1.28) | 1(0.36) | | Distantmetastases(Mstage)a | | | | M0 | 314(80.51) | 216(77.14) | | M1 | 76(19.49) | 64(22.86) | | Tumorsize(cm) | | | | Mean±SD | 6.1±4.1 | 6.1±4 | | Median(min–max) | 5.1(0.4–23.0) | 5.3(0.5–23.0) | | Nucleargradea | | | | 1 | 10(2.66) | 8(2.88) | | 2 | 149(39.62) | 115(41.37) | | 3 | 162(43.09) | 111(39.93) | | 4 | 55(14.63) | 44(15.82) | | Necrosisa | | | | No | 174(57.24) | 133(59.37) | | Yes | 130(42.76) | 91(40.63) |
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Description of clinical and pathological parameters of the overall study cohort (n=391) and clear cell RCC sub-cohort (n=280).
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| Covariate | Univariable | Multivariable | | HR (95%CI) | p-value | HR (95%CI) | p-value | | Age | 1.04 (1.02–1.06) | <0.001 | 1.04 (1.01–1.07) | 0.010 | | BMI | 0.94 (0.90–0.98) | 0.003 | 0.97 (0.93–1.02) | 0.209 | | Sex (ref: female) | 1.08 (0.64–1.82) | 0.767 | | | | Race (ref: non-African-American) | 1.21 (0.64–2.26) | 0.556 | | | | Pre-op ECOG performance status (ref: 0) | 3.35 (2.05–5.49) | <0.001 | 2.25 (1.31–3.86) | 0.003 | | 2009 T stage | | | | | | pT2 | 2.20 (0.85–5.68) | 0.102 | 0.49 (0.15–1.58) | 0.229 | | pT3 | 6.39 (3.50–11.68) | <0.001 | 0.88 (0.35–2.21) | 0.783 | | pT4 | 10.96 (3.58–33.59) | <0.001 | 1.54 (0.36–6.60) | 0.564 | | 2009 N stage (ref: N0) | 5.51 (3.33–9.12) | <0.001 | 1.82 (0.89–3.72) | 0.103 | | 2009 M stage (ref: M0) | 6.01 (3.65–9.89) | <0.001 | 1.31 (0.61–2.80) | 0.483 | | FNG (ref: G1–G2) | 3.64 (1.90–6.97) | <0.001 | 0.97 (0.39–2.41) | 0.951 | | Tumor dimensions (ref: <5 cm) | 4.31 (2.29–8.12) | <0.001 | 2.63 (1.09–6.34) | 0.031 | | RISK (ref: baseline) | | | | | | Low risk | 1.35 (0.37–4.92) | 0.645 | 0.72 (0.18–2.85) | 0.643 | | Intermediate risk | 8.64 (2.57–29.02) | <0.001 | 3.29 (0.83–13.06) | 0.090 | | High risk | 18.41 (5.60–60.58) | <0.001 | 4.80 (1.23–18.74) | 0.024 | | C-reactive protein (ref: <10 mg/L) | | | | | | 10–25 mg/L | 3.27 (1.45–7.34) | 0.004 | | | | >25 mg/L | 9.01 (5.05–16.07) | <0.001 | | | | Albumin (ref: > 3.5 mg/dL) | | | | | | 2.5–3.5 mg/dL | 4.44 (2.61–7.53) | <0.001 | | | | <2.5 mg/dL | 6.15 (2.64–14.32) | <0.001 | | | | ESR (ref: 0–22 (male)/0–29 (female) mm/h) | | | | | | 22–45 (male)/29–55 (female) mm/h | 2.94 (1.29–6.70) | 0.01 | | | | ≥45 (male)/≥55 (female) mm/h | 10.08 (5.02–20.24) | <0.001 | | | | AST/ALT ratio (ref: 1.1 (male)/1.23 (female)) | | | | | | 1.1–1.54 (male)/1.23–1.54 (female) | 1.08 (0.59–1.97) | 0.803 | | | | >1.54 | 2.65 (1.46–4.84) | 0.001 | | | | Calcium (ref: <9.7 mg/dL) | | | | | | 9.7–10.11 mg/dL | 2.12 (1.02–4.39) | 0.044 | | | | >10.11 mg/dL | 6.94 (3.58–13.42) | <0.001 | | |
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Univariate and multivariate association of overall survival in the overall cohort (N=391).
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| Covariate | Univariable | Multivariable | | HR (95%CI) | p-value | HR (95%CI) | p-value | | Age | 1.03 (1.00–1.05) | 0.035 | 1.02 (0.98–1.05) | 0.346 | | BMI | 0.94 (0.9–0.98) | 0.004 | 0.97 (0.92–1.01) | 0.132 | | Sex (ref: female) | 1.15 (0.65–2.02) | 0.631 | | | | Race (ref: non-African-American) | 2.85 (1.46–5.56) | 0.001 | | | | Pre-op ECOG performance status (ref: 0) | 2.84 (1.66–4.86) | <0.001 | 2.15 (1.19–3.90) | 0.012 | | 2009 T stage | | | | | | pT2 | 1.82 (0.59–5.59) | 0.295 | 0.32 (0.08–1.22) | 0.094 | | pT3 | 5.85 (3.07–11.12) | <0.001 | 0.74 (0.28–1.99) | 0.554 | | pT4 | 5.56 (0.72–43.12) | 0.101 | 0.68 (0.07–6.23) | 0.735 | | 2009 N stage (ref: N0) | 5.18 (2.99–8.97) | <0.001 | 1.89 (0.87–4.11) | | | 2009 M stage (ref: M0) | 5.24 (3.05–9.02) | <0.001 | 1.13 (0.50–2.55) | | | FNG (ref: G1–G2) | 3.47 (1.79–6.73) | <0.001 | 0.83 (0.30–2.25) | 0.710 | | Tumor dimensions (ref: <5 cm) | 4.88 (2.37–10.03) | <0.001 | 2.95 (1.15–7.55) | 0.024 | | RISK (ref: baseline) | | | | | | Low risk | 1.31 (0.34–5.07) | 0.696 | 0.74 (0.17–3.26) | 0.886 | | Intermediate risk | 9.55 (2.83–32.25) | <0.001 | 5.36 (1.23–23.46) | 0.026 | | High risk | 16.44 (4.92–54.93) | <0.001 | 5.52 (1.29–23.55) | 0.021 | | C-reactive protein (ref: <10 mg/L) | | | | | | 10–25 mg/L | 3.96 (1.71–9.18) | 0.001 | | | | >25 mg/L | 7.62 (4.03–14.41) | <0.001 | | | | Albumin (ref: > 3.5 mg/dL) | | | | | | 2.5–3.5 mg/dL | 4.33 (2.44–7.68) | <0.001 | | | | <2.5 mg/dL | 4.62 (1.73–12.33) | 0.002 | | | | ESR (ref: 0–22 (male)/0–29 (female) mm/h) | | | | | | 22–45 (male)/29–55 (female) mm/h | 2.84 (1.15–6.98) | 0.023 | | | | ≥45 (male)/≥55 (female) mm/h | 8.72 (4.16–18.25) | <0.001 | | | | AST/ALT ratio (ref: 1.1 (male)/1.23 (female)) | | | | | | 1.1–1.54 (male)/1.23–1.54 (female) | 1.41 (0.76–2.62) | 0.276 | | | | >1.54 | 2.67 (1.32–5.39) | 0.006 | | | | Calcium (ref: <9.7 mg/dL) | | | | | | 9.7–10.11 mg/dL | 2.43 (1.09–5.42) | 0.029 | | | | >10.11 mg/dL | 6.90 (3.35–14.21) | <0.001 | | |
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Univariate and multivariate association of overall survival in the clear cell RCC sub-cohort (n=280).
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KaplaneMeier curves predicting overall survival in the overall cohort (n=391), categorized by RISK group. RCC, renal cell carcinoma.
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