Urologic Oncology: Seminars and Original Investigations 32 (2014) 1277–1284
Original article
Preoperative neutrophil-lymphocyte ratio predicts death among patients with localized clear cell renal carcinoma undergoing nephrectomy Boyd R. Viers, M.D.a, Robert Houston Thompson, M.D.a, Stephen A. Boorjian, M.D.a, Christine M. Lohse, M.S.b, Bradley C. Leibovich, M.D.a, Matthew K. Tollefson, M.D.a,* a
b
Department of Urology, Mayo Clinic, Rochester, MN Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN
Received 12 March 2014; received in revised form 30 April 2014; accepted 31 May 2014
Abstract Objectives: The neutrophil-lymphocyte ratio (NLR) is an indicator of the systemic inflammatory response. An increased pretreatment NLR has been associated with adverse outcomes in other malignancies, but its role in localized (M0) clear cell renal cell carcinoma (ccRCC) remains unclear. As such, we evaluated the ability of preoperative NLR to predict oncologic outcomes in patients with M0 ccRCC undergoing radical nephrectomy (RN). Methods and materials: From 1995 to 2008, 952 patients underwent RN for M0 ccRCC. Of these, 827 (87%) had pretreatment NLR collected within 90 days before RN. Metastasis-free, cancer-specific, and overall survival was estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate models were used to analyze the association of NLR with clinicopathologic outcomes. Results: At a median follow-up of 9.3 years, 302, 233, and 436 patients had distant metastasis, death from ccRCC, and all-cause mortality, respectively. Higher NLR was associated with larger tumor size, higher nuclear grade, histologic tumor necrosis, and sarcomatoid differentiation (all, P o 0.001). A NLR Z 4.0 was significantly associated with worse 5-year cancer-specific (66% vs. 85%) and overall survival (66% vs. 85%). Finally, after controlling for clinicopathologic features, NLR remained independently associated with risks of death from ccRCC and all-cause mortality (hazard ratio for 1-unit increase: 1.02, P o 0.01). Conclusions: Our results suggest that NLR is independently associated with increased risks of cancer-specific and all-cause mortality among patients with M0 ccRCC undergoing RN. Accordingly, NLR, an easily obtained marker of biologically aggressive ccRCC, may be useful in preoperative patient risk stratification. r 2014 Elsevier Inc. All rights reserved.
Keywords: Neutrophil-lymphocyte ratio; Clear cell; Nonmetastatic; Renal cancer; Radical nephrectomy
1. Introduction There has been an increase in the incidence of renal cell carcinoma (RCC) in the last 3 decades [1] with most patients with RCC (480%) presenting with the clear cell (cc) histologic subtype [2]. Although surgical resection remains the “gold standard” treatment for patients with Take-Home Message: Pretreatment NLR is independently associated with an increased risk of cancer-specific and all-cause mortality among patients with clinically localized ccRCC undergoing RN. Accordingly, NLR, an easily obtained marker of biologically aggressive ccRCC, may be useful in preoperative patient risk stratification. * Corresponding author. Tel.: þ1-507-266-6091; fax: þ1-507-284-4951. E-mail address: [email protected] (M.K. Tollefson). http://dx.doi.org/10.1016/j.urolonc.2014.05.014 1078-1439/r 2014 Elsevier Inc. All rights reserved.
clinically localized disease, approximately 10% to 60% of such patients develop recurrence following surgical extirpation [3], and of these patients, a significant proportion die of their disease [4]. Therefore, advancements in patient risk stratification are needed to appropriately identify patients at highest risk of cancer-related mortality who may be candidates for adjuvant therapy trial enrollment. One significant challenge in the identification of the patients at highest risk is the limited pretreatment risk data that are available for patients presenting with a solid renal mass. Not surprisingly, then, most current predictive models rely almost exclusively on postoperative pathologic analysis of the surgical specimen with minimal consideration for associated patient-related variables [5–7]. As such, the
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potential exists that the prognostic accuracy of these models may be significantly improved with the addition of inflammatory and molecular tumor biomarkers [8]. Nevertheless, a paucity of preoperative data exists to facilitate appropriate patient counseling and guide clinic trial enrollment, and thereby there remains a need to identify biomarkers that will incrementally improve preoperative risk stratification. The neutrophil-lymphocyte ratio (NLR) represents an easily measured, reproducible, and inexpensive marker of systemic inflammation that has been associated with oncologic outcomes in multiple malignancies, including colorectal and gastric cancers [9,10]. It has been hypothesized that the synthesis of inflammatory cytokines triggered by the tumor microenvironment alters acute phase reactants and hematological components including serum neutrophil and lymphocyte counts [11,12]. Evaluation of NLR in ccRCC might be particularly relevant as inflammation has been correlated with tumor stage, grade, and proliferative index and, moreover, has been associated with disease-free and overall survival as well [13,14]. Indeed, ccRCC is currently one of the few malignancies in which immunotherapy has been employed, in some cases (high-dose IL-2), with remarkable responses. In fact, both lymphocytosis and C-reactive protein have been observed to be predictive of oncologic outcomes in patients treated for advanced RCC [15,16]. For those with RCC undergoing curative resection, lymphocytopenia and an elevated CRP have been associated with worse cancer-related outcomes, suggesting a correlation between inflammation and disease biology [17,18]. Nevertheless, limited data exist regarding the potential prognostic value of NLR in nonmetastatic (M0) ccRCC [19–21]. Moreover, these studies have been limited by relatively small patient numbers, heterogeneous histologic subtypes, short-term follow-up, and differing clinical end points. We hypothesize that a greater preoperative NLR is associated with adverse outcomes among patients treated for RCC. Accordingly, we sought to determine the association between pretreatment NLR and oncologic outcomes in a large cohort of patients with M0 ccRCC treated with radical nephrectomy (RN) with long-term follow-up.
2. Materials and methods Following institutional review board approval, we reviewed the Mayo Clinic Nephrectomy Registry to identify 952 patients treated with RN for sporadic, unilateral, noncystic M0 ccRCC at our institution between 1995 and 2008. The clinic variables recorded included age, sex, year of RN, surgical approach (open vs. laparoscopic), symptoms at presentation, smoking status, Eastern Cooperative Oncology Group (ECOG) performance status, Charlson
comorbidity index, body mass index (BMI), obesity (defined as BMI Z 30), neutrophil count, lymphocyte count, pretreatment NLR, estimated blood loss during RN, and units of blood transfused during surgery or hospitalization. Patients with a palpable flank or abdominal mass, discomfort, gross hematuria, acute-onset varicocele, or constitutional symptoms including rash, sweats, weight loss, fatigue, early satiety, and anorexia were considered symptomatic. Neutrophil and lymphocyte counts closest to RN, but within 3 months before, were used for analysis. When multiple values existed for a patient, the values closest to the date of RN were utilized. The pathologic features studied included histologic subtype classified according to the Union Internationale Contre le Cancer, American Joint Committee on Cancer, and Heidelberg guidelines, tumor size, the 2009 primary tumor and regional lymph node classifications, nuclear grade, coagulative tumor necrosis, and sarcomatoid differentiation. One genitourinary pathologist (J.C.C.) re-reviewed the microscopic slides from all specimens without knowledge of patient outcome. The primary tumor stage, size, nuclear grade, and coagulative tumor necrosis characteristics were combined to calculate the Stage, Size, Grade, and Necrosis (SSIGN) score [5]. The SSIGN score was developed at our institution to stratify cancer-specific survival in patients with ccRCC undergoing nephrectomy. Lymph node dissection was performed at the discretion of the treating surgeon at the time of RN. At our institution, follow-up after RN was generally done quarterly for the first 2 years, semiannually for the next 2 years, and annually thereafter for patients without evidence of recurrent disease. For survival end points, vital status was identified from death certificates or physician correspondence. For patients followed up elsewhere, the Nephrectomy Registry monitors outcomes annually by correspondence with the patient and the local treating physician. Comparisons of clinicopathologic features and presurgical NLR were performed using the Wilcoxon rank sum, chi-square, Fisher exact, and Cochran-Armitage trend tests, as appropriate. Metastasis-free, cancer-specific, and overall survivals were estimated as the time from RN to event, or last follow-up, using the Kaplan-Meier method and compared with the log-rank test. A visual assessment of the association of NLR with patient outcome (i.e., a plot of martingale residuals from a null Cox model against NLR) indicated that this association was fairly linear, with an optimal cutpoint for increased risk of metastases or death from ccRCC occurring at a NLR of approximately 4.0. As such, associations of NLR with patient outcome were evaluated using NLR as a continuous variable and using a cutpoint Z4.0. Cox proportional hazard regression models were used to evaluate the association of NLR with outcomes, controlling for clinicopathologic variables. A P o 0.05 was considered statistically significant. Statistical analyses were performed using the SAS software package (SAS Institute, Cary, NC).
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3. Results Of the 952 patients who underwent RN at our institution between 1995 and 2008, 827 (87%) had preoperative neutrophil and lymphocyte counts available for analysis. Patients with an available NLR were treated earlier in the study time frame (median year of RN 2001 vs. 2003; P o 0.001), were older (median age 65 vs. 60 y; P ¼ 0.008), and were less likely to be treated with laparoscopic RN (13% vs. 22%, P ¼ 0.008) compared with patients without an available NLR. None of the other clinicopathologic features studied were significantly different between patients with and without available NLR. Overall median NLR was 3.51 (interquartile range [IQR] ¼ 2.43–6.12), of which 476 (58%) had a NLR o 4.0 and 351 (42%) had a NLR Z 4.0. Clinicopathologic features for patients with preoperative NLR Z and o4.0 are provided in Table 1. As depicted, patients with NLR Z 4.0 were more likely to be men, have a lower BMI, have greater blood loss at RN, undergo open RN, have worse ECOG performance score, have local or constitutional symptoms, and require blood transfusion during RN or hospitalization (all, P o 0.05). Pathologically, patients with a NLR Z 4.0 had a greater SSIGN score (median ¼ 5 vs. 3), larger tumor size (median ¼ 8 vs. 6.5 cm), pathologically advanced (pT3/4) tumors (50% vs. 32%), level I to IV tumor thrombuses (20% vs. 6%), greater nuclear grade, and coagulative tumor necrosis or sarcomatoid differentiation (all, P o 0.05). The median duration of follow-up after surgery was 9.3 years (IQR ¼ 6.3–12.8). During that time, 302 experienced disease recurrence at a median 1.2 years following RN (IQR ¼ 0.4–3.3). Furthermore, 436 died (median 3.6 y after RN; IQR ¼ 1.5–6.9), of whom 233 died of ccRCC (median 2.4 y after RN; IQR ¼ 1.1–5.1). We found that, when compared with patients with a NLR o 4.0, patients with a NLR Z 4.0 had significantly worse 5-year distant metastasisfree (58% vs. 74%) (Fig. 1), cancer-specific (66% vs. 85%) (Fig. 2), and overall survival (55% vs. 76%) (Fig. 3). We then investigated the association between NLR and distant metastasis, cancer-specific, and all-cause mortality on multivariate analysis, controlling for clinical variables such as tumor size, performance status, symptoms, and demographic variables (Table 2). We found here that preoperative NLR remained independently associated with increased risk of death due to M0 ccRCC (hazard ratio [HR] ¼ 1.02, P ¼ 0.009) and all-cause mortality (HR ¼ 1.02, P ¼ 0.004). That is, for every 1-unit increase in the NLR, there was a 2% increased risk of death due to ccRCC and all-cause mortality. Meanwhile, worse ECOG performance status, presence of constitutional symptoms, and tumor size were likewise associated with increased risks of death following RN. The addition of NLR enhanced the predictive capability of the multivariate models for cancer-specific (C-index ¼ 0.744 vs. 0.739) and all-cause mortality (C-index ¼ 0.706 vs. 0.701).
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We next assessed the association of NLR with cancerrelated mortality on multivariate analysis, controlling for pathologic-related variables using the SSIGN score (Table 3). We found here that preoperative NLR (evaluated as a continuous variable), remained independently associated with significantly increased risks of death from M0 ccRCC, such that each 1-unit increase in NLR was associated with a 2% increased risk of death due to ccRCC (HR ¼ 1.02, P ¼ 0.010). Meanwhile, the addition of NLR enhanced the predictive capability of the SSIGN score (C-index ¼ 0.82 vs. 0.81).
4. Discussion In a large cohort of patients undergoing RN for M0 ccRCC with long-term postoperative follow-up, we found that preoperative NLR was independently associated with an increased risk of cancer-specific and all-cause mortality. After controlling for a validated [22] predictive algorithm, the SSIGN score, NLR remained independently associated with risk of cancer-related mortality. These results may prove useful during patient counseling in the preoperative setting by guiding a clinician's choice to pursue nodal dissection and the frequency of surveillance following RN among those at a higher risk of mortality. The association between a host's inflammatory response and cancer-specific outcomes remains complex. An elevated NLR reflects both a heightened neutrophil-dependent inflammatory reaction and a decreased lymphocytemediated antitumor immune response. Both of these factors may contribute to aggressive tumor biology, cancer progression, and poor prognosis [9,23]. For example, circulating neutrophils have been shown to produce cytokines, such as tumor necrosis factor, IL-1, and IL-6, and to secrete the proangiogenic factor vascular endothelial growth factor [24]. Furthermore, a relative lymphocytopenia may reflect a lower count of CD4þ T-helper lymphocytes, resulting in a suboptimal lymphocyte-mediated immune response to malignancy. Thus, the NLR may reflect the combined prognostic information of these 2 processes and be a stronger predictor of the outcome than either of them considered alone. To date, an elevated NLR has been associated with adverse oncologic outcomes in multiple malignancies, including colorectal, gastric, and urothelial malignancies [9,10,25]. Proctor et al. [23] performed a Scottish Cancer Registry review across 11 different malignancies, including 8,759 patients, and noted a significantly increased risk of cancer-specific (HR ¼ 1.76) and overall mortality (HR ¼ 1.77) in patients with a preoperative NLR 4 5. Moreover, 2 studies have demonstrated worse survival with an elevated NLR among patients with metastatic RCC undergoing cytoreductive nephrectomy or receiving targeted therapy [26,27]. That is, in 48 patients treated with cytoreductive nephrectomy, Ohno et al. found a significant
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Table 1 Clinicopathologic characteristics of cohort Total (n ¼ 827)
NLR o 4.0 (n ¼ 476)
NLR Z 4.0 (n ¼ 351)
P value
65 1 28.1 8.0 5 500
0.13 0.090 0.014 o0.001 o0.001 o0.001
Median (IQR) Feature Age at nephrectomy, y Charlson score BMI, kg/m2 (n ¼ 724) Tumor size, cm (n ¼ 825) SSIGN score (n ¼ 824) Blood loss, ml (n ¼ 765)
65 1 28.7 7.0 4 30
(56–73) (0–2) (25.7–32.8) (5.0–9.7) (2–7) (200–800)
64 1 29.3 6.5 3 300
(55–72) (0–2) (26.1–33.3) (4.5–9.0) (2–5) (150–600)
(57–74) (0–2) (25.3–32.1) (5.2–10.5) (3–7) (200–1,100)
n (%) Sex Female Male
292 (35) 535 (65)
185 (39) 291 (61)
107 (30) 244 (70)
0.013
Type of radical nephrectomy Open Laparoscopic
716 (87) 111 (13)
398 (84) 78 (16)
318 (91) 33 (9)
Symptoms (n ¼ 826) Constitutional symptoms (n ¼ 826) Current or former smoker (n ¼ 813)
518 (63) 201 (24) 477 (59)
279 (59) 90 (19) 264 (56)
239 (68) 111 (32) 213 (62)
ECOG performance status (n ¼ 826) 0 1 2 3 4
692 98 19 16 1
413 46 12 4 1
279 (80) 52 (15) 7 (2) 12 (3) 0
Obesity (BMI 4 30 kg/m2, n ¼ 724)
306 (42)
189 (44)
117 (39)
Units of blood during nephrectomy (n ¼ 823) 0 Z1
599 (73) 224 (27)
389 (82) 85 (18)
210 (60) 139 (40)
Units of blood during hospitalization (n ¼ 823) 0 Z1
563 (68) 260 (32)
367 (77) 107 (23)
196 (56) 153 (44)
Tumor thrombus None Level 0 Level I, II, III, or IV
616 (74) 113 (14) 98 (12)
389 (82) 58 (12) 29 (6)
227 (65) 55 (16) 69 (20)
2009 Primary tumor classification (n ¼ 825) pT1a pT1b pT2a pT2b pT3a pT3b pT3c pT4
136 206 105 47 223 78 15 15
94 133 64 28 122 21 6 7
42 73 41 19 101 57 9 8
pN pNX pN0 pN1
520 (63) 252 (30) 55 (7)
308 (65) 142 (30) 26 (5)
212 (60) 110 (31) 29 (8)
Nuclear grade 1 2 3 4
34 289 408 96
25 185 234 32
9 104 174 64
Coagulative tumor necrosis Sarcomatoid differentiation
281 (34) 25 (3)
0.004
0.006 o0.001 0.11 0.008
(84) (12) (2) (2) (o1)
(87) (10) (3) (1) (o1)
0.17 o0.001
o0.001
o0.001
o0.001 (16) (25) (13) (6) (27) (9) (2) (2)
(20) (28) (13) (6) (26) (4) (1) (1)
(12) (21) (12) (5) (29) (16) (3) (2) 0.36
o0.001 (4) (35) (49) (12)
(5) (39) (49) (7)
123 (26) 6 (1)
(3) (30) (50) (18)
158 (45) 19 (5)
o0.001 o0.001
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Fig. 1. Distant metastasis-free survival following RN for M0 clear cell RCC, stratified by NLR.
difference in overall survival among those with a NLR Z 4 (10.2 mo) vs. o4 (36.5 mo). In this series, NLR remained significantly associated with survival after controlling for other clinical variables (HR = 3.43) [26]. Furthermore, Keizman et al. [27] found that in patients with advanced RCC treated with sunitinib, pretreatment NLR r 3 was an independent predictor of improved progression-free (HR ¼ 0.29) and overall survival (HR ¼ 0.30). While the prognostic value of NLR in these disease states has been previously demonstrated, the value in patients with nonmetastatic RCC remains to be defined, with variable reported results to date [19–21,28]. In particular, 3 prior series have published conflicting data regarding the association of NLR with oncologic outcomes in M0 ccRCC [19,21,28]. That is, in a study of 198 patients
treated with RN with a median follow-up of 93 months, Ohno et al. [21] noted a significant difference in 5-year recurrence-free survival among those with a NLR o 2.7 (94%) vs. Z 2.7 (78%). However, a limitation of this study was the omission of pathologic variables such as tumor stage, size, grade, and the histologic presence of necrosis which have been proven to be highly predictive of tumor recurrence for patients with clinically localized disease [29]. Meanwhile, in a series of 678 patients, with a mean followup of 44 months, Pichler et al. [19] reported no difference in metastasis-free or cancer-specific survival but found an independent association with overall survival at a NLR cutoff Z3.3 (HR ¼ 1.59). A potential criticism, in both of these series, was the utilization of a categorized NLR cutpoint only in the analyses. Indeed, a specified cutpoint
Fig. 2. Cancer-specific survival following RN for M0 clear cell RCC, stratified by NLR.
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Fig. 3. Overall survival following RN for M0 clear cell RCC, stratified by NLR.
may not be applicable for differing patient populations or may falsely associate a categorized variable with defined outcome. Lastly, Jagdev et al. [28] evaluated 286 patients undergoing curative or cytoreductive nephrectomy and found that NLR, as a continuous variable, was independently associated with cancer-specific survival (HR for every 1 log-unit increase ¼ 4.2) but not disease-free or overall survival. This was the only study to find a correlation with cancer-specific survival; however, 16% demonstrated non-cc histology and importantly 20% had metastasis at presentation, limiting the generalizability of those findings in patients with clinically localized tumors [28]. Our analysis then expands on these previous studies in a larger cohort of patients, with extended follow-up to evaluate the association of NLR with survival outcomes in patients with M0 ccRCC treated with RN. We demonstrate that NLR is an independent predictor of cancer-specific and all-cause mortality. Specifically, we found that, after controlling for preoperative clinical features and tumor size, for every 1-unit increase in NLR, there was a 2% greater risk of death from M0 ccRCC and all-cause mortality. We further highlight the prognostic value of
NLR as it remained independently associated with risk of cancer-related death after controlling for a validated cancer-specific survival nomogram [22], the SSIGN score. As such, NLR's prognostic significance reflects the complex interplay between a patient's innate immune response and cancer outcomes, which is likely influenced by patient frailty, competing comorbidities, and biologically aggressive disease. Therefore, we feel that preoperative NLR is an important biomarker that can enhance patient counseling, guide nodal dissection, tailor surveillance protocols, and potentially serve as a criterion for clinical trial enrollment as additional adjuvant therapies are explored. We recognize that our study is limited by its retrospective, nonrandomized nature. Furthermore, we acknowledge the relatively arbitrary cutpoint used for the Kaplan-Meier analyses in our study for NLR (4.0); nevertheless, this threshold allows our data to be contextualized in light of prior series that likewise used a cutpoint. Moreover, we analyzed the association of preoperative NLR with outcomes on our multivariate models as a continuous variable. Finally, we recognize that these data are from a single,
Table 2 Multivariate analysis of preoperative features associated with distant metastasis, death due to clear cell RCC, and all-cause mortality following RN Distant metastasis
a
Age at surgery Male (vs. female) ECOG performance status Z1 (vs. 0) Tumor size, cma Constitutional symptoms (vs. none) Preoperative NLR (continuous)a a
Death due to RCC
All-cause mortality
HR
95% CI
P value
HR
95% CI
P value
HR
95% CI
P value
1.00 1.31 1.44 1.15 1.79 1.01
0.99–1.01 1.02–1.68 1.02–2.03 1.12–1.18 1.39–2.30 1.00–1.03
0.45 0.04 0.04 o0.001 o0.001 0.09
1.01 1.12 2.06 1.17 2.23 1.02
1.00–1.02 0.84–1.50 1.42–2.98 1.14–1.21 1.69–2.94 1.01–1.04
0.18 0.45 o0.001 o0.001 o0.001 0.009
1.04 1.14 2.45 1.09 1.67 1.02
1.03–1.05 0.93–1.41 1.92–3.13 1.07–1.12 1.35–2.06 1.01–1.03
o0.001 0.20 o0.001 o0.001 o0.001 0.004
HR represents a 1-unit increase in the feature listed.
B.R. Viers et al. / Urologic Oncology: Seminars and Original Investigations 32 (2014) 1277–1284 Table 3 Multivariate analysis of pathologic features associated with death due to clear cell RCC following RN
[10]
Death from RCC
SSIGN scorea,b NLR (continuous)b
HR
95% CI
P value
1.50 1.02
1.43–1.58 1.01–1.04
o0.001 0.010
a SSIGN score: prediction of cancer-specific survival following RN including pathologic tumor stage, tumor size, nuclear grade, and histologic tumor necrosis. b Hazard ratio represents a 1-unit increase in the feature listed.
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Original article
Preoperative neutrophil-lymphocyte ratio predicts death among patients with localized clear cell renal carcinoma undergoing nephrectomy Boyd R. Viers, M.D.a, Robert Houston Thompson, M.D.a, Stephen A. Boorjian, M.D.a, Christine M. Lohse, M.S.b, Bradley C. Leibovich, M.D.a, Matthew K. Tollefson, M.D.a,* a
b
Department of Urology, Mayo Clinic, Rochester, MN Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN
Received 12 March 2014; received in revised form 30 April 2014; accepted 31 May 2014
Abstract Objectives: The neutrophil-lymphocyte ratio (NLR) is an indicator of the systemic inflammatory response. An increased pretreatment NLR has been associated with adverse outcomes in other malignancies, but its role in localized (M0) clear cell renal cell carcinoma (ccRCC) remains unclear. As such, we evaluated the ability of preoperative NLR to predict oncologic outcomes in patients with M0 ccRCC undergoing radical nephrectomy (RN). Methods and materials: From 1995 to 2008, 952 patients underwent RN for M0 ccRCC. Of these, 827 (87%) had pretreatment NLR collected within 90 days before RN. Metastasis-free, cancer-specific, and overall survival was estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate models were used to analyze the association of NLR with clinicopathologic outcomes. Results: At a median follow-up of 9.3 years, 302, 233, and 436 patients had distant metastasis, death from ccRCC, and all-cause mortality, respectively. Higher NLR was associated with larger tumor size, higher nuclear grade, histologic tumor necrosis, and sarcomatoid differentiation (all, P o 0.001). A NLR Z 4.0 was significantly associated with worse 5-year cancer-specific (66% vs. 85%) and overall survival (66% vs. 85%). Finally, after controlling for clinicopathologic features, NLR remained independently associated with risks of death from ccRCC and all-cause mortality (hazard ratio for 1-unit increase: 1.02, P o 0.01). Conclusions: Our results suggest that NLR is independently associated with increased risks of cancer-specific and all-cause mortality among patients with M0 ccRCC undergoing RN. Accordingly, NLR, an easily obtained marker of biologically aggressive ccRCC, may be useful in preoperative patient risk stratification. r 2014 Elsevier Inc. All rights reserved.
Keywords: Neutrophil-lymphocyte ratio; Clear cell; Nonmetastatic; Renal cancer; Radical nephrectomy
1. Introduction There has been an increase in the incidence of renal cell carcinoma (RCC) in the last 3 decades [1] with most patients with RCC (480%) presenting with the clear cell (cc) histologic subtype [2]. Although surgical resection remains the “gold standard” treatment for patients with Take-Home Message: Pretreatment NLR is independently associated with an increased risk of cancer-specific and all-cause mortality among patients with clinically localized ccRCC undergoing RN. Accordingly, NLR, an easily obtained marker of biologically aggressive ccRCC, may be useful in preoperative patient risk stratification. * Corresponding author. Tel.: þ1-507-266-6091; fax: þ1-507-284-4951. E-mail address: [email protected] (M.K. Tollefson). http://dx.doi.org/10.1016/j.urolonc.2014.05.014 1078-1439/r 2014 Elsevier Inc. All rights reserved.
clinically localized disease, approximately 10% to 60% of such patients develop recurrence following surgical extirpation [3], and of these patients, a significant proportion die of their disease [4]. Therefore, advancements in patient risk stratification are needed to appropriately identify patients at highest risk of cancer-related mortality who may be candidates for adjuvant therapy trial enrollment. One significant challenge in the identification of the patients at highest risk is the limited pretreatment risk data that are available for patients presenting with a solid renal mass. Not surprisingly, then, most current predictive models rely almost exclusively on postoperative pathologic analysis of the surgical specimen with minimal consideration for associated patient-related variables [5–7]. As such, the
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potential exists that the prognostic accuracy of these models may be significantly improved with the addition of inflammatory and molecular tumor biomarkers [8]. Nevertheless, a paucity of preoperative data exists to facilitate appropriate patient counseling and guide clinic trial enrollment, and thereby there remains a need to identify biomarkers that will incrementally improve preoperative risk stratification. The neutrophil-lymphocyte ratio (NLR) represents an easily measured, reproducible, and inexpensive marker of systemic inflammation that has been associated with oncologic outcomes in multiple malignancies, including colorectal and gastric cancers [9,10]. It has been hypothesized that the synthesis of inflammatory cytokines triggered by the tumor microenvironment alters acute phase reactants and hematological components including serum neutrophil and lymphocyte counts [11,12]. Evaluation of NLR in ccRCC might be particularly relevant as inflammation has been correlated with tumor stage, grade, and proliferative index and, moreover, has been associated with disease-free and overall survival as well [13,14]. Indeed, ccRCC is currently one of the few malignancies in which immunotherapy has been employed, in some cases (high-dose IL-2), with remarkable responses. In fact, both lymphocytosis and C-reactive protein have been observed to be predictive of oncologic outcomes in patients treated for advanced RCC [15,16]. For those with RCC undergoing curative resection, lymphocytopenia and an elevated CRP have been associated with worse cancer-related outcomes, suggesting a correlation between inflammation and disease biology [17,18]. Nevertheless, limited data exist regarding the potential prognostic value of NLR in nonmetastatic (M0) ccRCC [19–21]. Moreover, these studies have been limited by relatively small patient numbers, heterogeneous histologic subtypes, short-term follow-up, and differing clinical end points. We hypothesize that a greater preoperative NLR is associated with adverse outcomes among patients treated for RCC. Accordingly, we sought to determine the association between pretreatment NLR and oncologic outcomes in a large cohort of patients with M0 ccRCC treated with radical nephrectomy (RN) with long-term follow-up.
2. Materials and methods Following institutional review board approval, we reviewed the Mayo Clinic Nephrectomy Registry to identify 952 patients treated with RN for sporadic, unilateral, noncystic M0 ccRCC at our institution between 1995 and 2008. The clinic variables recorded included age, sex, year of RN, surgical approach (open vs. laparoscopic), symptoms at presentation, smoking status, Eastern Cooperative Oncology Group (ECOG) performance status, Charlson
comorbidity index, body mass index (BMI), obesity (defined as BMI Z 30), neutrophil count, lymphocyte count, pretreatment NLR, estimated blood loss during RN, and units of blood transfused during surgery or hospitalization. Patients with a palpable flank or abdominal mass, discomfort, gross hematuria, acute-onset varicocele, or constitutional symptoms including rash, sweats, weight loss, fatigue, early satiety, and anorexia were considered symptomatic. Neutrophil and lymphocyte counts closest to RN, but within 3 months before, were used for analysis. When multiple values existed for a patient, the values closest to the date of RN were utilized. The pathologic features studied included histologic subtype classified according to the Union Internationale Contre le Cancer, American Joint Committee on Cancer, and Heidelberg guidelines, tumor size, the 2009 primary tumor and regional lymph node classifications, nuclear grade, coagulative tumor necrosis, and sarcomatoid differentiation. One genitourinary pathologist (J.C.C.) re-reviewed the microscopic slides from all specimens without knowledge of patient outcome. The primary tumor stage, size, nuclear grade, and coagulative tumor necrosis characteristics were combined to calculate the Stage, Size, Grade, and Necrosis (SSIGN) score [5]. The SSIGN score was developed at our institution to stratify cancer-specific survival in patients with ccRCC undergoing nephrectomy. Lymph node dissection was performed at the discretion of the treating surgeon at the time of RN. At our institution, follow-up after RN was generally done quarterly for the first 2 years, semiannually for the next 2 years, and annually thereafter for patients without evidence of recurrent disease. For survival end points, vital status was identified from death certificates or physician correspondence. For patients followed up elsewhere, the Nephrectomy Registry monitors outcomes annually by correspondence with the patient and the local treating physician. Comparisons of clinicopathologic features and presurgical NLR were performed using the Wilcoxon rank sum, chi-square, Fisher exact, and Cochran-Armitage trend tests, as appropriate. Metastasis-free, cancer-specific, and overall survivals were estimated as the time from RN to event, or last follow-up, using the Kaplan-Meier method and compared with the log-rank test. A visual assessment of the association of NLR with patient outcome (i.e., a plot of martingale residuals from a null Cox model against NLR) indicated that this association was fairly linear, with an optimal cutpoint for increased risk of metastases or death from ccRCC occurring at a NLR of approximately 4.0. As such, associations of NLR with patient outcome were evaluated using NLR as a continuous variable and using a cutpoint Z4.0. Cox proportional hazard regression models were used to evaluate the association of NLR with outcomes, controlling for clinicopathologic variables. A P o 0.05 was considered statistically significant. Statistical analyses were performed using the SAS software package (SAS Institute, Cary, NC).
B.R. Viers et al. / Urologic Oncology: Seminars and Original Investigations 32 (2014) 1277–1284
3. Results Of the 952 patients who underwent RN at our institution between 1995 and 2008, 827 (87%) had preoperative neutrophil and lymphocyte counts available for analysis. Patients with an available NLR were treated earlier in the study time frame (median year of RN 2001 vs. 2003; P o 0.001), were older (median age 65 vs. 60 y; P ¼ 0.008), and were less likely to be treated with laparoscopic RN (13% vs. 22%, P ¼ 0.008) compared with patients without an available NLR. None of the other clinicopathologic features studied were significantly different between patients with and without available NLR. Overall median NLR was 3.51 (interquartile range [IQR] ¼ 2.43–6.12), of which 476 (58%) had a NLR o 4.0 and 351 (42%) had a NLR Z 4.0. Clinicopathologic features for patients with preoperative NLR Z and o4.0 are provided in Table 1. As depicted, patients with NLR Z 4.0 were more likely to be men, have a lower BMI, have greater blood loss at RN, undergo open RN, have worse ECOG performance score, have local or constitutional symptoms, and require blood transfusion during RN or hospitalization (all, P o 0.05). Pathologically, patients with a NLR Z 4.0 had a greater SSIGN score (median ¼ 5 vs. 3), larger tumor size (median ¼ 8 vs. 6.5 cm), pathologically advanced (pT3/4) tumors (50% vs. 32%), level I to IV tumor thrombuses (20% vs. 6%), greater nuclear grade, and coagulative tumor necrosis or sarcomatoid differentiation (all, P o 0.05). The median duration of follow-up after surgery was 9.3 years (IQR ¼ 6.3–12.8). During that time, 302 experienced disease recurrence at a median 1.2 years following RN (IQR ¼ 0.4–3.3). Furthermore, 436 died (median 3.6 y after RN; IQR ¼ 1.5–6.9), of whom 233 died of ccRCC (median 2.4 y after RN; IQR ¼ 1.1–5.1). We found that, when compared with patients with a NLR o 4.0, patients with a NLR Z 4.0 had significantly worse 5-year distant metastasisfree (58% vs. 74%) (Fig. 1), cancer-specific (66% vs. 85%) (Fig. 2), and overall survival (55% vs. 76%) (Fig. 3). We then investigated the association between NLR and distant metastasis, cancer-specific, and all-cause mortality on multivariate analysis, controlling for clinical variables such as tumor size, performance status, symptoms, and demographic variables (Table 2). We found here that preoperative NLR remained independently associated with increased risk of death due to M0 ccRCC (hazard ratio [HR] ¼ 1.02, P ¼ 0.009) and all-cause mortality (HR ¼ 1.02, P ¼ 0.004). That is, for every 1-unit increase in the NLR, there was a 2% increased risk of death due to ccRCC and all-cause mortality. Meanwhile, worse ECOG performance status, presence of constitutional symptoms, and tumor size were likewise associated with increased risks of death following RN. The addition of NLR enhanced the predictive capability of the multivariate models for cancer-specific (C-index ¼ 0.744 vs. 0.739) and all-cause mortality (C-index ¼ 0.706 vs. 0.701).
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We next assessed the association of NLR with cancerrelated mortality on multivariate analysis, controlling for pathologic-related variables using the SSIGN score (Table 3). We found here that preoperative NLR (evaluated as a continuous variable), remained independently associated with significantly increased risks of death from M0 ccRCC, such that each 1-unit increase in NLR was associated with a 2% increased risk of death due to ccRCC (HR ¼ 1.02, P ¼ 0.010). Meanwhile, the addition of NLR enhanced the predictive capability of the SSIGN score (C-index ¼ 0.82 vs. 0.81).
4. Discussion In a large cohort of patients undergoing RN for M0 ccRCC with long-term postoperative follow-up, we found that preoperative NLR was independently associated with an increased risk of cancer-specific and all-cause mortality. After controlling for a validated [22] predictive algorithm, the SSIGN score, NLR remained independently associated with risk of cancer-related mortality. These results may prove useful during patient counseling in the preoperative setting by guiding a clinician's choice to pursue nodal dissection and the frequency of surveillance following RN among those at a higher risk of mortality. The association between a host's inflammatory response and cancer-specific outcomes remains complex. An elevated NLR reflects both a heightened neutrophil-dependent inflammatory reaction and a decreased lymphocytemediated antitumor immune response. Both of these factors may contribute to aggressive tumor biology, cancer progression, and poor prognosis [9,23]. For example, circulating neutrophils have been shown to produce cytokines, such as tumor necrosis factor, IL-1, and IL-6, and to secrete the proangiogenic factor vascular endothelial growth factor [24]. Furthermore, a relative lymphocytopenia may reflect a lower count of CD4þ T-helper lymphocytes, resulting in a suboptimal lymphocyte-mediated immune response to malignancy. Thus, the NLR may reflect the combined prognostic information of these 2 processes and be a stronger predictor of the outcome than either of them considered alone. To date, an elevated NLR has been associated with adverse oncologic outcomes in multiple malignancies, including colorectal, gastric, and urothelial malignancies [9,10,25]. Proctor et al. [23] performed a Scottish Cancer Registry review across 11 different malignancies, including 8,759 patients, and noted a significantly increased risk of cancer-specific (HR ¼ 1.76) and overall mortality (HR ¼ 1.77) in patients with a preoperative NLR 4 5. Moreover, 2 studies have demonstrated worse survival with an elevated NLR among patients with metastatic RCC undergoing cytoreductive nephrectomy or receiving targeted therapy [26,27]. That is, in 48 patients treated with cytoreductive nephrectomy, Ohno et al. found a significant
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Table 1 Clinicopathologic characteristics of cohort Total (n ¼ 827)
NLR o 4.0 (n ¼ 476)
NLR Z 4.0 (n ¼ 351)
P value
65 1 28.1 8.0 5 500
0.13 0.090 0.014 o0.001 o0.001 o0.001
Median (IQR) Feature Age at nephrectomy, y Charlson score BMI, kg/m2 (n ¼ 724) Tumor size, cm (n ¼ 825) SSIGN score (n ¼ 824) Blood loss, ml (n ¼ 765)
65 1 28.7 7.0 4 30
(56–73) (0–2) (25.7–32.8) (5.0–9.7) (2–7) (200–800)
64 1 29.3 6.5 3 300
(55–72) (0–2) (26.1–33.3) (4.5–9.0) (2–5) (150–600)
(57–74) (0–2) (25.3–32.1) (5.2–10.5) (3–7) (200–1,100)
n (%) Sex Female Male
292 (35) 535 (65)
185 (39) 291 (61)
107 (30) 244 (70)
0.013
Type of radical nephrectomy Open Laparoscopic
716 (87) 111 (13)
398 (84) 78 (16)
318 (91) 33 (9)
Symptoms (n ¼ 826) Constitutional symptoms (n ¼ 826) Current or former smoker (n ¼ 813)
518 (63) 201 (24) 477 (59)
279 (59) 90 (19) 264 (56)
239 (68) 111 (32) 213 (62)
ECOG performance status (n ¼ 826) 0 1 2 3 4
692 98 19 16 1
413 46 12 4 1
279 (80) 52 (15) 7 (2) 12 (3) 0
Obesity (BMI 4 30 kg/m2, n ¼ 724)
306 (42)
189 (44)
117 (39)
Units of blood during nephrectomy (n ¼ 823) 0 Z1
599 (73) 224 (27)
389 (82) 85 (18)
210 (60) 139 (40)
Units of blood during hospitalization (n ¼ 823) 0 Z1
563 (68) 260 (32)
367 (77) 107 (23)
196 (56) 153 (44)
Tumor thrombus None Level 0 Level I, II, III, or IV
616 (74) 113 (14) 98 (12)
389 (82) 58 (12) 29 (6)
227 (65) 55 (16) 69 (20)
2009 Primary tumor classification (n ¼ 825) pT1a pT1b pT2a pT2b pT3a pT3b pT3c pT4
136 206 105 47 223 78 15 15
94 133 64 28 122 21 6 7
42 73 41 19 101 57 9 8
pN pNX pN0 pN1
520 (63) 252 (30) 55 (7)
308 (65) 142 (30) 26 (5)
212 (60) 110 (31) 29 (8)
Nuclear grade 1 2 3 4
34 289 408 96
25 185 234 32
9 104 174 64
Coagulative tumor necrosis Sarcomatoid differentiation
281 (34) 25 (3)
0.004
0.006 o0.001 0.11 0.008
(84) (12) (2) (2) (o1)
(87) (10) (3) (1) (o1)
0.17 o0.001
o0.001
o0.001
o0.001 (16) (25) (13) (6) (27) (9) (2) (2)
(20) (28) (13) (6) (26) (4) (1) (1)
(12) (21) (12) (5) (29) (16) (3) (2) 0.36
o0.001 (4) (35) (49) (12)
(5) (39) (49) (7)
123 (26) 6 (1)
(3) (30) (50) (18)
158 (45) 19 (5)
o0.001 o0.001
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Fig. 1. Distant metastasis-free survival following RN for M0 clear cell RCC, stratified by NLR.
difference in overall survival among those with a NLR Z 4 (10.2 mo) vs. o4 (36.5 mo). In this series, NLR remained significantly associated with survival after controlling for other clinical variables (HR = 3.43) [26]. Furthermore, Keizman et al. [27] found that in patients with advanced RCC treated with sunitinib, pretreatment NLR r 3 was an independent predictor of improved progression-free (HR ¼ 0.29) and overall survival (HR ¼ 0.30). While the prognostic value of NLR in these disease states has been previously demonstrated, the value in patients with nonmetastatic RCC remains to be defined, with variable reported results to date [19–21,28]. In particular, 3 prior series have published conflicting data regarding the association of NLR with oncologic outcomes in M0 ccRCC [19,21,28]. That is, in a study of 198 patients
treated with RN with a median follow-up of 93 months, Ohno et al. [21] noted a significant difference in 5-year recurrence-free survival among those with a NLR o 2.7 (94%) vs. Z 2.7 (78%). However, a limitation of this study was the omission of pathologic variables such as tumor stage, size, grade, and the histologic presence of necrosis which have been proven to be highly predictive of tumor recurrence for patients with clinically localized disease [29]. Meanwhile, in a series of 678 patients, with a mean followup of 44 months, Pichler et al. [19] reported no difference in metastasis-free or cancer-specific survival but found an independent association with overall survival at a NLR cutoff Z3.3 (HR ¼ 1.59). A potential criticism, in both of these series, was the utilization of a categorized NLR cutpoint only in the analyses. Indeed, a specified cutpoint
Fig. 2. Cancer-specific survival following RN for M0 clear cell RCC, stratified by NLR.
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Fig. 3. Overall survival following RN for M0 clear cell RCC, stratified by NLR.
may not be applicable for differing patient populations or may falsely associate a categorized variable with defined outcome. Lastly, Jagdev et al. [28] evaluated 286 patients undergoing curative or cytoreductive nephrectomy and found that NLR, as a continuous variable, was independently associated with cancer-specific survival (HR for every 1 log-unit increase ¼ 4.2) but not disease-free or overall survival. This was the only study to find a correlation with cancer-specific survival; however, 16% demonstrated non-cc histology and importantly 20% had metastasis at presentation, limiting the generalizability of those findings in patients with clinically localized tumors [28]. Our analysis then expands on these previous studies in a larger cohort of patients, with extended follow-up to evaluate the association of NLR with survival outcomes in patients with M0 ccRCC treated with RN. We demonstrate that NLR is an independent predictor of cancer-specific and all-cause mortality. Specifically, we found that, after controlling for preoperative clinical features and tumor size, for every 1-unit increase in NLR, there was a 2% greater risk of death from M0 ccRCC and all-cause mortality. We further highlight the prognostic value of
NLR as it remained independently associated with risk of cancer-related death after controlling for a validated cancer-specific survival nomogram [22], the SSIGN score. As such, NLR's prognostic significance reflects the complex interplay between a patient's innate immune response and cancer outcomes, which is likely influenced by patient frailty, competing comorbidities, and biologically aggressive disease. Therefore, we feel that preoperative NLR is an important biomarker that can enhance patient counseling, guide nodal dissection, tailor surveillance protocols, and potentially serve as a criterion for clinical trial enrollment as additional adjuvant therapies are explored. We recognize that our study is limited by its retrospective, nonrandomized nature. Furthermore, we acknowledge the relatively arbitrary cutpoint used for the Kaplan-Meier analyses in our study for NLR (4.0); nevertheless, this threshold allows our data to be contextualized in light of prior series that likewise used a cutpoint. Moreover, we analyzed the association of preoperative NLR with outcomes on our multivariate models as a continuous variable. Finally, we recognize that these data are from a single,
Table 2 Multivariate analysis of preoperative features associated with distant metastasis, death due to clear cell RCC, and all-cause mortality following RN Distant metastasis
a
Age at surgery Male (vs. female) ECOG performance status Z1 (vs. 0) Tumor size, cma Constitutional symptoms (vs. none) Preoperative NLR (continuous)a a
Death due to RCC
All-cause mortality
HR
95% CI
P value
HR
95% CI
P value
HR
95% CI
P value
1.00 1.31 1.44 1.15 1.79 1.01
0.99–1.01 1.02–1.68 1.02–2.03 1.12–1.18 1.39–2.30 1.00–1.03
0.45 0.04 0.04 o0.001 o0.001 0.09
1.01 1.12 2.06 1.17 2.23 1.02
1.00–1.02 0.84–1.50 1.42–2.98 1.14–1.21 1.69–2.94 1.01–1.04
0.18 0.45 o0.001 o0.001 o0.001 0.009
1.04 1.14 2.45 1.09 1.67 1.02
1.03–1.05 0.93–1.41 1.92–3.13 1.07–1.12 1.35–2.06 1.01–1.03
o0.001 0.20 o0.001 o0.001 o0.001 0.004
HR represents a 1-unit increase in the feature listed.
B.R. Viers et al. / Urologic Oncology: Seminars and Original Investigations 32 (2014) 1277–1284 Table 3 Multivariate analysis of pathologic features associated with death due to clear cell RCC following RN
[10]
Death from RCC
SSIGN scorea,b NLR (continuous)b
HR
95% CI
P value
1.50 1.02
1.43–1.58 1.01–1.04
o0.001 0.010
a SSIGN score: prediction of cancer-specific survival following RN including pathologic tumor stage, tumor size, nuclear grade, and histologic tumor necrosis. b Hazard ratio represents a 1-unit increase in the feature listed.
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[14]
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