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Preoperative Erythrocyte Sedimentation Rate Independently Predicts Overall Survival in Localized Renal Cell Carcinoma following Radical Nephrectomy

Preoperative Erythrocyte Sedimentation Rate Independently Predicts Overall Survival in Localized... Hindawi Publishing Corporation International Journal of Surgical Oncology Volume 2012, Article ID 524981, 6 pages doi:10.1155/2012/524981 Research Article Preoperative Erythrocyte Sedimentation Rate Independently Predicts Overall Survival in Localized Renal Cell Carcinoma following Radical Nephrectomy 1 1 1 1 1 Brian W. Cross, Timothy V. Johnson, Austin B. DeRosa, Kenneth Ogan, John G. Pattaras, 1 2, 3 2, 3 1, 3 Peter T. Nieh, Omer Kucuk, Wayne B. Harris, and Viraj A. Master Department of Urology, Emory University, Atlanta, GA 30322, USA Department of Medical Oncology, Emory University, Atlanta, GA 30322, USA Emory Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA Correspondence should be addressed to Viraj A. Master, vmaster@emory.edu Received 1 April 2012; Accepted 11 June 2012 Academic Editor: Marcos Tobias-Machado Copyright © 2012 Brian W. Cross et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objectives. To determine the relationship between preoperative erythrocyte sedimentation rate (ESR) and overall survival in localized renal cell carcinoma (RCC) following nephrectomy. Methods. 167 patients undergoing nephrectomy for localized RCC had ESR levels measured preoperatively. Receiver Operating Characteristics curves were used to determine Area Under the Curve and relative sensitivity and specificity of preoperative ESR in predicting overall survival. Cut-offs for low (0.0–20.0 mm/hr), intermediate (20.1–50.0 mm/hr), and high risk (>50.0 mm/hr) groups were created. Kaplan-Meier analysis was conducted to assess the univariate impact of these ESR-based groups on overall survival. Univariate and multivariate Cox regression analysis was conducted to assess the potential of these groups to predict overall survival, adjusting for other patient and tumor characteristics. Results. Overall, 55.2% were low risk, while 27.0% and 17.8% were intermediate and high risk, respectively. Median (95% CI) survival was 44.1 (42.6–45.5) months, 35.5 (32.3–38.8) months, and 32.1 (25.5–38.6) months, respectively. After controlling for other patient and tumor characteristics, intermediate and high risk groups experienced a 4.5-fold (HR: 4.509, 95% CI: 0.735–27.649) and 18.5-fold (HR: 18.531, 95% CI: 2.117–162.228) increased risk of overall mortality, respectively. Conclusion. Preoperative ESR values represent a robust predictor of overall survival following nephrectomy in localized RCC. 1. Introduction in survival between stages [5], and this has fostered the search for other prognostic markers to more clearly stratify those Over 50,000 Americans are diagnosed with renal cell carci- patients in whom a poor outcome can be expected. noma (RCC) each year, approximately 30% of whom will Recently, efforts at identifying markers of disease pro- ultimately develop metastatic progression of their disease gression in RCC have focused on the readily available and despite apparent curative nephrectomy for localized cancer cost-effective clinical indices of preoperative laboratory at the time of clinical presentation [1, 2]. Metastatic RCC, values [7]. It is becoming increasingly clear that neoplastic untreated, has a dismal 5-year survival rate of <10% and a progression depends on an orchestrated interface between median overall survival of less than one year [3–6]. As such, tumor biology and the host inflammatory response [8]. The there has been a long-standing interest in accurately identi- systemic inflammatory response, as represented by aberra- fying those patients most likely to suffer from postoperative tions in circulating levels of acute-phase reactants, has pre- disease progression, and much research in recent years has focused on the development of prognostic models to aid in viously been shown to be a predictor of poor overall survival in a variety of advanced malignancies [9–11]. Indeed, we and surveillance strategies and patient counseling. Currently, the most commonly used tool to predict outcome in RCC is the multiple other groups have recently shown preoperative C- TNM staging system. However, there is considerable overlap reactive protein (CRP) levels are an independent predictor 2 International Journal of Surgical Oncology of metastasis and mortality following extirpative surgery for based on six stages (T1a, T1b, T2, T3a, T3b, and T3c). How- localized RCC [12]. ever, one-way analysis of variance revealed no significant The determination of the erythrocyte sedimentation rate difference in outcomes between T1a and T1b and between (ESR) is by a simple and inexpensive laboratory test in- T3a, T3b, and T3c. Additionally, there was no significant troduced by Westergren in 1921. It measures the distance difference between T3 and T4 disease. Therefore, patients erythrocytes have fallen after one hour in a vertical column were divided into three groups based on T-stages: T1, T2, and of anticoagulated blood under the influence of gravity [13]. T3-4. Though its clinical usefulness as a diagnostic tool has dimin- Prior to surgery, clinical stage, routine laboratory mea- ished as more intricate methods of analysis have emerged, it surements and ESR levels were assessed. The inter- and intra- remains paramount in the specific diagnosis of a few condi- assay variability for all laboratory values were <10%. Post- tions, including temporal arteritis, polymyalgia rheumatica, operatively, we assessed overall survival via Social Security and rheumatoid arthritis. Moreover, an extreme elevation Death Index. is mostly associated with infection or malignancy [13]. Frequency and descriptive analyses were conducted to Numerous studies over three decades have substantiated the characterize the patient population. Kaplan-Meier analysis prognostic utility of ESR in patients with RCC [7, 14–23], was conducted to assess the univariate impact of these ESR- with recent data from the Mayo Clinic showing elevated based risk groups on overall survival. Finally, univariate and ESR levels predicting the presence of aggressive disease and multivariate Cox regression analysis was conducted to assess poorer outcomes [22]. the potential of these groups to predict overall survival, Despite these numerous observations, the ESR level is not adjusting for other patient and tumor characteristics. Statis- routinely incorporated into current prognostic models for tical significance in this study was set at P< 0.05. All analyses RCC, likely due to the nonspecific nature of its elevation [24– were performed using SPSS version 16.0. 26], and the relationship between ESR and survival in local- ized RCC following potentially curative nephrectomy has 3. Results not been fully elucidated. We hypothesized preoperative ESR values were an independent prognostic indicator of overall This study cohort consisted of 167 patients who underwent survival in localized renal cell carcinoma following radical potentially curative nephrectomy for localized clear cell nephrectomy and could have potential benefit with respect RCC. Receiver Operating Characteristics (ROC) curves were to overall clinical management as well as preoperative patient constructed and used to determine the Area Under the Curve counseling, especially constructing specific risk categories on (AUC) and relative sensitivity and specificity of preoperative the basis of ESR levels. ESR in predicting overall survival. From this curve, cut- offs for low risk (0.0–20.0 mm/hr), intermediate risk (20.1– 50.0 mm/hr), and high risk (>50.0 mm/hr) groups were 2. Methods created. Of the total cohort, 101 patients (55.2%) were One hundred sixty-seven patients who underwent poten- in the low risk group, while 40 patients (27.0%) and 26 tially curative radical nephrectomy (all macroscopic tumor patients (17.8%) were in the intermediate risk and high was removed with negative surgical margins) for clear cell risk groups, respectively. The majority of patients in all risk RCC had ESR measured preoperatively between November categories were Caucasian males, with mean (SD) ages of 2006 and February 2010. There were a total of 192 patients 56.5 (±12.7) years, 64.4 (±14.2) years, and 64.2 (±11.7) with RCC during this time period, 15% of which did not years for the low, intermediate, and high risk categories, have a preoperative ESR value measured, mostly due to respectively (Table 1). The majority of patients in the low error in paperwork. Follow-up data was available through and intermediate risk groups had T1 disease, while higher August 25, 2010. Patients underwent standard followup for T-stages predominated in the high risk group, with nearly post-nephrectomy RCC patients, including imaging studies half of these patients having either T3 or T4 RCC. Likewise, every 3 months for 1 year, then spaced to every 6 months higher nuclear grades prevailed in the high risk group, with until 5 years postoperatively, then every year thereafter. almost 70% of high risk patients having either Fuhrman Routine laboratory studies including CRP, serum creatinine, nuclear grade III or IV. The mean (SD) ESR values were and ESR were checked every 3 months and physical exams 10.1 (5.0) mm/hr, 31.5 (7.3) mm/hr, and 82.5 (24.9) mm/hr were performed at office visits. Perioperative deaths (within for the low, intermediate, and high risk groups, respectively 30 days of surgery) were excluded from analysis. Inclusion (Table 1). criteria consisted of clear cell histology, and exclusion criteria Median (95% CI) survival for the ESR-based risk groups consisted of nodal or metastatic disease, or age less than was 44.1 (42.6–45.5) months, 35.5 (32.3–38.8) months, and 18 years. All patients underwent a cross-sectional imaging 32.1 (25.5–38.6) months for the low, intermediate, and high study (MRI or IV-contrasted CT) of the chest, abdomen, and risk groups, respectively. Univariate and multivariate Cox pelvis before surgery. No patients received systemic therapy regression analysis of overall survival showed a 3.2-fold following nephrectomy. The Emory University Institutional (HR: 3.265, 95% CI: 0.993-10.733) increased risk of overall Review Board approved this clinical database project. mortality for the intermediate risk group and a 8.4-fold (HR: Patients were staged pathologically according to the 8.409, 95% CI: 2.740-25.805) increased risk for the high AJCC TNM renal tumor classification [27], and tumors were risk group. After controlling for patient age, race, gender, graded based on Fuhrman criteria [28]. Staging was initially Charlson Comorbidity Index, T-Stage, Fuhrman Nuclear International Journal of Surgical Oncology 3 Table 1: Patient characteristics. Low risk Intermediate risk High risk All patients Variables (≤20.0 mm/hr) (20.1–50.0 mm/hr) (≥50.1 mm/hr) (n = 167) (n = 101) (n = 40) (n = 26) Age (y) Mean (SD) 56.5 (12.7) 64.4 (14.2) 64.2 (11.7) 59.4 (12.8) Race (%white/%nonwhite) 84.3/15.7 79.4/20.6 60.0/40.0 72.1/27.9 Gender (%male) 70.3 52.5 50.0 64.8 Charlson Comorbidity Index Mean (SD) 2.9 (1.6) 3.0 (1.7) 4.0 (2.3) 3.1 (1.7) T-Stage (%T1/%T2/%T3-4) 84.3/7.9/7.9 68.4/10.5/21.1 35.5/16.7/45.8 72.3/10.3/17.4 Fuhrman Nuclear Grade (%I-II/%III/%IV) 59.1/39.8/1.1 50.0/44.7/5.3 29.2/54.2/16.7 49.5/43.2/7.3 Tumor size (cm) Mean (SD) 4.4 (2.6) 4.9 (2.9) 7.0 (4.3) 5.0 (3.2) ESR (mm/hr) Mean (SD) 10.1 (5.0) 31.5 (7.3) 82.5 (24.9) 28.5 (29.4) Erythrocyte Sedimentation Rate. Table 2: Univariate and multivariate Cox regression analyses of predictors of overall survival (OS). Variable Crude HR 95% CI Adjusted HR 95% CI ESR -Based Risk Categories Low risk Reference Reference Intermediate risk 3.265 0.993–10.733 4.509 0.735–27.649 ∗∗ High risk 8.409 2.740–25.805 18.531 2.117–162.228 Age 1.028 0.992–1.065 1.030 0.971–1.093 Gender Female Reference Reference Male 1.502 0.610–3.697 1.306 0.322–5.298 Race White Reference Reference Non-white 0.658 0.149–2.896 0.150 0.018–1.243 Stage 1 Reference Reference 2 1.675 0.195–14.374 0.761 0.050–11.573 3-4 10.077 3.436–29.552 4.685 0.721–30.449 Charlson Comorbidity Index 1.274 1.098–1.480 0.754 0.506–1.123 Grade Reference Reference 1-2 3 3.266 0.883–12.076 1.373 0.222–8.493 4 32.595 7.684–138.264 21.902 1.937–247.590 Tumor size 1.176 1.072–1.290 1.001 0.820–1.221 Erythrocyte Sedimentation Rate. P = 0.033. ∗∗ P< 0.001. grade, and tumor size, intermediate risk and high risk groups Kaplan-Meier survival analysis of probability of survival experienced a 4.5-fold (HR: 4.509, 95% CI: 0.735–27.649, versus time since surgery stratified by preoperative ESR risk P = 0.033) and 18.5-fold (HR: 18.531, 95% CI: 2.117– category into low, intermediate, and high risk groups showed 162.228, P< 0.001) increased risk of overall mortality, a statistically significant difference in survival when compar- respectively (Table 2). ing the low risk group to both the high risk group (P< 0.001) 4 International Journal of Surgical Oncology has also undergone multiple refinements since its inception in 1974. Regardless, many elements of the TNM staging sys- tem are cause for debate. This has led to the development of 0.8 numerous integrated staging systems such as the UCLA/UISS (UCLA Integrated staging system) as well as the SSIGN (Stage, Size, Grade, and Necrosis) scoring algorithm [33]. 0.6 Of note, none of these staging systems incorporates any measured serum markers. 0.4 Several recent studies have focused on the prognostic value of preoperative ESR levels in RCC following potentially curative nephrectomy for clinically localized disease [22, 23], 0.2 as this is a quick and inexpensive laboratory test costing less than thirty dollars at our institution. In a recent meta-analysis, Wu and colleagues found the 012 24 36 48 systemic inflammatory response to be a predictor of poor overall survival in patients with renal cell carcinoma [34]. In Time since diagnosis (months) a total of 47 studies included for meta-analysis, the combined ESR-based risk categories hazard ratios (HRs) for survival of CRP, platelet count (PC), Low risk (0–20 mm/hr) and ESR were 3.46, 3.22, and 3.85, respectively. All three Intermediate risk (20.1–50 mm/hr) inflammatory indicators also predicted relapse-free survival High risk (>50 mm/hr) (HRs > 2.0). Figure 1: Kaplan-Meier survival analysis of probability of survival Another recent study specifically analyzing the role of versus time since surgery (days) by preoperative ESR Risk Category preoperative ESR values found that both tumor stage and among patients diagnosed with localized clear cell RCC undergoing preoperative ESR levels were both significant independent potentially curative nephrectomy. Patients categorized into Low prognostic indicators of progression-free survival as well as Risk (≤20.0 mm/hr), Intermediate Risk (20.1–50.0 mm/hr), and disease-specific survival [23]. When analysis was limited to High Risk (>50.0 mm/hr) based on preoperative ESR levels. Log- pT1 tumors, only ESR was an independent prognostic factor rank: Low Risk versus High Risk (P< 0.001), Low Risk versus for disease-specific survival. Intermediate Risk (P = 0.033), Intermediate Risk versus High Risk (P = 0.066). Two recent studies from the Mayo Clinic have reported elevated preoperative ESR levels portended an increased risk of death from RCC [7, 22], however, neither of these studies stratified patients preoperatively into low, intermediate, or as well as comparing the low risk group to the intermediate high risk based on their ESR level. risk group (P = 0.033). No statistically significant difference The incidence of elevated ESR in patients with RCC has in survival was observed between the intermediate and high been reported to range between 23% and 50% [22], and risk groups (P = 0.066), although a trend was observed has been noted as an independent prognostic factor for (Figure 1). disease-specific survival (DSS) as well as progression-free survival (PFS) following nephrectomy [23]. However, as noted previously, despite these observations ESR is not 4. Discussion incorporated into current prognostic algorithms for RCC. Renal cell carcinoma can be ranked among the great mas- This could be due to many factors, not the least of which is queraders of clinical medicine, and its diagnosis at a stage its nonspecific nature as well as the poorly understood early enough for curative nephrectomy remains a significant mechanism by which it reaches elevated levels. Early studies challenge. Clinically localized tumors are often symptom- on the prognostic significance of ESR were fraught with free, and by the time clinical symptoms become apparent, uncertainty owing mainly to a lack of histologic stratification more advanced tumors have a complex clinical course with and the relatively small number of patients in each series. These issues have been addressed in a more recent study of increased morbidity and mortality. As such, numerous stud- ies over several decades have focused on the identification larger cohorts of patients grouped by histologic subtype from of other objective measures for both diagnostic as well the Mayo Clinic [22]. This study evaluated the prognostic as prognostic use in defining risk groups for preoperative significance of preoperative ESR in 1075 patients who under- patient counseling and postoperative surveillance strategies went nephrectomy for RCC over 30 years. These authors [7, 12, 14, 22, 23, 29, 30]. observed an association between elevated preoperative ESR With the rapid and evolving understanding of renal (defined as >22 mm/hr in male patients and >29 mm/hr in tumor biology, RCC staging systems have likewise evolved female patients) and death from clear cell RCC, papillary RCC, and chromophobe RCC, with risk ratios of 3.6, 3.8, and over time. The first formal staging system dates to 1958, later modified by Robson in 1969 [31, 32]. Subsequent refine- 10.3, respectively. ments have led to the development of the often-cited TNM Urologists are long familiar with the use of serum mark- ers to risk-stratify patients with cancer. For example, dif- classification, which stratifies patients’ primary tumor into one of four classifications (I–IV). Similarly, this classification ferent levels of PSA prior to definitive local therapy can Probability of survival International Journal of Surgical Oncology 5 be helpful in predicting outcome, as well as the previously [2] B.C.Leibovich,M.L.Blute,J.C.Chevilleetal., “Prediction of progression after radical nephrectomy for patients with clear mentioned prognostic value of preoperative CRP in renal cell renal cell carcinoma: a stratification tool for prospective cell carcinoma. To our knowledge, the current study is the clinical trials,” Cancer, vol. 97, no. 7, pp. 1663–1671, 2003. first to stratify patients based on preoperative ESR level into [3] T. Klatte, J. S. Lam, B. Shuch, A. S. Belldegrun, and A. J. low, intermediate, and high risk categories based on overall Pantuck, “Surveillance for renal cell carcinoma: why and how? survival following nephrectomy for localized RCC. 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Preoperative Erythrocyte Sedimentation Rate Independently Predicts Overall Survival in Localized Renal Cell Carcinoma following Radical Nephrectomy

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References (45)

Publisher
Hindawi Publishing Corporation
Copyright
Copyright © 2012 Brian W. Cross et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ISSN
2090-1402
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2090-1410
DOI
10.1155/2012/524981
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Hindawi Publishing Corporation International Journal of Surgical Oncology Volume 2012, Article ID 524981, 6 pages doi:10.1155/2012/524981 Research Article Preoperative Erythrocyte Sedimentation Rate Independently Predicts Overall Survival in Localized Renal Cell Carcinoma following Radical Nephrectomy 1 1 1 1 1 Brian W. Cross, Timothy V. Johnson, Austin B. DeRosa, Kenneth Ogan, John G. Pattaras, 1 2, 3 2, 3 1, 3 Peter T. Nieh, Omer Kucuk, Wayne B. Harris, and Viraj A. Master Department of Urology, Emory University, Atlanta, GA 30322, USA Department of Medical Oncology, Emory University, Atlanta, GA 30322, USA Emory Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA Correspondence should be addressed to Viraj A. Master, vmaster@emory.edu Received 1 April 2012; Accepted 11 June 2012 Academic Editor: Marcos Tobias-Machado Copyright © 2012 Brian W. Cross et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objectives. To determine the relationship between preoperative erythrocyte sedimentation rate (ESR) and overall survival in localized renal cell carcinoma (RCC) following nephrectomy. Methods. 167 patients undergoing nephrectomy for localized RCC had ESR levels measured preoperatively. Receiver Operating Characteristics curves were used to determine Area Under the Curve and relative sensitivity and specificity of preoperative ESR in predicting overall survival. Cut-offs for low (0.0–20.0 mm/hr), intermediate (20.1–50.0 mm/hr), and high risk (>50.0 mm/hr) groups were created. Kaplan-Meier analysis was conducted to assess the univariate impact of these ESR-based groups on overall survival. Univariate and multivariate Cox regression analysis was conducted to assess the potential of these groups to predict overall survival, adjusting for other patient and tumor characteristics. Results. Overall, 55.2% were low risk, while 27.0% and 17.8% were intermediate and high risk, respectively. Median (95% CI) survival was 44.1 (42.6–45.5) months, 35.5 (32.3–38.8) months, and 32.1 (25.5–38.6) months, respectively. After controlling for other patient and tumor characteristics, intermediate and high risk groups experienced a 4.5-fold (HR: 4.509, 95% CI: 0.735–27.649) and 18.5-fold (HR: 18.531, 95% CI: 2.117–162.228) increased risk of overall mortality, respectively. Conclusion. Preoperative ESR values represent a robust predictor of overall survival following nephrectomy in localized RCC. 1. Introduction in survival between stages [5], and this has fostered the search for other prognostic markers to more clearly stratify those Over 50,000 Americans are diagnosed with renal cell carci- patients in whom a poor outcome can be expected. noma (RCC) each year, approximately 30% of whom will Recently, efforts at identifying markers of disease pro- ultimately develop metastatic progression of their disease gression in RCC have focused on the readily available and despite apparent curative nephrectomy for localized cancer cost-effective clinical indices of preoperative laboratory at the time of clinical presentation [1, 2]. Metastatic RCC, values [7]. It is becoming increasingly clear that neoplastic untreated, has a dismal 5-year survival rate of <10% and a progression depends on an orchestrated interface between median overall survival of less than one year [3–6]. As such, tumor biology and the host inflammatory response [8]. The there has been a long-standing interest in accurately identi- systemic inflammatory response, as represented by aberra- fying those patients most likely to suffer from postoperative tions in circulating levels of acute-phase reactants, has pre- disease progression, and much research in recent years has focused on the development of prognostic models to aid in viously been shown to be a predictor of poor overall survival in a variety of advanced malignancies [9–11]. Indeed, we and surveillance strategies and patient counseling. Currently, the most commonly used tool to predict outcome in RCC is the multiple other groups have recently shown preoperative C- TNM staging system. However, there is considerable overlap reactive protein (CRP) levels are an independent predictor 2 International Journal of Surgical Oncology of metastasis and mortality following extirpative surgery for based on six stages (T1a, T1b, T2, T3a, T3b, and T3c). How- localized RCC [12]. ever, one-way analysis of variance revealed no significant The determination of the erythrocyte sedimentation rate difference in outcomes between T1a and T1b and between (ESR) is by a simple and inexpensive laboratory test in- T3a, T3b, and T3c. Additionally, there was no significant troduced by Westergren in 1921. It measures the distance difference between T3 and T4 disease. Therefore, patients erythrocytes have fallen after one hour in a vertical column were divided into three groups based on T-stages: T1, T2, and of anticoagulated blood under the influence of gravity [13]. T3-4. Though its clinical usefulness as a diagnostic tool has dimin- Prior to surgery, clinical stage, routine laboratory mea- ished as more intricate methods of analysis have emerged, it surements and ESR levels were assessed. The inter- and intra- remains paramount in the specific diagnosis of a few condi- assay variability for all laboratory values were <10%. Post- tions, including temporal arteritis, polymyalgia rheumatica, operatively, we assessed overall survival via Social Security and rheumatoid arthritis. Moreover, an extreme elevation Death Index. is mostly associated with infection or malignancy [13]. Frequency and descriptive analyses were conducted to Numerous studies over three decades have substantiated the characterize the patient population. Kaplan-Meier analysis prognostic utility of ESR in patients with RCC [7, 14–23], was conducted to assess the univariate impact of these ESR- with recent data from the Mayo Clinic showing elevated based risk groups on overall survival. Finally, univariate and ESR levels predicting the presence of aggressive disease and multivariate Cox regression analysis was conducted to assess poorer outcomes [22]. the potential of these groups to predict overall survival, Despite these numerous observations, the ESR level is not adjusting for other patient and tumor characteristics. Statis- routinely incorporated into current prognostic models for tical significance in this study was set at P< 0.05. All analyses RCC, likely due to the nonspecific nature of its elevation [24– were performed using SPSS version 16.0. 26], and the relationship between ESR and survival in local- ized RCC following potentially curative nephrectomy has 3. Results not been fully elucidated. We hypothesized preoperative ESR values were an independent prognostic indicator of overall This study cohort consisted of 167 patients who underwent survival in localized renal cell carcinoma following radical potentially curative nephrectomy for localized clear cell nephrectomy and could have potential benefit with respect RCC. Receiver Operating Characteristics (ROC) curves were to overall clinical management as well as preoperative patient constructed and used to determine the Area Under the Curve counseling, especially constructing specific risk categories on (AUC) and relative sensitivity and specificity of preoperative the basis of ESR levels. ESR in predicting overall survival. From this curve, cut- offs for low risk (0.0–20.0 mm/hr), intermediate risk (20.1– 50.0 mm/hr), and high risk (>50.0 mm/hr) groups were 2. Methods created. Of the total cohort, 101 patients (55.2%) were One hundred sixty-seven patients who underwent poten- in the low risk group, while 40 patients (27.0%) and 26 tially curative radical nephrectomy (all macroscopic tumor patients (17.8%) were in the intermediate risk and high was removed with negative surgical margins) for clear cell risk groups, respectively. The majority of patients in all risk RCC had ESR measured preoperatively between November categories were Caucasian males, with mean (SD) ages of 2006 and February 2010. There were a total of 192 patients 56.5 (±12.7) years, 64.4 (±14.2) years, and 64.2 (±11.7) with RCC during this time period, 15% of which did not years for the low, intermediate, and high risk categories, have a preoperative ESR value measured, mostly due to respectively (Table 1). The majority of patients in the low error in paperwork. Follow-up data was available through and intermediate risk groups had T1 disease, while higher August 25, 2010. Patients underwent standard followup for T-stages predominated in the high risk group, with nearly post-nephrectomy RCC patients, including imaging studies half of these patients having either T3 or T4 RCC. Likewise, every 3 months for 1 year, then spaced to every 6 months higher nuclear grades prevailed in the high risk group, with until 5 years postoperatively, then every year thereafter. almost 70% of high risk patients having either Fuhrman Routine laboratory studies including CRP, serum creatinine, nuclear grade III or IV. The mean (SD) ESR values were and ESR were checked every 3 months and physical exams 10.1 (5.0) mm/hr, 31.5 (7.3) mm/hr, and 82.5 (24.9) mm/hr were performed at office visits. Perioperative deaths (within for the low, intermediate, and high risk groups, respectively 30 days of surgery) were excluded from analysis. Inclusion (Table 1). criteria consisted of clear cell histology, and exclusion criteria Median (95% CI) survival for the ESR-based risk groups consisted of nodal or metastatic disease, or age less than was 44.1 (42.6–45.5) months, 35.5 (32.3–38.8) months, and 18 years. All patients underwent a cross-sectional imaging 32.1 (25.5–38.6) months for the low, intermediate, and high study (MRI or IV-contrasted CT) of the chest, abdomen, and risk groups, respectively. Univariate and multivariate Cox pelvis before surgery. No patients received systemic therapy regression analysis of overall survival showed a 3.2-fold following nephrectomy. The Emory University Institutional (HR: 3.265, 95% CI: 0.993-10.733) increased risk of overall Review Board approved this clinical database project. mortality for the intermediate risk group and a 8.4-fold (HR: Patients were staged pathologically according to the 8.409, 95% CI: 2.740-25.805) increased risk for the high AJCC TNM renal tumor classification [27], and tumors were risk group. After controlling for patient age, race, gender, graded based on Fuhrman criteria [28]. Staging was initially Charlson Comorbidity Index, T-Stage, Fuhrman Nuclear International Journal of Surgical Oncology 3 Table 1: Patient characteristics. Low risk Intermediate risk High risk All patients Variables (≤20.0 mm/hr) (20.1–50.0 mm/hr) (≥50.1 mm/hr) (n = 167) (n = 101) (n = 40) (n = 26) Age (y) Mean (SD) 56.5 (12.7) 64.4 (14.2) 64.2 (11.7) 59.4 (12.8) Race (%white/%nonwhite) 84.3/15.7 79.4/20.6 60.0/40.0 72.1/27.9 Gender (%male) 70.3 52.5 50.0 64.8 Charlson Comorbidity Index Mean (SD) 2.9 (1.6) 3.0 (1.7) 4.0 (2.3) 3.1 (1.7) T-Stage (%T1/%T2/%T3-4) 84.3/7.9/7.9 68.4/10.5/21.1 35.5/16.7/45.8 72.3/10.3/17.4 Fuhrman Nuclear Grade (%I-II/%III/%IV) 59.1/39.8/1.1 50.0/44.7/5.3 29.2/54.2/16.7 49.5/43.2/7.3 Tumor size (cm) Mean (SD) 4.4 (2.6) 4.9 (2.9) 7.0 (4.3) 5.0 (3.2) ESR (mm/hr) Mean (SD) 10.1 (5.0) 31.5 (7.3) 82.5 (24.9) 28.5 (29.4) Erythrocyte Sedimentation Rate. Table 2: Univariate and multivariate Cox regression analyses of predictors of overall survival (OS). Variable Crude HR 95% CI Adjusted HR 95% CI ESR -Based Risk Categories Low risk Reference Reference Intermediate risk 3.265 0.993–10.733 4.509 0.735–27.649 ∗∗ High risk 8.409 2.740–25.805 18.531 2.117–162.228 Age 1.028 0.992–1.065 1.030 0.971–1.093 Gender Female Reference Reference Male 1.502 0.610–3.697 1.306 0.322–5.298 Race White Reference Reference Non-white 0.658 0.149–2.896 0.150 0.018–1.243 Stage 1 Reference Reference 2 1.675 0.195–14.374 0.761 0.050–11.573 3-4 10.077 3.436–29.552 4.685 0.721–30.449 Charlson Comorbidity Index 1.274 1.098–1.480 0.754 0.506–1.123 Grade Reference Reference 1-2 3 3.266 0.883–12.076 1.373 0.222–8.493 4 32.595 7.684–138.264 21.902 1.937–247.590 Tumor size 1.176 1.072–1.290 1.001 0.820–1.221 Erythrocyte Sedimentation Rate. P = 0.033. ∗∗ P< 0.001. grade, and tumor size, intermediate risk and high risk groups Kaplan-Meier survival analysis of probability of survival experienced a 4.5-fold (HR: 4.509, 95% CI: 0.735–27.649, versus time since surgery stratified by preoperative ESR risk P = 0.033) and 18.5-fold (HR: 18.531, 95% CI: 2.117– category into low, intermediate, and high risk groups showed 162.228, P< 0.001) increased risk of overall mortality, a statistically significant difference in survival when compar- respectively (Table 2). ing the low risk group to both the high risk group (P< 0.001) 4 International Journal of Surgical Oncology has also undergone multiple refinements since its inception in 1974. Regardless, many elements of the TNM staging sys- tem are cause for debate. This has led to the development of 0.8 numerous integrated staging systems such as the UCLA/UISS (UCLA Integrated staging system) as well as the SSIGN (Stage, Size, Grade, and Necrosis) scoring algorithm [33]. 0.6 Of note, none of these staging systems incorporates any measured serum markers. 0.4 Several recent studies have focused on the prognostic value of preoperative ESR levels in RCC following potentially curative nephrectomy for clinically localized disease [22, 23], 0.2 as this is a quick and inexpensive laboratory test costing less than thirty dollars at our institution. In a recent meta-analysis, Wu and colleagues found the 012 24 36 48 systemic inflammatory response to be a predictor of poor overall survival in patients with renal cell carcinoma [34]. In Time since diagnosis (months) a total of 47 studies included for meta-analysis, the combined ESR-based risk categories hazard ratios (HRs) for survival of CRP, platelet count (PC), Low risk (0–20 mm/hr) and ESR were 3.46, 3.22, and 3.85, respectively. All three Intermediate risk (20.1–50 mm/hr) inflammatory indicators also predicted relapse-free survival High risk (>50 mm/hr) (HRs > 2.0). Figure 1: Kaplan-Meier survival analysis of probability of survival Another recent study specifically analyzing the role of versus time since surgery (days) by preoperative ESR Risk Category preoperative ESR values found that both tumor stage and among patients diagnosed with localized clear cell RCC undergoing preoperative ESR levels were both significant independent potentially curative nephrectomy. Patients categorized into Low prognostic indicators of progression-free survival as well as Risk (≤20.0 mm/hr), Intermediate Risk (20.1–50.0 mm/hr), and disease-specific survival [23]. When analysis was limited to High Risk (>50.0 mm/hr) based on preoperative ESR levels. Log- pT1 tumors, only ESR was an independent prognostic factor rank: Low Risk versus High Risk (P< 0.001), Low Risk versus for disease-specific survival. Intermediate Risk (P = 0.033), Intermediate Risk versus High Risk (P = 0.066). Two recent studies from the Mayo Clinic have reported elevated preoperative ESR levels portended an increased risk of death from RCC [7, 22], however, neither of these studies stratified patients preoperatively into low, intermediate, or as well as comparing the low risk group to the intermediate high risk based on their ESR level. risk group (P = 0.033). No statistically significant difference The incidence of elevated ESR in patients with RCC has in survival was observed between the intermediate and high been reported to range between 23% and 50% [22], and risk groups (P = 0.066), although a trend was observed has been noted as an independent prognostic factor for (Figure 1). disease-specific survival (DSS) as well as progression-free survival (PFS) following nephrectomy [23]. However, as noted previously, despite these observations ESR is not 4. Discussion incorporated into current prognostic algorithms for RCC. Renal cell carcinoma can be ranked among the great mas- This could be due to many factors, not the least of which is queraders of clinical medicine, and its diagnosis at a stage its nonspecific nature as well as the poorly understood early enough for curative nephrectomy remains a significant mechanism by which it reaches elevated levels. Early studies challenge. Clinically localized tumors are often symptom- on the prognostic significance of ESR were fraught with free, and by the time clinical symptoms become apparent, uncertainty owing mainly to a lack of histologic stratification more advanced tumors have a complex clinical course with and the relatively small number of patients in each series. These issues have been addressed in a more recent study of increased morbidity and mortality. As such, numerous stud- ies over several decades have focused on the identification larger cohorts of patients grouped by histologic subtype from of other objective measures for both diagnostic as well the Mayo Clinic [22]. This study evaluated the prognostic as prognostic use in defining risk groups for preoperative significance of preoperative ESR in 1075 patients who under- patient counseling and postoperative surveillance strategies went nephrectomy for RCC over 30 years. These authors [7, 12, 14, 22, 23, 29, 30]. observed an association between elevated preoperative ESR With the rapid and evolving understanding of renal (defined as >22 mm/hr in male patients and >29 mm/hr in tumor biology, RCC staging systems have likewise evolved female patients) and death from clear cell RCC, papillary RCC, and chromophobe RCC, with risk ratios of 3.6, 3.8, and over time. The first formal staging system dates to 1958, later modified by Robson in 1969 [31, 32]. Subsequent refine- 10.3, respectively. ments have led to the development of the often-cited TNM Urologists are long familiar with the use of serum mark- ers to risk-stratify patients with cancer. For example, dif- classification, which stratifies patients’ primary tumor into one of four classifications (I–IV). Similarly, this classification ferent levels of PSA prior to definitive local therapy can Probability of survival International Journal of Surgical Oncology 5 be helpful in predicting outcome, as well as the previously [2] B.C.Leibovich,M.L.Blute,J.C.Chevilleetal., “Prediction of progression after radical nephrectomy for patients with clear mentioned prognostic value of preoperative CRP in renal cell renal cell carcinoma: a stratification tool for prospective cell carcinoma. To our knowledge, the current study is the clinical trials,” Cancer, vol. 97, no. 7, pp. 1663–1671, 2003. first to stratify patients based on preoperative ESR level into [3] T. Klatte, J. S. Lam, B. Shuch, A. S. Belldegrun, and A. J. low, intermediate, and high risk categories based on overall Pantuck, “Surveillance for renal cell carcinoma: why and how? survival following nephrectomy for localized RCC. In mul- When and how often?” Urologic Oncology,vol. 26, no.5,pp. tivariate analysis, preoperative ESR levels were significantly 550–554, 2008. associated with an increased risk of overall mortality, with [4] B. Ljungberg, “Prognostic markers in renal cell carcinoma,” the intermediate and high risk groups experiencing a 4.5-fold Current Opinion in Urology, vol. 17, no. 5, pp. 303–308, 2007. and 18.5-fold increased risk of overall mortality, respectively. [5] S. Ramsey, G. W. Lamb, M. Aitchison, and D. C. McMillan, These results support our hypothesis that preoperative “Prospective study of the relationship between the sys- ESR levels independently predict overall survival following temic inflammatory response, prognostic scoring systems and nephrectomy for clinically localized RCC and reinforce other relapse-free and cancer-specific survival in patients under- going potentially curative resection for renal cancer,” British studies asserting its prognostic significance. 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