Scandinavian Journal of Urology
ISSN: 2168-1805 (Print) 2168-1813 (Online) Journal homepage: http://www.tandfonline.com/loi/isju20
Prognostic significance of modified Glasgow Prognostic Score in patients with non-metastatic clear cell renal cell carcinoma Dae Sung Cho, Sun Il Kim, Seol Ho Choo, Seok Heun Jang, Hyun Soo Ahn & Se Joong Kim To cite this article: Dae Sung Cho, Sun Il Kim, Seol Ho Choo, Seok Heun Jang, Hyun Soo Ahn & Se Joong Kim (2016) Prognostic significance of modified Glasgow Prognostic Score in patients with non-metastatic clear cell renal cell carcinoma, Scandinavian Journal of Urology, 50:3, 186-191, DOI: 10.3109/21681805.2015.1136677 To link to this article: http://dx.doi.org/10.3109/21681805.2015.1136677
Published online: 15 Feb 2016.
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Date: 19 May 2016, At: 16:44
SCANDINAVIAN JOURNAL OF UROLOGY, 2016 VOL. 50, NO. 3, 186–191 http://dx.doi.org/10.3109/21681805.2015.1136677
ORIGINAL ARTICLE
Prognostic significance of modified Glasgow Prognostic Score in patients with non-metastatic clear cell renal cell carcinoma Dae Sung Choa, Sun Il Kimb, Seol Ho Choob, Seok Heun Janga, Hyun Soo Ahnb and Se Joong Kimb Department of Urology, Bundang Jesaeng General Hospital, Seongnam, Republic of Korea; bDepartment of Urology, Ajou University School of Medicine, Suwon, Republic of Korea
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a
ABSTRACT
ARTICLE HISTORY
Objective The aim of this study was to evaluate the usefulness of the modified Glasgow Prognostic Score (mGPS) as a prognostic factor in patients with non-metastatic clear cell renal cell carcinoma (RCC). Materials and methods Between June 1994 and July 2012, 469 patients with RCC underwent radical or partial nephrectomy at two hospitals. Among these patients, 65 with non-clear cell type histology and 16 with lymph-node or distant metastasis were excluded. The medical records of the remaining 388 patients were retrospectively reviewed. The mGPS was calculated using a selective combination of C-reactive protein (CRP) and albumin as previously described. The prognostic significance of various clinicopathological variables including mGPS was analyzed using univariate and multivariate analyses. Results Of the total 388 patients, 40 patients (10.3%) developed local recurrence or distant metastasis and 18 patients (4.6%) died of disease during the follow-up period. The univariate analysis identified CRP, mGPS, thrombocytosis, T stage, Fuhrman’s nuclear grade and lymphovascular invasion as significant prognostic factors for recurrence-free survival (RFS) and cancer-specific survival (CSS). The multivariate analysis indicated that mGPS (p50.001), T stage (p ¼ 0.024) and lymphovascular invasion (p ¼ 0.046) were independent prognostic factors for RFS, whereas mGPS (p ¼ 0.001) was the only independent prognostic factor for CSS. Conclusions The mGPS is an independent prognostic factor for RFS and CSS in patients with nonmetastatic clear cell RCC treated with radical or partial nephrectomy. These findings suggest that mGPS should be used for predicting recurrence or survival in patients undergoing nephrectomy for non-metastatic clear cell RCC.
Received 10 July 2015 Revised 7 December 2015 Accepted 21 December 2015
Introduction Renal cell carcinoma (RCC) is one of the most lethal urological cancers and accounts for about 3% of all adult neoplasms [1]. The incidence of RCC has been increasing worldwide over the past three decades in all age groups. Despite the established role of radical or partial nephrectomy as standard treatment for localized RCC, about 20–40% of patients will have local recurrence or distant metastasis after nephrectomy regardless of a finding of pathologically confined disease at the time of surgery [2]. According to a report, about 7% of patients with small RCC may have metastasis after nephrectomy [3,4]. Because the prognosis of RCC is variable, many investigators have tried to find the useful prognostic factors for recurrence and progression in RCC. Tumor stage and grade have been regarded as the most important prognostic factors for RCC. However, there is increasing evidence that patient-related factors, in particular the systemic inflammatory response, are associated with the development and progression of RCC independent of tumor stage or grade [5–7]. Although Creactive protein (CRP), an acute-phase reactant of the host’s immune response, remains one of the most valuable potential prognostic factors for RCC [8], some studies have tried to CONTACT Se Joong Kim, MD, PhD Suwon 443-721, Republic of Korea ß 2016 Taylor & Francis
[email protected]
KEYWORDS
Albumin; C-reactive protein; renal cell carcinoma; recurrence; survival
improve the predictive value by using a selective combination of CRP and albumin, termed the modified Glasgow Prognostic Score (mGPS) [9,10]. This has been shown to have prognostic value in several types of cancer, including lung, breast and gastrointestinal cancers and RCC [11–18]. However, studies on the relationship between mGPS and the recurrence and survival in patients treated surgically for non-metastatic RCC are still limited [16–18] and have not been performed in Asian populations. Thus, the present study evaluated the usefulness of the mGPS as a prognostic factor in patients with nonmetastatic clear cell RCC treated with radical or partial nephrectomy at two hospitals in the Republic of Korea.
Materials and methods This study was initiated with the approval of the institutional review boards of the two hospitals. Between June 1994 and July 2012, patients with RCC who underwent radical or partial nephrectomy were enrolled in this study. All blood samples were measured just before the operation. Staging of the tumors was performed according to the 2010 tumor, node, metastasis classification [19], and nuclear grade was assigned according to Fuhrman’s nuclear grading system [20].
Department of Urology, Ajou University School of Medicine, San-5, Wonchon-dong, Yeongtong-gu,
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Thrombocytosis was defined as a platelet count of at least 380,000/ml in men and at least 370,000/ml in women according to the normal reference range. The mGPS was calculated using a selective combination of CRP and albumin as previously described [10]. Patients with both an elevated CRP concentration (410 mg/l) and hypoalbuminemia (535 g/l) were allocated a score of 2. Those patients with an elevated CRP concentration (410 mg/l) were allocated a score of 1. Patients with a CRP concentration of 10 mg/l and any albumin concentration were allocated a score of 0. Postoperative follow-up examinations included basic laboratory examinations and chest X-ray every 3 months for the first 2 years, every 6 months for the next 2 years and annually thereafter. Abdominopelvic computed tomography was performed annually during follow-up or when clinically indicated. Disease recurrence was defined as local failure in the tumor bed, regional lymph nodes or distant metastasis.
Statistical analysis The chi-squared test was used to analyze the correlation between mGPS and the clinicopathological variables, including age, gender, tumor size, T stage, Fuhrman’s nuclear grade and lymphovascular invasion. Univariate and multivariate analyses were performed using the log-rank test and Cox’s proportional hazards regression model, respectively. All statistical analyses were performed using SPSS version 19.0 (SPSS, Chicago, IL). Values of p less than 0.05 were considered to be statistically significant in all of the analyses.
Results In total, 469 patients with RCC who underwent radical or partial nephrectomy were identified. Among these patients, 65 patients with non-clear cell type histology and 16 patients with lymph-node or distant metastasis were excluded. Those with comorbidity affecting the systemic inflammatory response or a history of anti-inflammatory drug use were also excluded, including one patient with systemic lupus erythematosus and two patients with rheumatoid arthritis, who had already been excluded because of metastasis or non-clear cell type histology. Thus, the medical records of the remaining 388 patients with non-metastatic clear cell RCC (263 men and 125 women) were retrospectively reviewed (Figure 1). Mean patient age was 56.0 years (range 18–81 years). The clinicopathological data of 388 patients with non-metastatic clear cell RCC are summarized in Table 1. There were 33 patients (8.5%) with hypoalbuminemia and 61 patients (15.7%) with CRP elevation. Of the total 388 patients, 327 patients (84.3%) were categorized as mGPS of 0, 38 patients (9.8%) as mGPS of 1 and 23 patients (5.9%) as mGPS of 2. Among the 33 patients with hypoalbuminemia, 23 patients were included in the mGPS 2 group and the remaining 10 were included in the mGPS 0 group. The median CRP level in all patients was 2.6 mg/l (range 0.1–315.7 mg/l) and was used as the cut-off value to evaluate prognostic significance. The median CRP levels for each subgroup were 1.7 mg/l (range 0.1–9.8 mg/l) for
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mGPS 0, 25.5 mg/l (range 10.6–181.5 mg/l) for mGPS 1 and 37.6 mg/l (range 15.1–315.7 mg/l) for mGPS 2. The median follow-up duration was 44 months (mean 53.7, range 4–215 months). The median follow-up duration of the mGPS 0 group was 45 months (mean 54.1, range 12–215 months), that of mGPS 1 was 33 months (mean 49.7, range 4–151 months) and that of mGPS 2 was 38 months (mean 54.8, range 10–171 months). Because there was no significant difference in followup duration (p ¼ 0.843), the imaging study was performed approximately at the same frequency among the mGPS groups. The median recurrence-free survival (RFS) for the total study population was 171 months. The median cancer-specific survival (CSS) was not reached. The median RFS for the mGPS 0 group was not reached, whereas that for mGPS 1 and mGPS 2 was 92 months and 40 months, respectively. The median CSS for the mGPS 2 group was 73 months, whereas the median CSS for the mGPS 0 and mGPS 1 groups was not reached. Forty patients (10.3%; eight patients with mGPS 0, 14 patients with mGPS 1 and 18 patients with mGPS 2) developed local recurrence or distant metastasis and 18 patients (4.6%; one patient with mGPS 0, seven patients with mGPS 1 and 10 patients with mGPS 2) died of disease during the follow-up period. The 5 year RFS and CSS rates for the total study population were 92.0% and 95.6%, respectively. The 5 year RFS and CSS rates for the mGPS 0 group were 99.3% and 100.0%, respectively; those for mGPS 1 were 73.8% and 82.6%, respectively; and those for mGPS 2 were 44.3% and 64.0%, respectively.mGPS was significantly correlated with thrombocytosis (p50.001), tumor size (p50.001), T stage (p50.001), Fuhrman’s nuclear grade (p ¼ 0.001) and lymphovascular invasion (p50.001), but not with age, gender or nephrectomy type (Table 2). Kaplan–Meier RFS and CSS curves according to mGPS score showed that RFS and CSS rates were lower in patients with higher mGPS score (Figures 2 and 3). The univariate analysis identified CRP, mGPS, thrombocytosis, T stage, Fuhrman’s nuclear grade and lymphovascular invasion as significant prognostic factors for RFS and CSS. The multivariate analysis indicated that mGPS (p50.001), T stage (p ¼ 0.024) and lymphovascular invasion (p ¼ 0.046) were independent prognostic factors for RFS, whereas mGPS (p ¼ 0.001) was the only independent prognostic factor for CSS (Tables 3 and 4).
Discussion The survival of patients with localized RCC who undergo nephrectomy is difficult to predict because of its heterogeneous biological nature. Therefore, many prognostic factors for RCC have been evaluated and these include biochemical parameters such as hemoglobin, calcium, lactate dehydrogenase, bilirubin, alkaline phosphatase, platelets and CRP [7,21– 23]. Recently, efforts have been made to improve prognostic power using combinations of these factors, such as a selective combination of CRP and albumin, denominated as mGPS [10,16–18]. CRP is an acute-phase reactant produced by the hepatocytes in response to cytokines such as interleukin-6 (IL-6), interleukin-1 and tumor necrosis factor [24]. If the serum
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Radical or partial nephrectomy for RCC Excluded:
N=469
Non-clear cell RCC (including 1 patient with SLE and 1 patient with RA) N=65
Clear cell RCC N=404
Excluded: Lymph node or distant metastasis (including 1 patient with RA) N=16
Localized clear cell RCC
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N=388
Excluded: comorbidity affecting systemic inflammatory response or history of anti-inflammatory drug use
Final inclusion
N=0
N=388 Figure 1. Flowchart of patients’ inclusion/exclusion. RCC: renal cell carcinoma; SLE: systemic lupus erythematosus; RA: rheumatoid arthritis. Table 1. Clinicopathological data of 388 patients with non-metastatic clear cell renal cell carcinoma. Characteristic Age (years) 60 460 Gender Male Female Thrombocytosis No Yes mGPS 0 1 2 Tumor size (cm) 7 47 T stage T1 T2 T3 T4 Grade 1 2 3 4 Lymphovascular invasion No Yes Nephrectomy type Partial Radical
Table 2. Clinicopathological characteristics of patients grouped by modified Glasgow Prognostic Score (mGPS) category.
No. of patients (%) 237 (61.1) 151 (38.9) 263 (67.8) 125 (32.2) 357 (92.0) 31 (8.0) 327 (84.3) 38 (9.8) 23 (5.9) 322 (83.0) 66 (17.0) 269 32 83 4
(69.2) (8.3) (21.5) (1.0)
26 125 202 35
(6.7) (32.2) (52.1) (9.0)
364 (93.8) 24 (6.2) 24 (6.2) 364 (93.8)
mGPS: modified Glasgow Prognostic Score.
concentration of this protein is elevated, it means that acute inflammation within 8–12 h is present. The association between RCC and CRP elevation is mainly explained by
No. of patients (%) Variable Age (years) 60 460 Gender Male Female Thrombocytosis No Yes Tumor size (cm) 7 47 T stage Low (T1 + T2) High (T3 + T4) Grade Low (G1 + G2) High (G3 + G4) Lymphovascular invasion No Yes Nephrectomy type Partial Radical a
mGPS 0
mGPS 1
mGPS 2
205 (62.7) 122 (37.3)
23 (60.5) 15 (39.5)
9 (39.1) 14 (60.9)
224 (68.5) 103 (31.5)
26 (68.4) 12 (31.6)
13 (56.5) 10 (43.5)
309 (94.5) 18 (5.5)
30 (78.9) 8 (21.1)
18 (78.3) 5 (21.7)
284 (86.9) 43 (13.1)
27 (71.1) 11 (28.9)
11 (47.8) 12 (52.2)
273 (83.5) 54 (16.5)
20 (52.6) 18 (47.4)
8 (34.8) 15 (65.2)
140 (42.8) 187 (57.2)
9 (23.7) 29 (76.3)
2 (8.7) 21 (91.3)
315 (96.3) 12 (3.7)
32 (84.2) 6 (15.8)
17 (73.9) 6 (26.1)
21 (6.4) 306 (93.6)
1 (2.6) 37 (97.4)
2 (8.7) 21 (91.3)
pa 0.081 0.492 50.001 50.001 50.001 0.001 50.001 0.575
Analyzed by chi-squared test.
overproduction of IL-6 by tumor cells [25]. Experimental studies on RCC cell lines showed that IL-6 was produced at high levels by RCC cell lines and functioned as an autocrine growth factor of RCC [26]. These findings suggest that the systemic inflammatory response may be associated with progression and metastasis of RCC. Hypoalbuminemia has also been reported to have poor outcome in patients with
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Figure 2. Kaplan–Meier recurrence-free survival curves based on modified Glasgow Prognostic Score (mGPS) category.
Figure 3. Kaplan–Meier cancer-specific survival curves based on modified Glasgow Prognostic Score (mGPS) category.
cancer [15,27]. Lindenmann et al. [27] suggested that nutritional defects were directly related to systemic inflammation in cancer patients and albumin was reduced during chronic inflammation by activation of acute-phase response proteins such as CRP, enhancement of vascular permeability for albumin and decreased hepatic albumin synthesis [28]. As a result, nutritional defects caused by chronic inflammation could lead to poor prognosis in cancer patients.
The Glasgow Prognostic Score (GPS) originated from selective combination of CRP and albumin and was first described in patients with advanced non-small cell lung cancer, by Forrest et al. [29]. They categorized patients according to CRP and albumin level, as follows. Patients with both CRP elevation (410 mg/l) and hypoalbuminemia (535 g/l) were given a score of 2, patients with only one of CRP elevation or hypoalbuminemia were given a score of 1, and patients with
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Table 3. Univariate and multivariate analysis of recurrence-free survival in 388 patients with non-metastatic clear cell renal cell carcinoma. Univariatea p Age ( 60 vs 460 years) Gender (male vs female) C-reactive protein ( 2.6 mg/l vs 42.6 mg/l) mGPS (0 vs 1 vs 2) Thrombocytosis (no vs yes) T stage (T1 + T2 vs T3 + T4) Grade (G1 + G2 vs G3 + G4) Lymphovascular invasion (no vs yes) Nephrectomy type (partial vs radical)
Multivariateb HR (95% CI)
0.328 0.091 50.001
1.147 (0.551–2.386) 1.054 (0.481–2.310) 1.536 (0.494–4.774)
50.001 0.003 50.001 50.001 50.001 0.949
2.794 1.224 2.433 2.276 2.466 0.756
p 0.714 0.896 0.458
(1.696–4.603) 50.001 (0.466–3.220) 0.682 (1.125–5.262) 0.024 (0.866–5.982) 0.095 (1.016–5.985) 0.046 (0.167–3.434) 0.718
a
Analyzed by log-rank test. Analyzed by Cox proportional hazards regression model.
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b
Table 4. Univariate and multivariate analysis of cancer-specific survival in 388 patients with non-metastatic clear cell renal cell carcinoma. Univariatea p Age (60 vs 460 years) Gender (male vs female) C-reactive protein ( 26 mg/l vs 426 mg/l) mGPS (0 vs 1 vs 2) Thrombocytosis (no vs yes) T stage (T1 + T2 vs T3 + T4) Grade (G1 + G2 vs G3 + G4) Lymphovascular invasion (no vs yes) Nephrectomy type (partial vs radical)
Multivariateb HR (95% CI)
p
0.151 0.239 50.001
1.583 (0.521–4.809) 0.418 1.273 (0.377–4.295) 0.697 2.352 (0.228–24.212) 0.472
50.001 0.047 50.001 0.001 50.001 0.961
3.704 0.947 2.114 5.252 2.424 0.866
(1.672–8.203) (0.199–4.494) (0.642–6.963) (0.614–44.936) (0.752–7.819) (0.099–7.565)
0.001 0.945 0.218 0.130 0.138 0.896
a
Analyzed by log-rank test. Analyzed by Cox proportional hazards regression model.
b
normal CRP and albumin level were given a score of 0. However, they failed to show the relationship between hypoalbuminemia and poor survival, because only 10% of patients had hypoalbuminemia. McMillan [30] also showed that there was no difference in CSS between patients with hypoalbuminemia and normal albumin level. Proctor et al. [10] indicated that a low albumin level alone was associated with poor survival rate in some tumors such as breast, hematological and pulmonary tumors, but not in other tumors such as bladder, gynecological, prostate, gastroesophageal, renal, colorectal, head and neck and hepatopancreaticobiliary tumors, in their large cohort study. Therefore, GPS was modified as mGPS by giving a score of 1 only for an elevated CRP. mGPS is easy to measure preoperatively, and has been proven to have prognostic value in several types of cancers, including RCC [11–18]. In patients with metastatic RCC treated with immunotherapy, GPS was an independent prognostic factor for CSS [15]. For localized RCC, Tai et al. [16] reported that mGPS was significantly associated with RFS in 129 patients with clinically localized clear cell RCC. Intermediate-risk (mGPS ¼ 1) and highrisk (mGPS ¼ 2) patients experienced a four-fold and seven-fold risk of metastasis within 1 year of radical nephrectomy compared to low-risk (mGPS ¼ 0) patients, respectively. Qayyum et al. [17] demonstrated that mGPS was an independent predictor of CSS in 79 patients with surgically resected clear cell RCC. Lamb et al. [18] also showed that mGPS was an independent predictor of CSS in 169 patients with surgically
treated clear cell RCC. They suggested that mGPS was at least equivalent to and independent of other current validated prognostic scoring systems for patients undergoing curative nephrectomy for clear cell RCC. The results of the present study are in agreement with those of previous studies, showing that mGPS was an independent prognostic factor for RFS and CSS in patients with surgically treated non-metastatic clear cell RCC, and it was superior to CRP alone. Kaplan–Meier survival curves indicated the significant decline in RFS and CSS in patients with higher mGPS. Based on this study, it may be important to evaluate whether new prognostic scoring systems based on the mGPS could be useful for predicting the prognosis of nonmetastatic clear cell RCC. This study has several limitations. First, only patients with clear cell RCC were included in this study because of the small number of patients with other histology. Further study including RCC with other histology should be performed in the future. Secondly, the study did not consider patient characteristics such as obesity, smoking history or alcohol consumption that could affect systemic inflammation. Thirdly, data from only two hospitals were included in this study and the sample size was modest. Therefore, validation in a multicenter study with a larger sample size is mandatory. In conclusion, the mGPS is an independent prognostic factor for RFS and CSS in patients with non-metastatic clear cell RCC treated with radical or partial nephrectomy. These findings suggest that mGPS should be used for predicting recurrence or survival in patients undergoing nephrectomy for nonmetastatic clear cell RCC.
Disclosure statement No potential conflict of interest was reported by the authors.
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Prognostic significance of modified Glasgow Prognostic Score in patients with non-metastatic clear cell renal cell carcinoma Dae Sung Cho, Sun Il Kim, Seol Ho Choo, Seok Heun Jang, Hyun Soo Ahn & Se Joong Kim To cite this article: Dae Sung Cho, Sun Il Kim, Seol Ho Choo, Seok Heun Jang, Hyun Soo Ahn & Se Joong Kim (2016) Prognostic significance of modified Glasgow Prognostic Score in patients with non-metastatic clear cell renal cell carcinoma, Scandinavian Journal of Urology, 50:3, 186-191, DOI: 10.3109/21681805.2015.1136677 To link to this article: http://dx.doi.org/10.3109/21681805.2015.1136677
Published online: 15 Feb 2016.
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Date: 19 May 2016, At: 16:44
SCANDINAVIAN JOURNAL OF UROLOGY, 2016 VOL. 50, NO. 3, 186–191 http://dx.doi.org/10.3109/21681805.2015.1136677
ORIGINAL ARTICLE
Prognostic significance of modified Glasgow Prognostic Score in patients with non-metastatic clear cell renal cell carcinoma Dae Sung Choa, Sun Il Kimb, Seol Ho Choob, Seok Heun Janga, Hyun Soo Ahnb and Se Joong Kimb Department of Urology, Bundang Jesaeng General Hospital, Seongnam, Republic of Korea; bDepartment of Urology, Ajou University School of Medicine, Suwon, Republic of Korea
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a
ABSTRACT
ARTICLE HISTORY
Objective The aim of this study was to evaluate the usefulness of the modified Glasgow Prognostic Score (mGPS) as a prognostic factor in patients with non-metastatic clear cell renal cell carcinoma (RCC). Materials and methods Between June 1994 and July 2012, 469 patients with RCC underwent radical or partial nephrectomy at two hospitals. Among these patients, 65 with non-clear cell type histology and 16 with lymph-node or distant metastasis were excluded. The medical records of the remaining 388 patients were retrospectively reviewed. The mGPS was calculated using a selective combination of C-reactive protein (CRP) and albumin as previously described. The prognostic significance of various clinicopathological variables including mGPS was analyzed using univariate and multivariate analyses. Results Of the total 388 patients, 40 patients (10.3%) developed local recurrence or distant metastasis and 18 patients (4.6%) died of disease during the follow-up period. The univariate analysis identified CRP, mGPS, thrombocytosis, T stage, Fuhrman’s nuclear grade and lymphovascular invasion as significant prognostic factors for recurrence-free survival (RFS) and cancer-specific survival (CSS). The multivariate analysis indicated that mGPS (p50.001), T stage (p ¼ 0.024) and lymphovascular invasion (p ¼ 0.046) were independent prognostic factors for RFS, whereas mGPS (p ¼ 0.001) was the only independent prognostic factor for CSS. Conclusions The mGPS is an independent prognostic factor for RFS and CSS in patients with nonmetastatic clear cell RCC treated with radical or partial nephrectomy. These findings suggest that mGPS should be used for predicting recurrence or survival in patients undergoing nephrectomy for non-metastatic clear cell RCC.
Received 10 July 2015 Revised 7 December 2015 Accepted 21 December 2015
Introduction Renal cell carcinoma (RCC) is one of the most lethal urological cancers and accounts for about 3% of all adult neoplasms [1]. The incidence of RCC has been increasing worldwide over the past three decades in all age groups. Despite the established role of radical or partial nephrectomy as standard treatment for localized RCC, about 20–40% of patients will have local recurrence or distant metastasis after nephrectomy regardless of a finding of pathologically confined disease at the time of surgery [2]. According to a report, about 7% of patients with small RCC may have metastasis after nephrectomy [3,4]. Because the prognosis of RCC is variable, many investigators have tried to find the useful prognostic factors for recurrence and progression in RCC. Tumor stage and grade have been regarded as the most important prognostic factors for RCC. However, there is increasing evidence that patient-related factors, in particular the systemic inflammatory response, are associated with the development and progression of RCC independent of tumor stage or grade [5–7]. Although Creactive protein (CRP), an acute-phase reactant of the host’s immune response, remains one of the most valuable potential prognostic factors for RCC [8], some studies have tried to CONTACT Se Joong Kim, MD, PhD Suwon 443-721, Republic of Korea ß 2016 Taylor & Francis
[email protected]
KEYWORDS
Albumin; C-reactive protein; renal cell carcinoma; recurrence; survival
improve the predictive value by using a selective combination of CRP and albumin, termed the modified Glasgow Prognostic Score (mGPS) [9,10]. This has been shown to have prognostic value in several types of cancer, including lung, breast and gastrointestinal cancers and RCC [11–18]. However, studies on the relationship between mGPS and the recurrence and survival in patients treated surgically for non-metastatic RCC are still limited [16–18] and have not been performed in Asian populations. Thus, the present study evaluated the usefulness of the mGPS as a prognostic factor in patients with nonmetastatic clear cell RCC treated with radical or partial nephrectomy at two hospitals in the Republic of Korea.
Materials and methods This study was initiated with the approval of the institutional review boards of the two hospitals. Between June 1994 and July 2012, patients with RCC who underwent radical or partial nephrectomy were enrolled in this study. All blood samples were measured just before the operation. Staging of the tumors was performed according to the 2010 tumor, node, metastasis classification [19], and nuclear grade was assigned according to Fuhrman’s nuclear grading system [20].
Department of Urology, Ajou University School of Medicine, San-5, Wonchon-dong, Yeongtong-gu,
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Thrombocytosis was defined as a platelet count of at least 380,000/ml in men and at least 370,000/ml in women according to the normal reference range. The mGPS was calculated using a selective combination of CRP and albumin as previously described [10]. Patients with both an elevated CRP concentration (410 mg/l) and hypoalbuminemia (535 g/l) were allocated a score of 2. Those patients with an elevated CRP concentration (410 mg/l) were allocated a score of 1. Patients with a CRP concentration of 10 mg/l and any albumin concentration were allocated a score of 0. Postoperative follow-up examinations included basic laboratory examinations and chest X-ray every 3 months for the first 2 years, every 6 months for the next 2 years and annually thereafter. Abdominopelvic computed tomography was performed annually during follow-up or when clinically indicated. Disease recurrence was defined as local failure in the tumor bed, regional lymph nodes or distant metastasis.
Statistical analysis The chi-squared test was used to analyze the correlation between mGPS and the clinicopathological variables, including age, gender, tumor size, T stage, Fuhrman’s nuclear grade and lymphovascular invasion. Univariate and multivariate analyses were performed using the log-rank test and Cox’s proportional hazards regression model, respectively. All statistical analyses were performed using SPSS version 19.0 (SPSS, Chicago, IL). Values of p less than 0.05 were considered to be statistically significant in all of the analyses.
Results In total, 469 patients with RCC who underwent radical or partial nephrectomy were identified. Among these patients, 65 patients with non-clear cell type histology and 16 patients with lymph-node or distant metastasis were excluded. Those with comorbidity affecting the systemic inflammatory response or a history of anti-inflammatory drug use were also excluded, including one patient with systemic lupus erythematosus and two patients with rheumatoid arthritis, who had already been excluded because of metastasis or non-clear cell type histology. Thus, the medical records of the remaining 388 patients with non-metastatic clear cell RCC (263 men and 125 women) were retrospectively reviewed (Figure 1). Mean patient age was 56.0 years (range 18–81 years). The clinicopathological data of 388 patients with non-metastatic clear cell RCC are summarized in Table 1. There were 33 patients (8.5%) with hypoalbuminemia and 61 patients (15.7%) with CRP elevation. Of the total 388 patients, 327 patients (84.3%) were categorized as mGPS of 0, 38 patients (9.8%) as mGPS of 1 and 23 patients (5.9%) as mGPS of 2. Among the 33 patients with hypoalbuminemia, 23 patients were included in the mGPS 2 group and the remaining 10 were included in the mGPS 0 group. The median CRP level in all patients was 2.6 mg/l (range 0.1–315.7 mg/l) and was used as the cut-off value to evaluate prognostic significance. The median CRP levels for each subgroup were 1.7 mg/l (range 0.1–9.8 mg/l) for
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mGPS 0, 25.5 mg/l (range 10.6–181.5 mg/l) for mGPS 1 and 37.6 mg/l (range 15.1–315.7 mg/l) for mGPS 2. The median follow-up duration was 44 months (mean 53.7, range 4–215 months). The median follow-up duration of the mGPS 0 group was 45 months (mean 54.1, range 12–215 months), that of mGPS 1 was 33 months (mean 49.7, range 4–151 months) and that of mGPS 2 was 38 months (mean 54.8, range 10–171 months). Because there was no significant difference in followup duration (p ¼ 0.843), the imaging study was performed approximately at the same frequency among the mGPS groups. The median recurrence-free survival (RFS) for the total study population was 171 months. The median cancer-specific survival (CSS) was not reached. The median RFS for the mGPS 0 group was not reached, whereas that for mGPS 1 and mGPS 2 was 92 months and 40 months, respectively. The median CSS for the mGPS 2 group was 73 months, whereas the median CSS for the mGPS 0 and mGPS 1 groups was not reached. Forty patients (10.3%; eight patients with mGPS 0, 14 patients with mGPS 1 and 18 patients with mGPS 2) developed local recurrence or distant metastasis and 18 patients (4.6%; one patient with mGPS 0, seven patients with mGPS 1 and 10 patients with mGPS 2) died of disease during the follow-up period. The 5 year RFS and CSS rates for the total study population were 92.0% and 95.6%, respectively. The 5 year RFS and CSS rates for the mGPS 0 group were 99.3% and 100.0%, respectively; those for mGPS 1 were 73.8% and 82.6%, respectively; and those for mGPS 2 were 44.3% and 64.0%, respectively.mGPS was significantly correlated with thrombocytosis (p50.001), tumor size (p50.001), T stage (p50.001), Fuhrman’s nuclear grade (p ¼ 0.001) and lymphovascular invasion (p50.001), but not with age, gender or nephrectomy type (Table 2). Kaplan–Meier RFS and CSS curves according to mGPS score showed that RFS and CSS rates were lower in patients with higher mGPS score (Figures 2 and 3). The univariate analysis identified CRP, mGPS, thrombocytosis, T stage, Fuhrman’s nuclear grade and lymphovascular invasion as significant prognostic factors for RFS and CSS. The multivariate analysis indicated that mGPS (p50.001), T stage (p ¼ 0.024) and lymphovascular invasion (p ¼ 0.046) were independent prognostic factors for RFS, whereas mGPS (p ¼ 0.001) was the only independent prognostic factor for CSS (Tables 3 and 4).
Discussion The survival of patients with localized RCC who undergo nephrectomy is difficult to predict because of its heterogeneous biological nature. Therefore, many prognostic factors for RCC have been evaluated and these include biochemical parameters such as hemoglobin, calcium, lactate dehydrogenase, bilirubin, alkaline phosphatase, platelets and CRP [7,21– 23]. Recently, efforts have been made to improve prognostic power using combinations of these factors, such as a selective combination of CRP and albumin, denominated as mGPS [10,16–18]. CRP is an acute-phase reactant produced by the hepatocytes in response to cytokines such as interleukin-6 (IL-6), interleukin-1 and tumor necrosis factor [24]. If the serum
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Radical or partial nephrectomy for RCC Excluded:
N=469
Non-clear cell RCC (including 1 patient with SLE and 1 patient with RA) N=65
Clear cell RCC N=404
Excluded: Lymph node or distant metastasis (including 1 patient with RA) N=16
Localized clear cell RCC
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N=388
Excluded: comorbidity affecting systemic inflammatory response or history of anti-inflammatory drug use
Final inclusion
N=0
N=388 Figure 1. Flowchart of patients’ inclusion/exclusion. RCC: renal cell carcinoma; SLE: systemic lupus erythematosus; RA: rheumatoid arthritis. Table 1. Clinicopathological data of 388 patients with non-metastatic clear cell renal cell carcinoma. Characteristic Age (years) 60 460 Gender Male Female Thrombocytosis No Yes mGPS 0 1 2 Tumor size (cm) 7 47 T stage T1 T2 T3 T4 Grade 1 2 3 4 Lymphovascular invasion No Yes Nephrectomy type Partial Radical
Table 2. Clinicopathological characteristics of patients grouped by modified Glasgow Prognostic Score (mGPS) category.
No. of patients (%) 237 (61.1) 151 (38.9) 263 (67.8) 125 (32.2) 357 (92.0) 31 (8.0) 327 (84.3) 38 (9.8) 23 (5.9) 322 (83.0) 66 (17.0) 269 32 83 4
(69.2) (8.3) (21.5) (1.0)
26 125 202 35
(6.7) (32.2) (52.1) (9.0)
364 (93.8) 24 (6.2) 24 (6.2) 364 (93.8)
mGPS: modified Glasgow Prognostic Score.
concentration of this protein is elevated, it means that acute inflammation within 8–12 h is present. The association between RCC and CRP elevation is mainly explained by
No. of patients (%) Variable Age (years) 60 460 Gender Male Female Thrombocytosis No Yes Tumor size (cm) 7 47 T stage Low (T1 + T2) High (T3 + T4) Grade Low (G1 + G2) High (G3 + G4) Lymphovascular invasion No Yes Nephrectomy type Partial Radical a
mGPS 0
mGPS 1
mGPS 2
205 (62.7) 122 (37.3)
23 (60.5) 15 (39.5)
9 (39.1) 14 (60.9)
224 (68.5) 103 (31.5)
26 (68.4) 12 (31.6)
13 (56.5) 10 (43.5)
309 (94.5) 18 (5.5)
30 (78.9) 8 (21.1)
18 (78.3) 5 (21.7)
284 (86.9) 43 (13.1)
27 (71.1) 11 (28.9)
11 (47.8) 12 (52.2)
273 (83.5) 54 (16.5)
20 (52.6) 18 (47.4)
8 (34.8) 15 (65.2)
140 (42.8) 187 (57.2)
9 (23.7) 29 (76.3)
2 (8.7) 21 (91.3)
315 (96.3) 12 (3.7)
32 (84.2) 6 (15.8)
17 (73.9) 6 (26.1)
21 (6.4) 306 (93.6)
1 (2.6) 37 (97.4)
2 (8.7) 21 (91.3)
pa 0.081 0.492 50.001 50.001 50.001 0.001 50.001 0.575
Analyzed by chi-squared test.
overproduction of IL-6 by tumor cells [25]. Experimental studies on RCC cell lines showed that IL-6 was produced at high levels by RCC cell lines and functioned as an autocrine growth factor of RCC [26]. These findings suggest that the systemic inflammatory response may be associated with progression and metastasis of RCC. Hypoalbuminemia has also been reported to have poor outcome in patients with
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Figure 2. Kaplan–Meier recurrence-free survival curves based on modified Glasgow Prognostic Score (mGPS) category.
Figure 3. Kaplan–Meier cancer-specific survival curves based on modified Glasgow Prognostic Score (mGPS) category.
cancer [15,27]. Lindenmann et al. [27] suggested that nutritional defects were directly related to systemic inflammation in cancer patients and albumin was reduced during chronic inflammation by activation of acute-phase response proteins such as CRP, enhancement of vascular permeability for albumin and decreased hepatic albumin synthesis [28]. As a result, nutritional defects caused by chronic inflammation could lead to poor prognosis in cancer patients.
The Glasgow Prognostic Score (GPS) originated from selective combination of CRP and albumin and was first described in patients with advanced non-small cell lung cancer, by Forrest et al. [29]. They categorized patients according to CRP and albumin level, as follows. Patients with both CRP elevation (410 mg/l) and hypoalbuminemia (535 g/l) were given a score of 2, patients with only one of CRP elevation or hypoalbuminemia were given a score of 1, and patients with
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Table 3. Univariate and multivariate analysis of recurrence-free survival in 388 patients with non-metastatic clear cell renal cell carcinoma. Univariatea p Age ( 60 vs 460 years) Gender (male vs female) C-reactive protein ( 2.6 mg/l vs 42.6 mg/l) mGPS (0 vs 1 vs 2) Thrombocytosis (no vs yes) T stage (T1 + T2 vs T3 + T4) Grade (G1 + G2 vs G3 + G4) Lymphovascular invasion (no vs yes) Nephrectomy type (partial vs radical)
Multivariateb HR (95% CI)
0.328 0.091 50.001
1.147 (0.551–2.386) 1.054 (0.481–2.310) 1.536 (0.494–4.774)
50.001 0.003 50.001 50.001 50.001 0.949
2.794 1.224 2.433 2.276 2.466 0.756
p 0.714 0.896 0.458
(1.696–4.603) 50.001 (0.466–3.220) 0.682 (1.125–5.262) 0.024 (0.866–5.982) 0.095 (1.016–5.985) 0.046 (0.167–3.434) 0.718
a
Analyzed by log-rank test. Analyzed by Cox proportional hazards regression model.
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b
Table 4. Univariate and multivariate analysis of cancer-specific survival in 388 patients with non-metastatic clear cell renal cell carcinoma. Univariatea p Age (60 vs 460 years) Gender (male vs female) C-reactive protein ( 26 mg/l vs 426 mg/l) mGPS (0 vs 1 vs 2) Thrombocytosis (no vs yes) T stage (T1 + T2 vs T3 + T4) Grade (G1 + G2 vs G3 + G4) Lymphovascular invasion (no vs yes) Nephrectomy type (partial vs radical)
Multivariateb HR (95% CI)
p
0.151 0.239 50.001
1.583 (0.521–4.809) 0.418 1.273 (0.377–4.295) 0.697 2.352 (0.228–24.212) 0.472
50.001 0.047 50.001 0.001 50.001 0.961
3.704 0.947 2.114 5.252 2.424 0.866
(1.672–8.203) (0.199–4.494) (0.642–6.963) (0.614–44.936) (0.752–7.819) (0.099–7.565)
0.001 0.945 0.218 0.130 0.138 0.896
a
Analyzed by log-rank test. Analyzed by Cox proportional hazards regression model.
b
normal CRP and albumin level were given a score of 0. However, they failed to show the relationship between hypoalbuminemia and poor survival, because only 10% of patients had hypoalbuminemia. McMillan [30] also showed that there was no difference in CSS between patients with hypoalbuminemia and normal albumin level. Proctor et al. [10] indicated that a low albumin level alone was associated with poor survival rate in some tumors such as breast, hematological and pulmonary tumors, but not in other tumors such as bladder, gynecological, prostate, gastroesophageal, renal, colorectal, head and neck and hepatopancreaticobiliary tumors, in their large cohort study. Therefore, GPS was modified as mGPS by giving a score of 1 only for an elevated CRP. mGPS is easy to measure preoperatively, and has been proven to have prognostic value in several types of cancers, including RCC [11–18]. In patients with metastatic RCC treated with immunotherapy, GPS was an independent prognostic factor for CSS [15]. For localized RCC, Tai et al. [16] reported that mGPS was significantly associated with RFS in 129 patients with clinically localized clear cell RCC. Intermediate-risk (mGPS ¼ 1) and highrisk (mGPS ¼ 2) patients experienced a four-fold and seven-fold risk of metastasis within 1 year of radical nephrectomy compared to low-risk (mGPS ¼ 0) patients, respectively. Qayyum et al. [17] demonstrated that mGPS was an independent predictor of CSS in 79 patients with surgically resected clear cell RCC. Lamb et al. [18] also showed that mGPS was an independent predictor of CSS in 169 patients with surgically
treated clear cell RCC. They suggested that mGPS was at least equivalent to and independent of other current validated prognostic scoring systems for patients undergoing curative nephrectomy for clear cell RCC. The results of the present study are in agreement with those of previous studies, showing that mGPS was an independent prognostic factor for RFS and CSS in patients with surgically treated non-metastatic clear cell RCC, and it was superior to CRP alone. Kaplan–Meier survival curves indicated the significant decline in RFS and CSS in patients with higher mGPS. Based on this study, it may be important to evaluate whether new prognostic scoring systems based on the mGPS could be useful for predicting the prognosis of nonmetastatic clear cell RCC. This study has several limitations. First, only patients with clear cell RCC were included in this study because of the small number of patients with other histology. Further study including RCC with other histology should be performed in the future. Secondly, the study did not consider patient characteristics such as obesity, smoking history or alcohol consumption that could affect systemic inflammation. Thirdly, data from only two hospitals were included in this study and the sample size was modest. Therefore, validation in a multicenter study with a larger sample size is mandatory. In conclusion, the mGPS is an independent prognostic factor for RFS and CSS in patients with non-metastatic clear cell RCC treated with radical or partial nephrectomy. These findings suggest that mGPS should be used for predicting recurrence or survival in patients undergoing nephrectomy for nonmetastatic clear cell RCC.
Disclosure statement No potential conflict of interest was reported by the authors.
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