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Prognostic significance of the controlling nutritional status (CONUT) score in advanced urothelial carcinoma patients
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Urologic Oncology: Seminars and Original Investigations 000 (2019) 1−7
Clinical-Bladder cancer
Prognostic significance of the controlling nutritional status (CONUT) score in advanced urothelial carcinoma patients Hiroaki Suzuki, M.D., Masaya Ito, M.D.*, Kosuke Takemura, M.D., Yasukazu Nakanishi, M.D., Madoka Kataoka, M.D., Kazumasa Sakamoto, M.D., Ken-ichi Tobisu, M.D., Fumitaka Koga, M.D.* Department of Urology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan Received 25 May 2019; accepted 29 October 2019
Abstract Introduction & Objectives: The controlling nutritional status (CONUT) score, consisting of serum albumin, total lymphocyte count, and total cholesterol, is a validated and objective tool for nutritional assessment. Cancer-bearing patients often suffer from malnutrition in association with cachexia. We explored the prognostic role of malnutrition evaluated by the CONUT score in advanced urothelial carcinoma (aUC) patients. Materials & Methods: Between 2003 and 2018, 201 aUC patients with cT4 and/or metastases to lymph nodes/distant organs were treated at a single cancer center. Of these, 185 were subjects of this retrospective study, with 16 excluded due to missing data. Clinical variables examined included age, sex, performance status (PS), body mass index (BMI), primary tumor site, lymph node/visceral metastasis, treatments before and after the diagnosis of aUC, hemoglobin, lactate dehydrogenase, alkaline phosphatase (ALP), C-reactive protein (CRP) and the CONUT score. Associations between clinical variables and overall survival (OS) were examined using the Cox proportional hazards model. Results: The median (range) CONUT score was 2 (0−8). A higher CONUT score was associated with poorer PS (P < 0.001), lower BMI (P = 0.007), lower hemoglobin (P < 0.001), higher ALP (P = 0.005), and higher CRP (P < 0.001). During follow-up (median 12.3 months), 133 (72%) patients died. The median OS periods for patients with CONUT scores of 0 to 1, 2 to 3 and ≥4 were 19.3, 13.3, and 7.7 months, respectively (P < 0.001). Multivariate analysis revealed a higher CONUT score to be an independent and significant adverse prognostic factor (2−3 vs. 0−1, hazard ratio [HR] 1.57, P = 0.024; ≥4 vs 0−1, HR 2.94, P < 0.001), along with greater age (P = 0.003), poorer PS (P = 0.006), lower BMI (P = 0.008), primary tumor site in the upper tract (P = 0.004), higher CRP (P < 0.001), no usage of pembrolizumab (P = 0.005), and no curative treatment after the diagnosis of aUC (P = 0.035). Conclusion: This study showed the prognostic significance of the CONUT score in aUC patients. The CONUT score indicates a patient’s general condition from the aspect of nutritional status, and appears to be independent of PS as a prognosticator. Ó 2019 Elsevier Inc. All rights reserved.
Keywords: Advanced urothelial carcinoma; Malnutrition; Prognostic factor; controlling nutritional status (CONUT) score
1. Introduction Urothelial carcinoma (UC), mostly comprising bladder cancer and upper tract urinary cancer (UTUC), was estimated to account for 85,000 new cases and 18,000 deaths in the United States in 2018 [1]. Although nonmetastatic and localized UC patients are subjects for curative treatment such as transurethral resection, radical cystectomy, and radical *Corresponding authors. Tel: +81-3-3823-2101; fax: +81-3-3823-5433. E-mail addresses: [email protected] (M. Ito), [email protected] (F. Koga). https://doi.org/10.1016/j.urolonc.2019.10.014 1078-1439/Ó 2019 Elsevier Inc. All rights reserved.
nephroureterectomy with or without perioperative chemotherapy, systemic chemotherapy has been the mainstay of treatment in advanced UC (aUC) patients. However, aUC patients have a poor prognosis, with a median overall survival (OS) of 13 to 16 months despite receiving systemic chemotherapy [2]. Recently, immune checkpoint inhibitors (ICI) have been introduced, and are reported to prolong the median OS by 3 months in aUC patients [3]. However, the long-term outcomes of ICI are unclear in the real-world practice. Assessment of the general conditions of cancer-bearing patients is crucial for therapeutic decision-making and
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prognosis. The most common parameter used to assess a patient’s general conditions is performance status (PS), which greatly impacts the prognosis of aUC patients [4−6]. Although PS is an established prognostic factor for aUC patients, assessment of PS is subjective and potentially carries poor interobserver agreement [7]. An objective assessment system for patients’ general condition is desirable. Nutritional status is an indicator of general condition and is often compromised by cancer cachexia in advanced cancer patients. Methods to evaluate nutritional status are classified into 2 major categories: subjective global assessment and objective data assessment [8, 9]. Subjective global assessment involves taking a medical history and physical examinations including loss of triceps subcutaneous fat and muscle wasting of the quadriceps, ankle and sacral edema, which are complicated and require expert knowledge for accurate measurement [8]. In contrast, the controlling nutritional status (CONUT) score is a simple and validated objective data assessment system consisting of serum albumin, total lymphocyte count, and total cholesterol concentration [10]. Previous studies have demonstrated the prognostic role of malnutrition evaluated by the CONUT score in patients with several cancer types, including esophageal carcinoma, colorectal carcinoma, gastric carcinoma, lung squamous cell carcinoma, hepatocellular carcinoma and renal cell carcinoma [11−16]. However, no study to date has investigated the prognostic impact of the CONUT score in aUC patients. We therefore retrospectively assessed the prognostic role of the CONUT score in aUC patients who were not subjects of upfront curative surgery due to cT4 or distant or nodal metastatic diseases. 2. Materials and methods 2.1. Patients Our Institutional Ethical Committee approved the present retrospective study protocol. A total of 201 consecutive aUC patients (inoperable cT4 and/or metastasis to lymph nodes/distant organs) treated at a single cancer center between 2003 and 2018 were enrolled in the study. Of the 201 patients, 16 patients were excluded due to missing data required for the CONUT score (12 patients without total cholesterol concentration and 4 patients without total lymphocyte count). Ultimately, data on 185 patients were subjected to analysis. The comprehensive clinical data collected were as follows: age, sex, Eastern Cooperative Oncology Group PS, body mass index (BMI), primary tumor site (bladder or upper urinary tract), clinical tumor stage, lymph node/visceral metastasis (lung, liver, or bone), presence of curative treatment before the diagnosis of aUC, treatments given after the diagnosis of aUC, hemoglobin, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), C-reactive protein (CRP), and the components of the
Table 1 Scoring and interpretation of controlling nutritional status (CONUT) scores Parameters Albumin (g/dl) Score Lymphocyte count (/ml) Score Total cholesterol (mg/dl) Score
Ranges of values and scores for each parameter ≥3.50 (0) ≥1,600
3.00−3.49 (2) 1,200−1,599
2.50−2.99 (4) 800−1,199
<2.50 (6) <800
(0) ≥180
(1) 140−179
(2) 100−139
(3) <100
(0)
(1)
(2)
(3)
Interpretation CONUT score (sum of the above scores)
0−1
2−4
5−8
9−12
Degree of malnutrition
None
Light
Moderate
Severe
CONUT score. CONUT scores were calculated from serum albumin, total lymphocyte count, and total cholesterol concentration (Table 1). 2.2. Statistical analyses The differences in variables between CONUT scores 0 to 1, 2 to 3 and ≥4 were evaluated using Fisher’s exact test or the chi-squared test for categorical variables, and the Wilcoxon rank-sum test for continuous variables. OS was defined as the time from diagnosis of aUC to either death or the last follow-up. The difference in the Kaplan Meier curves was evaluated by the log-rank test. Associations of variables with OS were assessed using the Cox proportional hazards model. Significant variables in the univariate analysis were included in the multivariate analysis. A reduced multivariate model was generated by backward elimination of the variable with the highest P value from each iteration of the multivariate analysis. Two-tailed P < 0.05 was regarded as significant. As a linear regression model, the martingale residuals were used to assess the fitting of optimal cutoffs for the following parameters: age, BMI, hemoglobin, LDH, ALP, CRP, albumin, total lymphocyte count, and total cholesterol concentration. The most appropriate cutoff value for each was determined as previously described [17]. All analyses were conducted using JMP 14.0.0 (SAS Institute Inc., Cary, NC) and R 3.5.3 (R Foundation for Statistical Computing, Vienna, Austria). 3. Results 3.1. Patient characteristics The demographics of the 185 patients are shown in Table 2. The median (range) age was 70 (38−92) years, and 125 (68%) patients were male. The primary sites of
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Table 2 Demographics of 185 patients with advanced urothelial carcinoma No. patients (%) Variables
Total (n = 185)
CONUT 0,1 (n = 91)
CONUT 2,3 (n = 72)
CONUT≥4 (n = 22)
Age (years), median (IQR) Sex Male Female PS 0 1 2 ≥3 BMI (kg/m2), median (IQR) Primary tumor site Bladder Upper urinary tract Clinical N stage 0 ≥1 Visceral metastasis (lung, liver, or bone) No Yes Curative treatment before the diagnosis of aUC None Surgery or Radiation Surgery Chemoradiation Pretreatment laboratory parameters, median (IQR) Hemoglobin (g/dl) LDH (U/L) ALP (U/L) CRP (mg/l) Albumin (g/dl) Lymphocyte count (/ml) Total cholesterol (mg/dl) Systemic chemotherapy after the diagnosis of aUC No Yes Pembrolizumab after chemotherapy failure Yes No Curative treatment after the diagnosis of aUC None Surgery or Radiation Surgery Radiation
70 (64−76)
69 (63−76)
72 (66−77)
73 (63−80)
125 (68) 60 (32)
59 (65) 32 (35)
52 (72) 20 (28)
14 (64) 8 (36)
122 (66) 45 (24) 13 (7) 5 (3) 22.2 (20.2−24.5)
63 (69) 24 (26) 4 (5) 0 23.0 (21.1−25.3)
52 (72) 15 (21) 3 (4) 2 (3) 22.0 (18.7−24.5)
7 (32) 6 (27) 6 (27) 3 (14) 21.0 (18.2−23.2)
104 (56) 81 (44)
52 (57) 39 (43)
38 (53) 34 (47)
14 (64) 8 (36)
46 (25) 139 (75)
20 (22) 71 (78)
18 (25) 54 (75)
8 (36) 14 (64)
118 (64) 67 (36)
60 (66) 31 (34)
47 (65) 25 (35)
11 (50) 11 (50)
122 (66) 63 (34) 56 (30) 7 (4)
64 (70) 27 (30) 23 (25) 4 (5)
42 (58) 30 (42) 27 (38) 3 (4)
16 (73) 6 (27) 6 (27) 0 (0)
12.4 (11.3−13.5) 191 (165−227) 263 (220−318) 6.2 (2.0−24.2) 4.0 (3.8−4.3) 1460 (1100−1965) 189 (165−213)
12.8 (12.1−13.9) 191 (164−220) 253 (206−301) 3.9 (1.7−16) 4.1 (3.9−4.4) 1850 (1510−2240) 196 (176−217)
12.1 (11.3−13.4) 192 (162−230) 259 (222−307) 6.0 (2.0−19.9) 4.0 (3.8−4.2) 1140 (940−1408) 180 (151−210)
10.7 (9.7−11.6) 198 (165−278) 318 (262−396) 32.4 (15.6−59.6) 3.2 (3.0−3.6) 1020 (612−1325) 170 (130−179)
47 (25) 138 (75)
19 (21) 72 (79)
19 (26) 53 (74)
9 (41) 13 (59)
12 (6) 173 (94)
6 (7) 85 (93)
5 (7) 67 (93)
1 (5) 21 (95)
138 (75) 47 (25) 29 (15) 18 (10)
64 (70) 27 (30) 20 (22) 7 (8)
57 (79) 15 (21) 8 (11) 7 (10)
17 (77) 5 (23) 1 (5) 4 (18)
P value 0.137 0.541
<0.001
0.007 0.663
0.383
0.368
0.222
<0.001 0.707 0.005 <0.001 <0.001 <0.001 <0.001 0.152
1.000
0.464
ALP = alkaline phosphatase; aUC = advanced urothelial carcinoma; BMI = body mass index; CONUT = controlling nutritional status score; CRP = Creactive protein; IQR = interquartile range; LDH = lactate dehydrogenase; PS = performance status.
aUC were the bladder in 104 (56%) patients and the upper urinary tract in 81 (44%) patients. Of the 185 patients, 63 (34%) patients developed aUC after curative treatment for their primary diseases; 56 (30%) patients had undergone curative surgery and the other 7 (4%) patients had received definitive chemoradiotherapy. At the time of diagnosis of aUC, lymph node and visceral metastases were observed in 139 (75%) and 67 (36%) patients, respectively. A total of 138 (75%) patients received first-line platinum-based systemic chemotherapy and the remaining 47 (25%) patients received curative treatment after the diagnosis of aUC; 29
(15%) patients underwent curative surgery and 18 (10%) patients received definitive chemoradiation therapy. Six patients selected best supportive care. Pembrolizumab was given to 12 patients with chemotherapy-refractory disease from December 2017 onward. 3.2. Associations of CONUT score with clinical parameters The CONUT score was 0, 1, 2, 3, and ≥4 in 39 (21%), 52 (28%), 46 (25%), 26 (14%), and 22 (12%) patients,
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respectively. The median (range) CONUT score was 2 (0 −8). A higher CONUT score was associated with poorer PS (P < 0.001), lower BMI (P = 0.007), lower hemoglobin (P < 0.001), higher ALP (P = 0.005), and higher CRP (P < 0.001, Table 2). 3.3. Associations of CONUT score with OS During the follow-up period (median 12.3 months), 133 patients died (131 cancer deaths and 2 deaths of other causes). The median OS was 14.9 months for the overall cohort. By univariate analysis, the HRs of CONUT scores 1, 2, 3, and ≥4 (reference, CONUT score 0) were 1.07 (95%CI: 0.64−1.79), 1.60 (0.95−2.71), 1.88 (1.04−3.41), and 5.14 (2.72−9.69), respectively. Accordingly, CONUT scores were regrouped into 3 categories: CONUT score 0 to1, 2 to 3, and ≥4. The median OS periods for patients with CONUT scores 0 to 1, 2 to 3 and ≥4 were 19.3, 13.3, and 7.7 months, respectively (P < 0.001, Fig. 1). Table 3 shows the associations of variables with OS. On univariate analysis, a higher CONUT score was significantly associated with shorter OS (2−3 vs. 0−1, HR 1.63, P = 0.011; ≥4 vs. 0−1, HR 4.96, P < 0.001), along with higher age (HR 1.85, P < 0.001), poorer PS (HR 4.61, P < 0.001), lower BMI (HR 1.84, P < 0.001), primary tumor site in the upper urinary tract (HR 1.54, P = 0.014), presence of visceral metastasis (HR 2.08, P < 0.001), lower hemoglobin (HR 2.01, P < 0.001), higher LDH (HR 4.11, P < 0.001), higher ALP (HR 3.59, P < 0.001), higher CRP (HR 2.44, P < 0.001), lower albumin (HR 3.48, P = 0.022), lower lymphocyte count (HR 1.84, P < 0.001), no usage of pembrolizumab (HR 4.23, P = 0.009), and no curative treatment after the diagnosis of aUC (HR 1.65, P = 0.012). On multivariate analysis, a higher CONUT score was
significantly and independently associated with shorter OS (2−3 vs. 0−1, HR 1.57, P = 0.024; ≥4 vs. 0−1, HR 2.94, P < 0.001), along with higher age (HR 1.80, P = 0.003), poorer PS (HR 2.34, P = 0.006), lower BMI (HR 1.64, P = 0.008), primary tumor site of the upper urinary tract (HR 1.69, P = 0.004), higher CRP (HR 2.57, P < 0.001), no usage of pembrolizumab (HR 4.73, P = 0.005), and no curative treatment after the diagnosis of aUC (HR 1.53, P = 0.035; multivariate model 1). To assess the prognostic significance of each component of CONUT, multivariate analysis was conducted using albumin, lymphocyte count, and total cholesterol instead of the CONUT score. Lower albumin (HR 4.78, P = 0.018) and lower total lymphocyte count (HR 1.68, P = 0.006) were identified as independent adverse prognostic factors, along with higher age (HR 1.65, P = 0.013), poorer PS (HR 2.43, P = 0.005), lower BMI (HR 1.69, P = 0.007), primary tumor site in the upper urinary tract (HR 1.75, P = 0.004), higher LDH (HR 3.58, P = 0.014), higher ALP (HR 2.70, P = 0.010), higher CRP (HR 2.74, P < 0.001), and no usage of pembrolizumab (HR 5.03, P = 0.004; multivariate model 2). 4. Discussion The present study demonstrated the prognostic significance of the CONUT score in aUC patients for the first time. A higher CONUT score was significantly and independently associated with shorter OS along with established prognostic factors including advanced age, poorer PS, lower BMI, and higher CRP. These results suggest the clinical relevance of malnutrition evaluated by CONUT as a prognostic factor in aUC patients. Considering its simplicity, objectivity, global availability and validity in evaluating nutrition status, the CONUT score may be a practical prog-
Fig. 1. Kaplan-Meier curves of overall survival for 185 patients with advanced urothelial carcinoma according to their controlling nutritional status (CONUT) scores.
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Table 3 Univariable and multivariable analyses for variables associated with overall survival in 185 patients Univariable analysis Variables
HR
95%CI
Age ≥67 (vs. <67 [years]) 1.85 1.27−2.72 Sex Male (vs. female) 1.10 0.77−1.61 PS ≥2 (vs. 0.1) 4.61 2.65−7.52 BMI <23 (vs. ≥23 [kg/m2]) 1.84 1.30−2.63 Primary tumor site Upper urinary tract (vs. bladder) 1.54 1.09−2.17 Clinical T stage 3, 4 (vs. ≤2) 1.01 0.70−1.46 Clinical N stage ≥1 (vs. 0) 1.17 0.79−1.78 Visceral metastasis (lung, liver, or bone) Yes (vs. No) 2.08 1.45−2.95 Curative treatment before the diagnosis of aUC No (vs. Yes) 1.26 0.88−1.83 Hemoglobin* <12/11.5 (vs. ≥12/11.5 [g/dl]) 2.01 1.40−2.86 LDH >360 (vs. ≤360 [U/L]) 4.11 2.00−7.53 ALP >450 (vs. ≤450 [U/L]) 3.59 2.00−6.00 CRP >32 (vs. ≤32 [mg/l]) 2.44 1.61−3.59 CONUT score 0, 1 ref 2, 3 1.63 1.12−2.38 ≥4 4.96 2.77−8.50 Albumin <3.0 (vs. ≥3.0 [g/dl]) 3.48 1.23−7.70 Lymphocyte count <1600 (vs. ≥1600 [ml]) 1.84 1.29−2.67 Total cholesterol <140 (vs. ≥140 [mg/dl]) 1.64 0.95−2.66 Systemic chemotherapy used after the diagnosis of aUC No (vs. Yes) 1.40 0.95−2.03 Pembrolizumab after chemotherapy failure No (vs. Yes) 4.23 1.34−25.6 Curative treatment after the diagnosis of aUC No (vs. Yes) 1.65 1.12−2.51
Multivariable model 1
Multivariable model 2
P value
HR
95%CI
P value
HR
95%CI
P value
<0.001
1.80
1.23−2.70
0.003
1.65
1.11−2.49
0.013
<0.001
2.34
1.29−4.04
0.006
2.43
1.32−4.23
0.005
<0.001
1.64
1.14−2.39
0.008
1.69
1.16−2.49
0.007
0.014
1.69
1.18−2.42
0.004
1.75
1.20−2.55
0.004
<0.001
3.58
1.34−8.10
0.014
<0.001
2.70
1.28−5.27
0.010
2.74
1.75−4.18
<0.001
0.610
0.937 0.432 <0.001 0.211 <0.001
<0.001
2.57
1.65−3.93
<0.001
0.011 <0.001
ref 1.57 2.94
1.06−2.31 1.62−5.14
0.024 <0.001
− − −
0.022
−
4.78
1.30−20.28
0.018
<0.001
−
1.68
1.16−2.47
0.006
0.076
−
5.03
1.56−30.79
0.004
0.091 0.009
4.73
1.48−28.8
0.005
0.012
1.53
1.03−2.35
0.035
ALP = alkaline phosphatase; aUC = advanced urothelial carcinoma; BMI = body mass index; CONUT = controlling nutritional status score; CRP = C-reactive protein; IQR = interquartile range; LDH = lactate dehydrogenase; PS = performance status. * Cutoff values are 12 g/dl and 11.5 g/dl for males and females, respectively.
nosticator for aUC patients, as well as an indicator of their general condition from the aspect of nutritional status. PS is an established prognostic factor in aUC patients [4−6] while its assessment includes potential problems in objectivity, accuracy and interobserver agreement [7]. We hypothesized that CONUT might be an objective and accurate alternative to PS as a prognostic factor representing the general condition of aUC patients. However, the present study demonstrated that, despite a significant association between CONUT and PS, the prognostic significance of the CONUT score was independent of that of PS.
Interestingly, this was not the case of sarcopenia, a degenerative loss of skeletal muscle mass, which canceled out the prognostic significance of PS in multivariate analysis in patient cohorts of aUC [18] and metastatic renal cell carcinoma [19]. Given that PS represents patients’ general condition from the aspect of activity of daily life, sarcopenia may be an objective alternative to PS as a prognosticator for aUC patients. The CONUT score appears to represent the general condition of aUC patients from the aspect of nutritional status as a prognostic factor, independently of PS.
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The established prognostic factors of aUC patients can be classified into 2 major categories: tumor factors and patient responses. The former include the primary tumor site and the presence of visceral metastasis, while the latter include PS, white blood cell count, hemoglobin, albumin, neutrophil-lymphocyte ratio (NLR) and CRP [4−6, 20, 21]. The latter reflect the development process of cancer cachexia, which involves proinflammatory cytokines including tumor necrosis factora, interleukin (IL)-6, IL-1, and IL-10 [22, 23]. Of note, among the 3 components of CONUT, both lymphocytopenia and hypoalbuminemia were significant and independent adverse prognostic factors in this study. Lymphocytopenia often develops in advanced cancer patients through several mechanisms of tumor immune evasion, including destruction of lymphocytes by tumor cells expressing proapoptotic ligands [24]. Programmed death ligand-1 expressed by tumor cells and macrophages can diminish the proliferation and survival of tumor-infiltrating lymphocytes in the tumor microenvironment, which may have a systemic impact [25]. Previous cytotoxic treatments also contribute to lymphocytopenia. Taken together with the fact that IL-6 reduces total cholesterol levels [26], the CONUT score in cancer-bearing patients reflects not simply nutritional status but more importantly the degree of immunosuppression and influences of proinflammatory cytokines that further deteriorate lymphocytopenia via the catabolic protein metabolism during the development of cachexia [27]. This pathophysiology may account for the prognostic role of the CONUT score in aUC patients. Once the prognostic significance of malnutrition has been identified in aUC patients, the next issue would be whether nutritional support can improve their prognosis. A randomized trial showed that an oral nutritional supplement containing eicosapentanoic acid, which can reduce proinflammatory cytokines and CRP, improved progression-free survival in patients with advanced nonsmall cell lung cancer [28], suggesting a role of nutritional support in improving the prognosis of advanced cancer patients. Considering the multifactorial mechanism of cancer cachexia, an energy-wasting and hyper-catabolic syndrome, a multimodal approach may more effectively improve the prognosis and quality of life of advanced cancer patients than nutritional support alone; such supportive treatments include the molecular targeting of proinflammatory cytokines [29, 30], metabolic intervention to block catabolic drive and to enhance anabolic pathways [31], and immunomodulation to prevent immunosuppression as well as sufficient nutrient intake and exercise to prevent sarcopenia [32, 33]. CONUT may serve as one assessment tool to evaluate the effects of multimodal approaches to prevent cachexia in advanced cancer patients. The present study had several limitations. First was possible bias by the retrospective nature. External validations with large patient multi-institutional cohorts are needed to confirm the generality of our findings, according to the
REMARK guidelines [17]. Second, only 12 patients received ICI, the current standard of care as second-line treatment in aUC patients. Pembrolizumab for aUC patients was approved by the Japanese national health insurance system in December 2017. Since our cohort consisted of patients treated between 2004 and 2018, most patients did not receive pembrolizumab. Contemporary cohorts of patients receiving ICI may yield different results. Third, we did not completely record statin use and thus it was not included as a variable in the present cohort. Adjustment for statin use may have provided more accurate prognostic information on the total cholesterol value, a component of CONUT. 5. Conclusion The present study demonstrated the prognostic significance of the CONUT score in aUC patients. Validation of multicentric larger patient cohorts is needed to confirm this finding. Since the CONUT score reflects malnutrition in the process of developing cachexia, a multimodal approach to improve cancer-induced malnutrition may improve the prognosis of aUC patients. Conflict of interest None References [1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68:7–30. [2] Bellmunt J, Hvd Maase, Mead GM, Skoneczna I, Santis MD, Daugaard G, et al. Randomized phase III study comparing Paclitaxel/Cisplatin/ Gemcitabine and Gemcitabine/Cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study 30987. J Clin Oncol 2012;30:1107–13. [3] Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee J-L, Fong L, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017;376:1015–26. [4] Bajorin DF, Dodd PM, Mazumdar M, Fazzari M, McCaffrey JA, Scher HI, et al. Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol 1999;17:3173–81. [5] Galsky MD, Moshier E, Krege S, Lin C-C, Hahn N, Ecke T, et al. Nomogram for predicting survival in patients with unresectable and/ or metastatic urothelial cancer who are treated with cisplatin-based chemotherapy. Cancer 2013;119:3012–9. [6] Iasonos A, Apolo AB, Bajorin DF, Small EJ, Philips GK, Ostrovnaya I, et al. Prognostic model for predicting survival of patients with metastatic urothelial cancer treated with cisplatin-based chemotherapy. J Natl Cancer Inst 2013;105:499–503. [7] Chow R, Chiu N, Bruera E, Krishnan M, Chiu L, Lam H, et al. Interrater reliability in performance status assessment among health care professionals: a systematic review. Ann Palliat Med 2016;5:83–92. [8] Detsky AS, McLaughlin JR, Baker JP, Johnston N, Whittaker S, Mendelson RA, et al. What is subjective global assessment of nutritional status? 1987. Classical article. Nutr Hosp 2008;23:400–7. [9] Hamada Y. Objective Data Assessment (ODA) methods as nutritional assessment tools. J Med Invest 2015;62:119–22.
ARTICLE IN PRESS H. Suzuki et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−7 [10] Ignacio de Ulibarri J, Gonzalez-Madrono A, de Villar NG, Gonzalez P, Gonzalez B, Mancha A, et al. CONUT: a tool for controlling nutritional status. First validation in a hospital population. Nutr Hosp 2005;20:38–45. [11] Toyokawa T, Kubo N, Tamura T, Sakurai K, Amano R, Tanaka H, et al. The pretreatment Controlling Nutritional Status (CONUT) score is an independent prognostic factor in patients with resectable thoracic esophageal squamous cell carcinoma: results from a retrospective study. BMC Cancer 2016;16:722-. [12] Iseki Y, Shibutani M, Maeda K, Nagahara H, Ohtani H, Sugano K, et al. Impact of the preoperative controlling nutritional status (CONUT) score on the survival after curative surgery for colorectal cancer. PLoS One 2015;10:e0132488-e. [13] Liu X, Zhang D, Lin E, Chen Y, Li W, Chen Y, et al. Preoperative controlling nutritional status (CONUT) score as a predictor of longterm outcome after curative resection followed by adjuvant chemotherapy in stage II-III gastric Cancer. BMC Cancer 2018;18:699. [14] Toyokawa G, Kozuma Y, Matsubara T, Haratake N, Takamori S, Akamine T, et al. Prognostic impact of controlling nutritional status score in resected lung squamous cell carcinoma. J Thorac Dis 2017;9:2942–51. [15] Harimoto N, Yoshizumi T, Inokuchi S, Itoh S, Adachi E, Ikeda Y, et al. Prognostic significance of preoperative controlling nutritional status (CONUT) score in patients undergoing hepatic resection for hepatocellular carcinoma: a multi-institutional study. Ann Surg Oncol 2018;25:3316–23. [16] Zheng Y, Bao L, Wang W, Wang Q, Pan Y, Gao X. Prognostic impact of the controlling nutritional status score following curative nephrectomy for patients with renal cell carcinoma. Medicine 2018; 97:e13409-e. [17] Altman DG, McShane LM, Sauerbrei W, Taube SE. Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): Explanation and Elaboration. PLoS Med 2012;9:e1001216. [18] Fukushima H, Yokoyama M, Nakanishi Y, K-i Tobisu, Koga F. Sarcopenia as a prognostic biomarker of advanced urothelial carcinoma. PLoS One 2015;10:e0115895-e. [19] Fukushima H, Nakanishi Y, Kataoka M, Tobisu K, Koga F. Prognostic significance of sarcopenia in patients with metastatic renal cell carcinoma. J Urol 2016;195:26–32. [20] Saito K, Urakami S, Komai Y, Yasuda Y, Kubo Y, Kitsukawa S, et al. Impact of C-reactive protein kinetics on survival of patients with advanced urothelial carcinoma treated by second-line chemotherapy with gemcitabine, etoposide and cisplatin. BJU Int 2012;110:1478–84. [21] Yip SM, Kaiser J, Li H, North S, Heng DYC, Alimohamed NS. Realworld outcomes in advanced urothelial cancer and the role of neutrophil to lymphocyte ratio. Clin Genitourin Cancer 2018;16:e637–e44.
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[22] Patel HJ, Patel BM. TNF-alpha and cancer cachexia: Molecular insights and clinical implications. Life Sci 2017;170:56–63. [23] Sun FB, Zhang DL, Zheng HM, Song B. [Association of interleukin10 gene polymorphism with cachexia in patients with gastric cancer]. Zhonghua Zhong Liu Za Zhi 2010;32:845–9. [24] Zhang B, Sun T, Xue L, Han X, Zhang B, Lu N, et al. Functional polymorphisms in FAS and FASL contribute to increased apoptosis of tumor infiltration lymphocytes and risk of breast cancer. Carcinogenesis 2007;28:1067–73. [25] Menetrier-Caux C, Ray-Coquard I, Blay JY, Caux C. Lymphopenia in cancer patients and its effects on response to immunotherapy: an opportunity for combination with Cytokines? J Immunother Cancer 2019;7:85. [26] Hashizume M, Yoshida H, Koike N, Suzuki M, Mihara M. Overproduced interleukin 6 decreases blood lipid levels via upregulation of very-low-density lipoprotein receptor. Ann Rheum Dis 2010;69: 741–6. [27] Contreras NA, Fontana L, Tosti V, Nikolich-Zugich J. Calorie restriction induces reversible lymphopenia and lymphoid organ atrophy due to cell redistribution. Geroscience 2018;40:279–91. [28] Sanchez-Lara K, Turcott JG, Juarez-Hernandez E, Nunez-Valencia C, Villanueva G, Guevara P, et al. Effects of an oral nutritional supplement containing eicosapentaenoic acid on nutritional and clinical outcomes in patients with advanced non-small cell lung cancer: randomised trial. Clin Nutr 2014;33:1017–23. [29] Hong DS, Hui D, Bruera E, Janku F, Naing A, Falchook GS, et al. MABp1, a first-in-class true human antibody targeting interleukin1alpha in refractory cancers: an open-label, phase 1 dose-escalation and expansion study. Lancet Oncol 2014;15:656–66. [30] Schuster M, Rigas JR, Orlov SV, Milovanovic B, Prabhash K, Smith JT, et al. ALD518, a humanized anti-IL-6 antibody, treats anemia in patients with advanced non-small cell lung cancer (NSCLC): Results of a phase II, randomized, double-blind, placebo-controlled trial. J Clin Oncol 2010;28:7631. [31] Crawford J, Prado CM, Johnston MA, Gralla RJ, Taylor RP, Hancock ML, et al. Study design and rationale for the phase 3 clinical development program of enobosarm, a selective androgen receptor modulator, for the prevention and treatment of muscle wasting in cancer patients (POWER Trials). Curr Oncol Rep 2016;18:37. [32] Currow DC, Abernethy AP. Anamorelin hydrochloride in the treatment of cancer anorexia-cachexia syndrome. Future Oncol 2014; 10:789–802. [33] Isenring EA, Teleni L. Nutritional counseling and nutritional supplements: a cornerstone of multidisciplinary cancer care for cachectic patients. Curr Opin Support Palliat Care 2013;7:390–5.
Urologic Oncology: Seminars and Original Investigations 000 (2019) 1−7
Clinical-Bladder cancer
Prognostic significance of the controlling nutritional status (CONUT) score in advanced urothelial carcinoma patients Hiroaki Suzuki, M.D., Masaya Ito, M.D.*, Kosuke Takemura, M.D., Yasukazu Nakanishi, M.D., Madoka Kataoka, M.D., Kazumasa Sakamoto, M.D., Ken-ichi Tobisu, M.D., Fumitaka Koga, M.D.* Department of Urology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan Received 25 May 2019; accepted 29 October 2019
Abstract Introduction & Objectives: The controlling nutritional status (CONUT) score, consisting of serum albumin, total lymphocyte count, and total cholesterol, is a validated and objective tool for nutritional assessment. Cancer-bearing patients often suffer from malnutrition in association with cachexia. We explored the prognostic role of malnutrition evaluated by the CONUT score in advanced urothelial carcinoma (aUC) patients. Materials & Methods: Between 2003 and 2018, 201 aUC patients with cT4 and/or metastases to lymph nodes/distant organs were treated at a single cancer center. Of these, 185 were subjects of this retrospective study, with 16 excluded due to missing data. Clinical variables examined included age, sex, performance status (PS), body mass index (BMI), primary tumor site, lymph node/visceral metastasis, treatments before and after the diagnosis of aUC, hemoglobin, lactate dehydrogenase, alkaline phosphatase (ALP), C-reactive protein (CRP) and the CONUT score. Associations between clinical variables and overall survival (OS) were examined using the Cox proportional hazards model. Results: The median (range) CONUT score was 2 (0−8). A higher CONUT score was associated with poorer PS (P < 0.001), lower BMI (P = 0.007), lower hemoglobin (P < 0.001), higher ALP (P = 0.005), and higher CRP (P < 0.001). During follow-up (median 12.3 months), 133 (72%) patients died. The median OS periods for patients with CONUT scores of 0 to 1, 2 to 3 and ≥4 were 19.3, 13.3, and 7.7 months, respectively (P < 0.001). Multivariate analysis revealed a higher CONUT score to be an independent and significant adverse prognostic factor (2−3 vs. 0−1, hazard ratio [HR] 1.57, P = 0.024; ≥4 vs 0−1, HR 2.94, P < 0.001), along with greater age (P = 0.003), poorer PS (P = 0.006), lower BMI (P = 0.008), primary tumor site in the upper tract (P = 0.004), higher CRP (P < 0.001), no usage of pembrolizumab (P = 0.005), and no curative treatment after the diagnosis of aUC (P = 0.035). Conclusion: This study showed the prognostic significance of the CONUT score in aUC patients. The CONUT score indicates a patient’s general condition from the aspect of nutritional status, and appears to be independent of PS as a prognosticator. Ó 2019 Elsevier Inc. All rights reserved.
Keywords: Advanced urothelial carcinoma; Malnutrition; Prognostic factor; controlling nutritional status (CONUT) score
1. Introduction Urothelial carcinoma (UC), mostly comprising bladder cancer and upper tract urinary cancer (UTUC), was estimated to account for 85,000 new cases and 18,000 deaths in the United States in 2018 [1]. Although nonmetastatic and localized UC patients are subjects for curative treatment such as transurethral resection, radical cystectomy, and radical *Corresponding authors. Tel: +81-3-3823-2101; fax: +81-3-3823-5433. E-mail addresses: [email protected] (M. Ito), [email protected] (F. Koga). https://doi.org/10.1016/j.urolonc.2019.10.014 1078-1439/Ó 2019 Elsevier Inc. All rights reserved.
nephroureterectomy with or without perioperative chemotherapy, systemic chemotherapy has been the mainstay of treatment in advanced UC (aUC) patients. However, aUC patients have a poor prognosis, with a median overall survival (OS) of 13 to 16 months despite receiving systemic chemotherapy [2]. Recently, immune checkpoint inhibitors (ICI) have been introduced, and are reported to prolong the median OS by 3 months in aUC patients [3]. However, the long-term outcomes of ICI are unclear in the real-world practice. Assessment of the general conditions of cancer-bearing patients is crucial for therapeutic decision-making and
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prognosis. The most common parameter used to assess a patient’s general conditions is performance status (PS), which greatly impacts the prognosis of aUC patients [4−6]. Although PS is an established prognostic factor for aUC patients, assessment of PS is subjective and potentially carries poor interobserver agreement [7]. An objective assessment system for patients’ general condition is desirable. Nutritional status is an indicator of general condition and is often compromised by cancer cachexia in advanced cancer patients. Methods to evaluate nutritional status are classified into 2 major categories: subjective global assessment and objective data assessment [8, 9]. Subjective global assessment involves taking a medical history and physical examinations including loss of triceps subcutaneous fat and muscle wasting of the quadriceps, ankle and sacral edema, which are complicated and require expert knowledge for accurate measurement [8]. In contrast, the controlling nutritional status (CONUT) score is a simple and validated objective data assessment system consisting of serum albumin, total lymphocyte count, and total cholesterol concentration [10]. Previous studies have demonstrated the prognostic role of malnutrition evaluated by the CONUT score in patients with several cancer types, including esophageal carcinoma, colorectal carcinoma, gastric carcinoma, lung squamous cell carcinoma, hepatocellular carcinoma and renal cell carcinoma [11−16]. However, no study to date has investigated the prognostic impact of the CONUT score in aUC patients. We therefore retrospectively assessed the prognostic role of the CONUT score in aUC patients who were not subjects of upfront curative surgery due to cT4 or distant or nodal metastatic diseases. 2. Materials and methods 2.1. Patients Our Institutional Ethical Committee approved the present retrospective study protocol. A total of 201 consecutive aUC patients (inoperable cT4 and/or metastasis to lymph nodes/distant organs) treated at a single cancer center between 2003 and 2018 were enrolled in the study. Of the 201 patients, 16 patients were excluded due to missing data required for the CONUT score (12 patients without total cholesterol concentration and 4 patients without total lymphocyte count). Ultimately, data on 185 patients were subjected to analysis. The comprehensive clinical data collected were as follows: age, sex, Eastern Cooperative Oncology Group PS, body mass index (BMI), primary tumor site (bladder or upper urinary tract), clinical tumor stage, lymph node/visceral metastasis (lung, liver, or bone), presence of curative treatment before the diagnosis of aUC, treatments given after the diagnosis of aUC, hemoglobin, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), C-reactive protein (CRP), and the components of the
Table 1 Scoring and interpretation of controlling nutritional status (CONUT) scores Parameters Albumin (g/dl) Score Lymphocyte count (/ml) Score Total cholesterol (mg/dl) Score
Ranges of values and scores for each parameter ≥3.50 (0) ≥1,600
3.00−3.49 (2) 1,200−1,599
2.50−2.99 (4) 800−1,199
<2.50 (6) <800
(0) ≥180
(1) 140−179
(2) 100−139
(3) <100
(0)
(1)
(2)
(3)
Interpretation CONUT score (sum of the above scores)
0−1
2−4
5−8
9−12
Degree of malnutrition
None
Light
Moderate
Severe
CONUT score. CONUT scores were calculated from serum albumin, total lymphocyte count, and total cholesterol concentration (Table 1). 2.2. Statistical analyses The differences in variables between CONUT scores 0 to 1, 2 to 3 and ≥4 were evaluated using Fisher’s exact test or the chi-squared test for categorical variables, and the Wilcoxon rank-sum test for continuous variables. OS was defined as the time from diagnosis of aUC to either death or the last follow-up. The difference in the Kaplan Meier curves was evaluated by the log-rank test. Associations of variables with OS were assessed using the Cox proportional hazards model. Significant variables in the univariate analysis were included in the multivariate analysis. A reduced multivariate model was generated by backward elimination of the variable with the highest P value from each iteration of the multivariate analysis. Two-tailed P < 0.05 was regarded as significant. As a linear regression model, the martingale residuals were used to assess the fitting of optimal cutoffs for the following parameters: age, BMI, hemoglobin, LDH, ALP, CRP, albumin, total lymphocyte count, and total cholesterol concentration. The most appropriate cutoff value for each was determined as previously described [17]. All analyses were conducted using JMP 14.0.0 (SAS Institute Inc., Cary, NC) and R 3.5.3 (R Foundation for Statistical Computing, Vienna, Austria). 3. Results 3.1. Patient characteristics The demographics of the 185 patients are shown in Table 2. The median (range) age was 70 (38−92) years, and 125 (68%) patients were male. The primary sites of
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Table 2 Demographics of 185 patients with advanced urothelial carcinoma No. patients (%) Variables
Total (n = 185)
CONUT 0,1 (n = 91)
CONUT 2,3 (n = 72)
CONUT≥4 (n = 22)
Age (years), median (IQR) Sex Male Female PS 0 1 2 ≥3 BMI (kg/m2), median (IQR) Primary tumor site Bladder Upper urinary tract Clinical N stage 0 ≥1 Visceral metastasis (lung, liver, or bone) No Yes Curative treatment before the diagnosis of aUC None Surgery or Radiation Surgery Chemoradiation Pretreatment laboratory parameters, median (IQR) Hemoglobin (g/dl) LDH (U/L) ALP (U/L) CRP (mg/l) Albumin (g/dl) Lymphocyte count (/ml) Total cholesterol (mg/dl) Systemic chemotherapy after the diagnosis of aUC No Yes Pembrolizumab after chemotherapy failure Yes No Curative treatment after the diagnosis of aUC None Surgery or Radiation Surgery Radiation
70 (64−76)
69 (63−76)
72 (66−77)
73 (63−80)
125 (68) 60 (32)
59 (65) 32 (35)
52 (72) 20 (28)
14 (64) 8 (36)
122 (66) 45 (24) 13 (7) 5 (3) 22.2 (20.2−24.5)
63 (69) 24 (26) 4 (5) 0 23.0 (21.1−25.3)
52 (72) 15 (21) 3 (4) 2 (3) 22.0 (18.7−24.5)
7 (32) 6 (27) 6 (27) 3 (14) 21.0 (18.2−23.2)
104 (56) 81 (44)
52 (57) 39 (43)
38 (53) 34 (47)
14 (64) 8 (36)
46 (25) 139 (75)
20 (22) 71 (78)
18 (25) 54 (75)
8 (36) 14 (64)
118 (64) 67 (36)
60 (66) 31 (34)
47 (65) 25 (35)
11 (50) 11 (50)
122 (66) 63 (34) 56 (30) 7 (4)
64 (70) 27 (30) 23 (25) 4 (5)
42 (58) 30 (42) 27 (38) 3 (4)
16 (73) 6 (27) 6 (27) 0 (0)
12.4 (11.3−13.5) 191 (165−227) 263 (220−318) 6.2 (2.0−24.2) 4.0 (3.8−4.3) 1460 (1100−1965) 189 (165−213)
12.8 (12.1−13.9) 191 (164−220) 253 (206−301) 3.9 (1.7−16) 4.1 (3.9−4.4) 1850 (1510−2240) 196 (176−217)
12.1 (11.3−13.4) 192 (162−230) 259 (222−307) 6.0 (2.0−19.9) 4.0 (3.8−4.2) 1140 (940−1408) 180 (151−210)
10.7 (9.7−11.6) 198 (165−278) 318 (262−396) 32.4 (15.6−59.6) 3.2 (3.0−3.6) 1020 (612−1325) 170 (130−179)
47 (25) 138 (75)
19 (21) 72 (79)
19 (26) 53 (74)
9 (41) 13 (59)
12 (6) 173 (94)
6 (7) 85 (93)
5 (7) 67 (93)
1 (5) 21 (95)
138 (75) 47 (25) 29 (15) 18 (10)
64 (70) 27 (30) 20 (22) 7 (8)
57 (79) 15 (21) 8 (11) 7 (10)
17 (77) 5 (23) 1 (5) 4 (18)
P value 0.137 0.541
<0.001
0.007 0.663
0.383
0.368
0.222
<0.001 0.707 0.005 <0.001 <0.001 <0.001 <0.001 0.152
1.000
0.464
ALP = alkaline phosphatase; aUC = advanced urothelial carcinoma; BMI = body mass index; CONUT = controlling nutritional status score; CRP = Creactive protein; IQR = interquartile range; LDH = lactate dehydrogenase; PS = performance status.
aUC were the bladder in 104 (56%) patients and the upper urinary tract in 81 (44%) patients. Of the 185 patients, 63 (34%) patients developed aUC after curative treatment for their primary diseases; 56 (30%) patients had undergone curative surgery and the other 7 (4%) patients had received definitive chemoradiotherapy. At the time of diagnosis of aUC, lymph node and visceral metastases were observed in 139 (75%) and 67 (36%) patients, respectively. A total of 138 (75%) patients received first-line platinum-based systemic chemotherapy and the remaining 47 (25%) patients received curative treatment after the diagnosis of aUC; 29
(15%) patients underwent curative surgery and 18 (10%) patients received definitive chemoradiation therapy. Six patients selected best supportive care. Pembrolizumab was given to 12 patients with chemotherapy-refractory disease from December 2017 onward. 3.2. Associations of CONUT score with clinical parameters The CONUT score was 0, 1, 2, 3, and ≥4 in 39 (21%), 52 (28%), 46 (25%), 26 (14%), and 22 (12%) patients,
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respectively. The median (range) CONUT score was 2 (0 −8). A higher CONUT score was associated with poorer PS (P < 0.001), lower BMI (P = 0.007), lower hemoglobin (P < 0.001), higher ALP (P = 0.005), and higher CRP (P < 0.001, Table 2). 3.3. Associations of CONUT score with OS During the follow-up period (median 12.3 months), 133 patients died (131 cancer deaths and 2 deaths of other causes). The median OS was 14.9 months for the overall cohort. By univariate analysis, the HRs of CONUT scores 1, 2, 3, and ≥4 (reference, CONUT score 0) were 1.07 (95%CI: 0.64−1.79), 1.60 (0.95−2.71), 1.88 (1.04−3.41), and 5.14 (2.72−9.69), respectively. Accordingly, CONUT scores were regrouped into 3 categories: CONUT score 0 to1, 2 to 3, and ≥4. The median OS periods for patients with CONUT scores 0 to 1, 2 to 3 and ≥4 were 19.3, 13.3, and 7.7 months, respectively (P < 0.001, Fig. 1). Table 3 shows the associations of variables with OS. On univariate analysis, a higher CONUT score was significantly associated with shorter OS (2−3 vs. 0−1, HR 1.63, P = 0.011; ≥4 vs. 0−1, HR 4.96, P < 0.001), along with higher age (HR 1.85, P < 0.001), poorer PS (HR 4.61, P < 0.001), lower BMI (HR 1.84, P < 0.001), primary tumor site in the upper urinary tract (HR 1.54, P = 0.014), presence of visceral metastasis (HR 2.08, P < 0.001), lower hemoglobin (HR 2.01, P < 0.001), higher LDH (HR 4.11, P < 0.001), higher ALP (HR 3.59, P < 0.001), higher CRP (HR 2.44, P < 0.001), lower albumin (HR 3.48, P = 0.022), lower lymphocyte count (HR 1.84, P < 0.001), no usage of pembrolizumab (HR 4.23, P = 0.009), and no curative treatment after the diagnosis of aUC (HR 1.65, P = 0.012). On multivariate analysis, a higher CONUT score was
significantly and independently associated with shorter OS (2−3 vs. 0−1, HR 1.57, P = 0.024; ≥4 vs. 0−1, HR 2.94, P < 0.001), along with higher age (HR 1.80, P = 0.003), poorer PS (HR 2.34, P = 0.006), lower BMI (HR 1.64, P = 0.008), primary tumor site of the upper urinary tract (HR 1.69, P = 0.004), higher CRP (HR 2.57, P < 0.001), no usage of pembrolizumab (HR 4.73, P = 0.005), and no curative treatment after the diagnosis of aUC (HR 1.53, P = 0.035; multivariate model 1). To assess the prognostic significance of each component of CONUT, multivariate analysis was conducted using albumin, lymphocyte count, and total cholesterol instead of the CONUT score. Lower albumin (HR 4.78, P = 0.018) and lower total lymphocyte count (HR 1.68, P = 0.006) were identified as independent adverse prognostic factors, along with higher age (HR 1.65, P = 0.013), poorer PS (HR 2.43, P = 0.005), lower BMI (HR 1.69, P = 0.007), primary tumor site in the upper urinary tract (HR 1.75, P = 0.004), higher LDH (HR 3.58, P = 0.014), higher ALP (HR 2.70, P = 0.010), higher CRP (HR 2.74, P < 0.001), and no usage of pembrolizumab (HR 5.03, P = 0.004; multivariate model 2). 4. Discussion The present study demonstrated the prognostic significance of the CONUT score in aUC patients for the first time. A higher CONUT score was significantly and independently associated with shorter OS along with established prognostic factors including advanced age, poorer PS, lower BMI, and higher CRP. These results suggest the clinical relevance of malnutrition evaluated by CONUT as a prognostic factor in aUC patients. Considering its simplicity, objectivity, global availability and validity in evaluating nutrition status, the CONUT score may be a practical prog-
Fig. 1. Kaplan-Meier curves of overall survival for 185 patients with advanced urothelial carcinoma according to their controlling nutritional status (CONUT) scores.
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Table 3 Univariable and multivariable analyses for variables associated with overall survival in 185 patients Univariable analysis Variables
HR
95%CI
Age ≥67 (vs. <67 [years]) 1.85 1.27−2.72 Sex Male (vs. female) 1.10 0.77−1.61 PS ≥2 (vs. 0.1) 4.61 2.65−7.52 BMI <23 (vs. ≥23 [kg/m2]) 1.84 1.30−2.63 Primary tumor site Upper urinary tract (vs. bladder) 1.54 1.09−2.17 Clinical T stage 3, 4 (vs. ≤2) 1.01 0.70−1.46 Clinical N stage ≥1 (vs. 0) 1.17 0.79−1.78 Visceral metastasis (lung, liver, or bone) Yes (vs. No) 2.08 1.45−2.95 Curative treatment before the diagnosis of aUC No (vs. Yes) 1.26 0.88−1.83 Hemoglobin* <12/11.5 (vs. ≥12/11.5 [g/dl]) 2.01 1.40−2.86 LDH >360 (vs. ≤360 [U/L]) 4.11 2.00−7.53 ALP >450 (vs. ≤450 [U/L]) 3.59 2.00−6.00 CRP >32 (vs. ≤32 [mg/l]) 2.44 1.61−3.59 CONUT score 0, 1 ref 2, 3 1.63 1.12−2.38 ≥4 4.96 2.77−8.50 Albumin <3.0 (vs. ≥3.0 [g/dl]) 3.48 1.23−7.70 Lymphocyte count <1600 (vs. ≥1600 [ml]) 1.84 1.29−2.67 Total cholesterol <140 (vs. ≥140 [mg/dl]) 1.64 0.95−2.66 Systemic chemotherapy used after the diagnosis of aUC No (vs. Yes) 1.40 0.95−2.03 Pembrolizumab after chemotherapy failure No (vs. Yes) 4.23 1.34−25.6 Curative treatment after the diagnosis of aUC No (vs. Yes) 1.65 1.12−2.51
Multivariable model 1
Multivariable model 2
P value
HR
95%CI
P value
HR
95%CI
P value
<0.001
1.80
1.23−2.70
0.003
1.65
1.11−2.49
0.013
<0.001
2.34
1.29−4.04
0.006
2.43
1.32−4.23
0.005
<0.001
1.64
1.14−2.39
0.008
1.69
1.16−2.49
0.007
0.014
1.69
1.18−2.42
0.004
1.75
1.20−2.55
0.004
<0.001
3.58
1.34−8.10
0.014
<0.001
2.70
1.28−5.27
0.010
2.74
1.75−4.18
<0.001
0.610
0.937 0.432 <0.001 0.211 <0.001
<0.001
2.57
1.65−3.93
<0.001
0.011 <0.001
ref 1.57 2.94
1.06−2.31 1.62−5.14
0.024 <0.001
− − −
0.022
−
4.78
1.30−20.28
0.018
<0.001
−
1.68
1.16−2.47
0.006
0.076
−
5.03
1.56−30.79
0.004
0.091 0.009
4.73
1.48−28.8
0.005
0.012
1.53
1.03−2.35
0.035
ALP = alkaline phosphatase; aUC = advanced urothelial carcinoma; BMI = body mass index; CONUT = controlling nutritional status score; CRP = C-reactive protein; IQR = interquartile range; LDH = lactate dehydrogenase; PS = performance status. * Cutoff values are 12 g/dl and 11.5 g/dl for males and females, respectively.
nosticator for aUC patients, as well as an indicator of their general condition from the aspect of nutritional status. PS is an established prognostic factor in aUC patients [4−6] while its assessment includes potential problems in objectivity, accuracy and interobserver agreement [7]. We hypothesized that CONUT might be an objective and accurate alternative to PS as a prognostic factor representing the general condition of aUC patients. However, the present study demonstrated that, despite a significant association between CONUT and PS, the prognostic significance of the CONUT score was independent of that of PS.
Interestingly, this was not the case of sarcopenia, a degenerative loss of skeletal muscle mass, which canceled out the prognostic significance of PS in multivariate analysis in patient cohorts of aUC [18] and metastatic renal cell carcinoma [19]. Given that PS represents patients’ general condition from the aspect of activity of daily life, sarcopenia may be an objective alternative to PS as a prognosticator for aUC patients. The CONUT score appears to represent the general condition of aUC patients from the aspect of nutritional status as a prognostic factor, independently of PS.
ARTICLE IN PRESS 6
H. Suzuki et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−7
The established prognostic factors of aUC patients can be classified into 2 major categories: tumor factors and patient responses. The former include the primary tumor site and the presence of visceral metastasis, while the latter include PS, white blood cell count, hemoglobin, albumin, neutrophil-lymphocyte ratio (NLR) and CRP [4−6, 20, 21]. The latter reflect the development process of cancer cachexia, which involves proinflammatory cytokines including tumor necrosis factora, interleukin (IL)-6, IL-1, and IL-10 [22, 23]. Of note, among the 3 components of CONUT, both lymphocytopenia and hypoalbuminemia were significant and independent adverse prognostic factors in this study. Lymphocytopenia often develops in advanced cancer patients through several mechanisms of tumor immune evasion, including destruction of lymphocytes by tumor cells expressing proapoptotic ligands [24]. Programmed death ligand-1 expressed by tumor cells and macrophages can diminish the proliferation and survival of tumor-infiltrating lymphocytes in the tumor microenvironment, which may have a systemic impact [25]. Previous cytotoxic treatments also contribute to lymphocytopenia. Taken together with the fact that IL-6 reduces total cholesterol levels [26], the CONUT score in cancer-bearing patients reflects not simply nutritional status but more importantly the degree of immunosuppression and influences of proinflammatory cytokines that further deteriorate lymphocytopenia via the catabolic protein metabolism during the development of cachexia [27]. This pathophysiology may account for the prognostic role of the CONUT score in aUC patients. Once the prognostic significance of malnutrition has been identified in aUC patients, the next issue would be whether nutritional support can improve their prognosis. A randomized trial showed that an oral nutritional supplement containing eicosapentanoic acid, which can reduce proinflammatory cytokines and CRP, improved progression-free survival in patients with advanced nonsmall cell lung cancer [28], suggesting a role of nutritional support in improving the prognosis of advanced cancer patients. Considering the multifactorial mechanism of cancer cachexia, an energy-wasting and hyper-catabolic syndrome, a multimodal approach may more effectively improve the prognosis and quality of life of advanced cancer patients than nutritional support alone; such supportive treatments include the molecular targeting of proinflammatory cytokines [29, 30], metabolic intervention to block catabolic drive and to enhance anabolic pathways [31], and immunomodulation to prevent immunosuppression as well as sufficient nutrient intake and exercise to prevent sarcopenia [32, 33]. CONUT may serve as one assessment tool to evaluate the effects of multimodal approaches to prevent cachexia in advanced cancer patients. The present study had several limitations. First was possible bias by the retrospective nature. External validations with large patient multi-institutional cohorts are needed to confirm the generality of our findings, according to the
REMARK guidelines [17]. Second, only 12 patients received ICI, the current standard of care as second-line treatment in aUC patients. Pembrolizumab for aUC patients was approved by the Japanese national health insurance system in December 2017. Since our cohort consisted of patients treated between 2004 and 2018, most patients did not receive pembrolizumab. Contemporary cohorts of patients receiving ICI may yield different results. Third, we did not completely record statin use and thus it was not included as a variable in the present cohort. Adjustment for statin use may have provided more accurate prognostic information on the total cholesterol value, a component of CONUT. 5. Conclusion The present study demonstrated the prognostic significance of the CONUT score in aUC patients. Validation of multicentric larger patient cohorts is needed to confirm this finding. Since the CONUT score reflects malnutrition in the process of developing cachexia, a multimodal approach to improve cancer-induced malnutrition may improve the prognosis of aUC patients. Conflict of interest None References [1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68:7–30. [2] Bellmunt J, Hvd Maase, Mead GM, Skoneczna I, Santis MD, Daugaard G, et al. Randomized phase III study comparing Paclitaxel/Cisplatin/ Gemcitabine and Gemcitabine/Cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study 30987. J Clin Oncol 2012;30:1107–13. [3] Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee J-L, Fong L, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017;376:1015–26. [4] Bajorin DF, Dodd PM, Mazumdar M, Fazzari M, McCaffrey JA, Scher HI, et al. Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol 1999;17:3173–81. [5] Galsky MD, Moshier E, Krege S, Lin C-C, Hahn N, Ecke T, et al. Nomogram for predicting survival in patients with unresectable and/ or metastatic urothelial cancer who are treated with cisplatin-based chemotherapy. Cancer 2013;119:3012–9. [6] Iasonos A, Apolo AB, Bajorin DF, Small EJ, Philips GK, Ostrovnaya I, et al. Prognostic model for predicting survival of patients with metastatic urothelial cancer treated with cisplatin-based chemotherapy. J Natl Cancer Inst 2013;105:499–503. [7] Chow R, Chiu N, Bruera E, Krishnan M, Chiu L, Lam H, et al. Interrater reliability in performance status assessment among health care professionals: a systematic review. Ann Palliat Med 2016;5:83–92. [8] Detsky AS, McLaughlin JR, Baker JP, Johnston N, Whittaker S, Mendelson RA, et al. What is subjective global assessment of nutritional status? 1987. Classical article. Nutr Hosp 2008;23:400–7. [9] Hamada Y. Objective Data Assessment (ODA) methods as nutritional assessment tools. J Med Invest 2015;62:119–22.
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