Abstract
Background/Aim: The impact of the controlling nutritional status (CONUT) score on oncological outcomes after radical cystectomy (RC) for advanced bladder cancer (BC) is unknown. Patients and Methods: We retrospectively evaluated 115 patients who underwent RC for advanced BC at our department between November 2003 and February 2019. The CONUT score was calculated from serum albumin levels, total lymphocyte counts, and total cholesterol levels. Relapse-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) after RC were analyzed. Results: For the CONUT score, the area under curve was 0.651 and the optimal cut-off value determined using the Youden index was 3. The high CONUT group had significantly shorter RFS, CSS, and OS than the low CONUT group. Multivariate analyses showed that the CONUT score was an independent prognostic factor of RFS, CSS, and OS. Conclusion: The CONUT score could be an effective predictor for survival and tolerability following RC for advanced BC.
Nutritional status can be impaired by cancer-induced chronic inflammation (1, 2). Accordingly, several systemic inflammatory or nutritional factors have been identified for prediction of patient survival (3, 4) and tolerability of surgery (5, 6) or systemic chemotherapy (7) in various types of cancer. In this context, the controlling nutritional status (CONUT) score, which consists of serum albumin levels, total lymphocyte counts, and total cholesterol levels, has been reported to be a useful predictor of survival in gastrointestinal cancer (8). The CONUT score has also been reported to be associated with prognosis in other types of cancers including renal cell carcinoma (9) and lung adenocarcinoma (10). These findings suggest that the CONUT score may be utilized for outcome prediction regardless of cancer types.
Bladder cancer (BC) is the second most common urologic cancer, and 25%-30% of cases present with advanced disease (11). For these cases, radical cystectomy (RC) is the standard treatment, but the postoperative prognosis and surgical complications remain problematic (12, 13). Therefore, effective predictors for outcome prediction following RC for advanced BC are needed. Several studies have suggested that nutrition and inflammatory factors, such as the modified Glasgow Prognostic Score, sarcopenia, and prognostic nutritional index, might be useful as predictive factors of prognosis in BC (14-16). Furthermore, we have previously reported that sarcopenia and the CONUT score were significantly associated with survival following radical nephroureterectomy in patients with upper tract urothelial carcinoma (17, 18).
This study aimed to evaluate the association between the CONUT score and postoperative outcomes including survival and tolerability following RC in advanced BC. We hypothesized that the CONUT score is associated with oncological outcomes in patients with advanced BC undergoing RC and can thus be used as an effective prognostic factor.
Patients and Methods
Study design and patients. This retrospective study was approved by the internal Ethics Review Board of Tokyo Women’s Medical University (ID: 5329) and was performed in accordance with the principles outlined in the Declaration of Helsinki.
The subjects were patients who underwent RC for advanced BC without distal organ metastases (i.e., cM0) at our department between November 2003 and February 2019. Of the 171 patients identified, we excluded 56 patients who had undergone maintenance dialysis (n=14), who had undergone prior radical nephroureterectomy for upper tract urothelial carcinoma (n=15), and whose clinical data before and after RC were missing (n=27). Finally, 115 patients were evaluated in this retrospective study. The patients were classified into two groups based on the cutoff CONUT score determined using the receiver operating characteristic (ROC) curve and the Youden index (19). The oncological outcomes including survival after RC and the rate and grade of postoperative complications were compared between the two groups. Risk factors for survival were also investigated.
Clinical and laboratory data were extracted from the electronic database and patients’ medical records. Tumor staging was according to Union for International Cancer Control TNM classification (20). The preoperative stage was determined based on findings from imaging examinations including computed tomography or magnetic resonance imaging.
Calculation of the CONUT score. The CONUT score was calculated from the serum albumin levels, total lymphocyte counts, and total cholesterol levels, as previously described (21) (Table I). We evaluated the CONUT score using peripheral blood samples obtained within 1 month before the RC in routine clinical practice.
Calculation of the CONUT score.
Evaluation of oncological outcomes. The survival impact of the CONUT score was evaluated according to relapse-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) after RC. Meanwhile, the impact of the CONUT score on tolerability to RC was evaluated according to the incidence rate and grade of postoperative complications and the duration of postoperative hospitalization after RC. Only postoperative complications that developed within 3 months after RC were analyzed, and their grades were also assessed based on the Clavien-Dindo classification (22).
Neoadjuvant chemotherapy. Neoadjuvant chemotherapy was considered when there was adequate time to conduct RC or when an anti-tumor benefit was expected for advanced BC, with careful consideration of the patients’ comorbidities, performance status, and willingness to undergo chemotherapy. The regimen generally consisted of cisplatin-based chemotherapy including 1-4 cycles of gemcitabine plus cisplatin or carboplatin or 1-2 cycles of methotrexate, vinblastine, adriamycin, plus cisplatin.
Statistical analysis. Continuous variables were analyzed using the Mann-Whitney U-test, whereas categorical variables were analyzed using the χ2 test. RFS was defined as the time from RC to the first local recurrence, metastasis to distal organs, or any-cause death. CSS and OS were defined as the time from RC to cancer-related death and any-cause death, respectively. All survival outcomes were calculated using the Kaplan-Meier method and compared using the log-rank test. To identify risk factors of survival after RC, multivariate analyses for RFS, CSS, and OS were performed using the Cox proportional hazards regression models. Risk was expressed as the hazard ratio (HR) with 95% confidence interval (CI). All analyses were preformed using the JMP software (version 15; SAS Institute Inc., Cary, NC, USA), and differences with a p value of <0.05 were considered statistically significant.
Results
Patients’ characteristics. The ROC analysis for the CONUT score showed that the area under curve predicting CSS was 0.65 (Figure 1). According to the maximum Youden index method, the cut-off of CONUT score was determined at 3. Based on this cut-off value, 22 patients (19.1%) were classified into the high CONUT group (i.e., CONUT score ≥3), whereas 93 patients (80.9%) were classified into the low CONUT group (i.e., <3). The specific scores of the individual factors of the CONUT score of the two groups are shown in Table II.
ROC curve for CONUT score. ROC curve predicted cancer-specific survival according to a preoperative CONUT score. According to the maximum Youden index method, the cut-off of CONUT score was determined at 3 (AUC=0.65). ROC: Receiver operating characteristic; CONUT: controlling nutritional status; AUC: area under the curve.
Number of patients according to the components of the CONUT score.
The patients’ characteristics are summarized in Table III. The patients in the high CONUT group were significantly older (median: 71.9 years vs. 66.9 years, p=0.0306) and had higher clinical T stage (cT3 or more vs. cT2 or less: 54.6% vs. 25.8%, p=0.0194). In addition, the clinical N stage tended to be higher in the high CONUT group (cN1 or more vs. cN0: 22.8% vs. 7.5%, p=0.0513). Meanwhile, there were no significant differences in sex, smoking history, initial symptom, tumor grade, lymphovascular invasion (LVI), presence of hydronephrosis before RC, or rate of neoadjuvant chemotherapy between the two groups (all, p>0.05).
Patient characteristics according to the CONUT score.
Survival according to CONUT score. During the follow-up period [median: 21 (interquartile range: 4-61) months], local recurrence or distant metastasis was observed in 36 patients (31.3%), and 23 (20.0%) and 26 (22.6%) patients died of cancer and any cause, respectively. Compared with the low CONUT group, the high CONUT group had significantly lower RFS (57.4% vs. 61.1%, p=0.0292), CSS (48.1% vs. 78.7%, p=0.0011), and OS (55.0% vs. 74.6%, p=0.0210) at 5 years after RC (Figure 2).
Relapse-free survival, cancer-specific survival, and overall survival according to the CONUT score. Kaplan-Meier curves for (a) relapse-free survival, (b) cancer-specific survival, and (c) overall survival following radical cystectomy for advanced bladder cancer according to the CONUT score. CONUT: Controlling nutritional status.
Risk factors for survival. Univariate analyses for RFS, CSS, and OS showed that hydronephrosis, pT stage, pN stage, presence of LVI, and the CONUT score were significant factors (all, p<0.05) (Table IV). Multivariate analyses of these factors further showed that the CONUT score was an independent factor for RFS (HR=3.55, 95%CI=1.41-8.50, p=0.0083), CSS (HR=6.01, 95%CI=2.23-16.0, p=0.0006), and OS (HR=3.83, 95%CI=1.44-9.56, p=0.0085) (Table V). In addition, pT stage was also an independent factor for RFS (HR=2.93, 95%CI=1.27-7.16, p=0.0114), CSS (HR=4.34, 95%CI=1.41-15.6, p=0.0094), and OS (HR=3.21, 95%CI=1.18-9.89, p=0.0216), and pN stage was an independent factor for CSS (HR=2.70, 95%CI=0.97-6.90, p=0.0566).
Univariate analysis for risk factors for RFS, CSS and OS after radical cystectomy for advanced bladder cancer.
Multivariate analysis for risk factors for RFS, CSS, and OS after radical cystectomy for advanced bladder cancer.
Complications according to the CONUT score. In total, 11 (50.0%) and 56 patients (60.2%) experienced any-grade postoperative complications in the high and low CONUT groups, respectively (Table VI). In addition, 3 and 17 patients experienced Grade ≥III complications in the high and low CONUT groups, respectively (Table VI). There were no significant between-group differences in the rate of any-grade (p=0.4724) and Grade ≥III (p=0.7607) complications. Grade IV or V complications did not occur. Meanwhile, the duration of hospitalization after RC was significantly longer in the high CONUT group than that in the low CONUT group (median: 36.0 days vs. 28.4 days, p=0.0458; Table VI).
Perioperative outcomes according to CONUT score.
Discussion
This study revealed that RFS, CSS, and OS following RC for advanced BC were significantly shorter in patients with high CONUT score than in those with low CONUT score. Multivariate analysis further showed that the CONUT score was an independent factor for these survival outcomes. Moreover, a high CONUT score was significantly associated with a longer duration of postoperative hospitalization. These findings suggested that the CONUT score was significantly associated with oncological outcomes including survival and tolerability of advanced BC patients undergoing RC.
The association between the CONUT score and prognosis in urological cancers has been previously investigated. In renal cell carcinoma, the CONUT score was significantly associated with survival, and this prognostic impact was superior to other nutritional factors such as the Prognostic Nutritional Index (23). The CONUT score was also an independent prognostic factor in prostate cancer with oligometastasis (24). Further, the CONUT score has recently been reported to have a prognostic impact in urothelial carcinoma. Specifically, the CONUT score was associated with PFS and OS in advanced urothelial carcinoma including BC patients who underwent multimodal treatment including surgery, platinum-based systemic chemotherapy, and radiation therapy (25). However, in that study, only 56% of the overall cohort had advanced BC. In contrast, we evaluated an exclusive cohort of advanced BC and found that the CONUT score has a prognostic impact in advanced BC.
In the past, it has also been reported that postoperative pancreatic fistula, one of the complications after pancreaticoduodenectomy for pancreatic cancer, occurred more frequently in patients with poor nutritional status (26). Interestingly, in the present study, although we did not find any difference in the rate or grade of complications according to the CONUT score, the duration of postoperative hospitalization was longer in the high CONUT group. This might suggest that there is a delay of recovery of the general condition from invasive surgery among patients with low nutritional status irrespective of complication development. To the best of our knowledge, this was the first study indicating the possibility of CONUT score as a predictive factor of tolerability for invasive surgery in urologic cancers.
The CONUT score is determined based on the serum albumin concentration, total lymphocyte count, and total cholesterol concentration. The serum albumin level is a major component of serum total protein and reflects nutrition and inflammation status (27). Lymphocytes generally inhibit or attenuate cancer cell growth and migration and promote the apoptosis of cancer cells (28). As for cholesterol, its role in cancer development, invasiveness, or aggressiveness remains unclear. However, serum cholesterol levels have been reported as a predictive or prognostic factor in cancer (29-31). Moreover, altered levels and mutations of genes involved in the cholesterol homeostasis pathways have been identified in cancer cells (32). These include increases in gene copy numbers, up-regulation of cholesterol synthesis gene expression, enhanced cholesterol import by low-density lipoprotein receptors, and decreased transport of cholesterol, which promote increased cellular cholesterol levels to aid cancer cell proliferation (33).
This study has several limitations. First, because this study was retrospectively conducted using a small sample size in a single center, the findings were affected by unavoidable bias. Therefore, external validations with a large sample size in multiple institutions are warranted to confirm our findings. Second, because the CONUT score was calculated at the time of post neoadjuvant chemotherapy, the patients’ nutritional status was expected to be affected to some extent. Further studies are needed to validate our findings.
Conclusion
The CONUT score was significantly associated with oncological outcomes including survival and tolerability following RC in advanced BC. Further, a higher CONUT score was associated with a longer duration of postoperative hospitalization. Considering that the CONUT score can be easily assessed using blood samples obtained in daily clinical practice, it can be a less invasive and effective predictor.
Acknowledgements
The Authors thank Ms. Nobuko Hata (Department of Urology, Tokyo Women’s Medical University) for her secretarial work.
Footnotes
Authors’ Contributions
Yuki Nemoto, Tsunenori Kondo, Hiroki Ishihara, Toshio Takagi, Hideki Ishida, and Kazunari Tanabe were involved in study design and data interpretation. Yuki Nemoto, Hiroki Ishihara were involved in data analysis. All Authors critically revised the manuscript, approved the manuscript to be published, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
This article is freely accessible online.
Conflicts of Interest
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
- Received December 19, 2020.
- Revision received January 2, 2021.
- Accepted January 4, 2021.
- Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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