|Year : 2017 | Volume
| Issue : 5 | Page : 837-843
The prognostic value of preoperative serum albumin-globulin ratio for high-grade bladder urothelial carcinoma treated with radical cystectomy: A propensity score-matched analysis
Zhenhua Liu1, Haichao Huang2, Shaobo Li3, Wei Yu1, Wei Li2, Jie Jin1, Xin Li1, Jinchun Xing2
1 Department of Urology, Peking University First Hospital and Institute of Urology, Peking University, National Urological Cancer Center, 8 Xishiku Street, Xicheng District, Beijing, China
2 Department of Urology, The First Affiliated Hospital of Xiamen University, 55 Zhenhai Road, Siming District, Xiamen, Fujian, China
3 Shanghai Medical School, Fudan University, 130 Dong`an Road, Shanghai, China
|Date of Web Publication||13-Dec-2017|
Department of Urology, The First Affiliated Hospital of Xiamen University, 55 Zhenhai Road, Siming District, Xiamen, Fujian 361003
Department of Urology, Peking University First Hospital and Institute of Urology, Peking University, National Urological Cancer Center, 8 Xishiku Street, Xicheng District, Beijing 100034
Source of Support: None, Conflict of Interest: None
Objectives: Albumin-globulin ratio (AGR) has been reported as an independent risk factor for survival outcomes of a variety of malignancies. We aimed to further examine the prognostic value of AGR for urothelial carcinoma of bladder (UCB) using a propensity score-matched (PSM) analysis.
Materials and Methods: The medical data of 189 high-grade UCB patients undergoing radical cystectomy were retrospectively reviewed. AGR was defined as the ratio of serum albumin to nonalbumins (serum total protein–albumin). The association of preoperative AGR with clinicopathologic characteristics and prognosis were assessed. Multivariate analyses using Cox regression models were applied to evaluate the independent prognostic factors.
Results: The receiver operating curve analysis indicated 1.55 as the optimal cutoff value to define low or high AGR. In prematched cohorts, Kaplan–Meier analysis indicated that AGR lower than 1.55 was associated with poorer overall survival (OS), progression-free survival (PFS), and tumor-specific survival (TSS) (P < 0.001 for all). Multivariable cox analyses also showed that AGR lower than 1.55 were an independent risk factor for survival outcomes, including OS, PFS, and TSS (P < 0.01 for all). In particular, AGR lower than 1.55 remained its prognostic value after PSM analysis.
Conclusion: Low AGR was a significant unfavorable factor for UCB patients treated with radical cystectomy. This viable parameter should be enrolled in the pretreatment risk stratification for UCB.
Keywords: Albumin-globulin ratio, high-grade, prognosis, propensity score-matched analysis, urothelial carcinoma of bladder
|How to cite this article:|
Liu Z, Huang H, Li S, Yu W, Li W, Jin J, Li X, Xing J. The prognostic value of preoperative serum albumin-globulin ratio for high-grade bladder urothelial carcinoma treated with radical cystectomy: A propensity score-matched analysis. J Can Res Ther 2017;13:837-43
|How to cite this URL:|
Liu Z, Huang H, Li S, Yu W, Li W, Jin J, Li X, Xing J. The prognostic value of preoperative serum albumin-globulin ratio for high-grade bladder urothelial carcinoma treated with radical cystectomy: A propensity score-matched analysis. J Can Res Ther [serial online] 2017 [cited 2020 Jul 13];13:837-43. Available from: http://www.cancerjournal.net/text.asp?2017/13/5/837/220464
Zhenhua Liu and Haichao Huang contributed equally to this research and should be both considered first author.
Xin Li and Jinchun Xing contributed equally to this research and should be both considered corresponding author.
| > Introduction|| |
Urothelial carcinoma of bladder (UCB) is one of the leading causes of morbidity and mortality of urinary tract diseases presenting heterogeneous features. On the one hand, low-grade Ta stage tumors show favorable survival outcomes and rarely present a grave threat to patients; on the other hand, high-grade tumors have quite poor prognosis with rapid tumor progression and high tumor-specific death rates. A variety of urothelial carcinoma characteristics have been studied in an attempt to predict various tumor behaviors, among which accurate staging and grading of the disease is the most important for therapeutic decision-making. However, the majority of parameters, which are capable of predicting survival outcomes of UCB, depend on the postoperative pathological results, leading to a challenge in pretreatment risk stratification for clinicians. Recently, emerging evidence suggested that systemic inflammatory response (SIR), a patient-related factor, is significantly associated with the survival of a variety of malignancies. Serum albumin and nonalbumins are biomarkers that reflect SIR levels. For instance, Wang et al. discovered that a decrease in the level of albumin was related to an increase in C-reactive protein (CRP) level in the serum in nonmall cell lung cancer patients. Moreover, many studies have shown that low serum albumin-globulin ratio (AGR), which is calculated as AGR = albumin/(serum total protein − albumin), indicates a poor survival outcome for several malignancies.,,,,, However, investigations about the association between UCB and AGR are not enough. In the present study, we established an ideal cutoff value to identify low or high AGR and utilized propensity score-matched (PSM) analysis to further evaluate the association between AGR and UCB survival.
| > Materials and Methods|| |
We retrospectively reviewed 189 consecutive primary high-grade UCB patients, who were diagnosed and treated in our center (Institute of Urology, Peking University) from January 2009 to December 2013. Patients with previous bladder tumors were excluded. Clinicopathological features, including age, gender, body mass index (BMI), the level of preoperative serum total protein and albumin, smoking history, operation methods (open or laparoscopic), tumor size and number, pathological tumor stage, presence of concomitant carcinoma in situ (CIS), lymphovascular invasion (LVI), prostatic urethra invasion (PUI), lymph node metastasis (LNM), postoperative adjuvant chemotherapy status, and prognostic outcomes were collected from individual medical records. As previously stated, AGR was calculated as AGR = albumin/(total protein − albumin). All patients enrolled in this study had serum chemistry analysis within 7 days of any therapeutic intervention. In case of pathological T stage, pT1 and pT2 were classified as organ-confined stages whereas pT3 and pT4 were classified as extravesical stages. Radical cystectomy (RC) with pelvic lymph node dissection (open or laparoscopic) with or without postoperative adjuvant chemotherapy was applied as the main therapy for all the patients. No patients had neoadjuvant chemotherapy. All the pathological data analyzed in this study were based on postoperative RC standard pathological procedures. Tumor stage was assessed according to the Union for International Cancer Control TNM classification of malignant tumors 2002. Tumor grade was assessed according to the WHO classification of 2004.
The patients were visited every 6 months after the operation. The follow-up visits consisted of a physical examination, laboratory tests, and ultrasonography. Other imaging analyses including chest radiography and abdominal CT were indicated if necessary. The causes of death were determined by reviewing death certificates or by consulting the treating clinicians. In addition, we defined disease progression as cancer being metastasized to other organs or UCB-related death. Eventually, complete follow-up data were available for 167 patients. This study was approved by the Institutional Ethics Committee of Peking University First Hospital. As a retrospective analysis of routine data, a waiver of written informed consent was granted from the ethics committee. Patient records/information was anonymized and deidentified before the analysis.
The optimal cutoff value of the preoperative AGR was estimated by the receiver operating characteristics (ROC) curve, as the value at the highest Youden index. Furthermore, to effectively control preoperative confounders, we performed a one-to-one PSM analysis using SPSS 22.0. The matching parameters were age (<60 vs. ≥60 years), gender (female vs. male), smoking history (yes vs. no), BMI (≥25 vs. <25 kg/m2), operation methods (open vs. laparoscopic), tumor size (≥3 cm in diameter vs. <3), tumor number (≥3 vs. <3), tumor stage (extravesical vs. organ confined), concomitant CIS (present and absent), LVI (present and absent), PUI (present and absent), LNM (present and absent), and postoperative adjuvant chemotherapy (yes vs. no).
For statistical analysis, numerical variables with t-test and categorical variables with Chi-square test and Fisher's exact test were used for comparative analyses. Overall survival (OS), progression-free survival (PFS), and tumor-specific survival (TSS) were evaluated using the Kaplan–Meier method and log-rank test. Univariate analysis was performed for each variable that may predict mortality, as mentioned above, using a Cox regression model. Then, statistically and clinically significant variables were further evaluated using multivariate Cox regression model. SPSS 22.0 was used in all statistical analyses. In all tests, P < 0.05 was considered to indicate significance. All methods were carried out in accordance with relevant guidelines and regulations.
| > Results|| |
Identifying the definition of high/low albumin-globulin ratio
To identify the optimal cutoff value of AGR for defining high or low AGR groups, a ROC analysis was used, in which 1.55 was determined as the optimal cutoff value of AGR [Figure 1]. Then, patients were divided into two groups based on this cutoff value (high AGR group vs. low AGR group, N = 79 vs. 110).
|Figure 1: Receiver operating curve analysis of the ideal albumin-globulin ratio cutoff value|
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Characteristics and survival analyses of the entire cohort before propensity score-matched analysis
Demographic and clinicopathologic characteristics of 189 patients who were involved in the whole cohort are described in [Table 1]. Low AGR group had a significantly larger proportion of patients older than 60 and had larger tumor sizes. The presence of LVI was more inclined to be detected in patients with low AGR. In addition, though without statistical significance, patients in low AGR group had a trend of LNM. Overall, complete follow-up data were available in 167 patients, with a median follow-up of 38 months (1–90 months). During the period of follow-up, 39 patients died from UCB, 52 patients experienced disease progression, 45 patients died from other causes. The low AGR group showed poorer outcomes of OS, PFS, and TSS in Kaplan–Meier curves [Figure 2]a, [Figure 2]b, [Figure 2]c. In both univariable and multivariable cox analyses, lower AGR, the presence of LNM, extravesical tumor stage (pT3/T4) were shown as independent risk factors of poorer OS, PFS, and TSS. The presence of PUI was significantly associated with poorer TSS in univariable analysis for patients older than 60 years of age, whereas statistical significance for age older than 60 was not found in the multivariate analysis. However, in the case of OS, age over 60 remained its statistical significance for poorer OS in multivariate analysis [Table 2].
|Table 1: Descriptive clinicopathologic characteristics of patients treated with radical cystectomy and bilateral lymphadenectomy for urothelial carcinoma of the bladder|
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|Figure 2: (a) Overall survival of patients with high albumin-globulin ratio or low albumin-globulin ratio before propensity score-matched analysis; (b) progression-free survival of patients with high albumin-globulin ratio or low albumin-globulin ratio before PSM analysis; (c) tumor-specific survival of patients with high albumin-globulin ratio or low albumin-globulin ratio before propensity score-matched analysis; (d) overall survival of patients with high albumin-globulin ratio or low albumin-globulin ratio after propensity score-matched analysis; (e) progression-free survival of patients with high albumin-globulin ratio or low albumin-globulin ratio after propensity score-matched analysis; (f) tumor-specific survival of patients with high albumin-globulin ratio or low albumin-globulin ratio after propensity score-matched analysis|
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|Table 2: Univariate and multivariate Cox regression analyses for the prediction of overall survival, progression-free survival, and tumor-specific survival in 189 patients treated with radical cystectomy and bilateral lymphadenectomy for high-grade urothelial carcinoma of the bladder|
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Characteristics and survival analyses of the propensity score-matched cohort
Given the unbalance of the baseline covariables, including age, tumor size, presence of LVI and LNM between the two groups, we conducted a PSM analysis to prevent a biased estimation of the effect of AGR in the prognostic outcomes of UCB. In the cohorts after PSM analysis (52 pairs, n = 104), no significant difference was observed between the two AGR groups. Similarly, patients with AGR lower than 1.55 had poorer OS, PFS, and TSS than those with higher AGR using Kaplan–Meier curves and log-rank test [Figure 2]d, [Figure 2]e, [Figure 2]f. Both univariable and multivariable cox analyses further confirmed that AGR lower than 1.55 was an independent risk factor of poorer OS, PFS, and TSS (P < 0.01 for all [Table 3]).
|Table 3: Univariate and multivariate Cox regression analyses for prediction of overall survival, progression-free survival and tumor-specific survival in 104 propensity-score matched patients treated with radical cystectomy and bilateral lymphadenectomy for high-grade urothelial carcinoma of the bladder|
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| > Discussion|| |
A variety of factors, including tumor-related and patient-related factors, have been suggested to affect the features of cancer. Until recently, the major efforts in predicting outcomes of patients with cancer mainly concentrated on tumor-related factors, such as tumor size, tumor number, and postoperative pathological tumor stage and grade. However, a growing body of evidence has suggested that various host-related factors, including malnutrition and SIR, play an important role in predicting clinical outcomes for cancer patients.,, Albumin and nonalbumins (including CRP, complement components, and immunoglobulins) were shown to be potential hematological biomarkers which represent SIR in cancer patients.
Serum albumin, a marker of acute phase response to an inflammatory state, is produced by liver cells. Mounting evidence suggested that low serum albumin level was significantly associated with poor oncological outcomes of cancer patients. Parker et al. reported that low albumin level was associated with poor OS for ovarian cancer patients. Lis et al. reported that low albumin level (lower than 3.5 g/dl) was associated with a higher death rate for breast cancer. Similarly, in patients of other malignancies, low serum albumin indicated poor clinical outcomes., The mechanisms through which albumin affects oncological outcomes have not been clearly illustrated; researchers, however, have put forward several possible hypotheses. Among which are antioxidant effect against carcinogens (e.g., nitrosamine and aflatoxin), stabilizing cell growth and DNA replication, and buffering sex hormone homeostasis to prevent sex hormone-induced malignancies, etc. In addition, low levels of serum albumin indicate malnutrition; several human immune defense mechanisms would be weakened under the condition, resulting in decreased response to treatment in cancer patients.,
In contrast to the predictive value of albumin in cancer prognosis, a recent study of the association between globulins and oncological outcomes of rectal cancer has shown that low globulin levels were significantly associated with favorable rectal cancer-specific survival. Furthermore, in lung cancer patients, poor survival was associated with high alpha and gamma globulin levels; in colorectal cancer patients, poor prognosis was noted with high complement 3 and IgA levels. In case of CRP, a nonspecific acute phase serum protein of inflammatory, plenty of studies have suggested that the elevated level of this protein was associated with poor oncological outcomes.,,
Thus, we believe reduced albumin levels negatively affect the oncological outcomes of cancers. AGRs have also gained considerable attention recently as a biomarker with predictive value in various malignancies. In our previous study, low AGR (lower than 1.45) was significantly associated with poor overall and cancer-specific survivals for the upper tract urothelial carcinoma (UTUC). Similarly, other studies also reported the predictive value of AGR in esophageal squamous cell carcinoma, rectal cancer, lung cancer,, hepatocellular carcinoma, and natural killer/T-cell lymphoma. However, the association between bladder urothelial carcinoma and AGR was not adequately reported. In a recent study, Liu et al. evaluated the prognostic value of AGR in patients with bladder urothelial carcinoma undergoing radical cystectomy, where low AGR was shown to be associated with poor survival. However, in their study, several baseline parameters, including age, BMI, pathological T stage, pathological N stage, and adjuvant chemotherapy status were unbalanced between different AGR groups, some of which are important risk factors for UCB patients. In this regard, conclusions derived from such cohorts with unbalanced baseline parameters may result in a biased evaluation.
PSM is a method, based on the propensity score, for reducing bias without the limitation of being able to use only a small number of covariates in the model. It was first proposed by Rosenbaum and Rubin. Thus, we enrolled 189 high-grade UCB patients undergoing RC and applied PSM analysis to control the baseline parameters of the cohort. In the present study, a variety of potential prognostic factors were taken into consideration and enrolled into the PSM analysis, including number of tumors, tumor sizes, T category, presence of concurrent CIS, and tumor grade (WHO 1973),, age, female gender, LNM, pathological T stage, presence of PUI, LVI, BMI, smoking history, and adjuvant chemotherapy status. For PSM analysis, a cohort of 52 matched pairs was established. Before PSM, several parameters of the cohorts including age, tumor size, and presence of LVI were significantly different between high and low AGR groups. However, no significant difference was detected between the two groups after the PSM analysis. Survival analyses of prematched cohorts, including Kaplan–Meier curves, log-rank test, and univariable and multivariable cox analysis, demonstrated that UCB patients with AGR lower than 1.55 were significantly more likely to subject to poor survival outcomes than those with AGR higher than 1.55. Such correlations remained their statistical significance in PSM cohorts. Thus, the results from prematched cohorts in combination with those from PSM cohorts suggested that patients with low AGR were noted with poor survival outcomes, including OS, PFS, and TSS.
In the present study, the ROC curves suggested 1.55 to be the most optimal cutoff value to identify high or low AGR cases, which was close to the previous studies (1.60). However, in our previous investigation on the predictive value of AGR for UTUC patients, 1.45 was determined as the best threshold to define AGR as high or low. Moreover, the ideal threshold of AG varies in other investigations of different malignancies, including 1.29 for small-cell lung cancer, 1.3 for esophageal squamous cell carcinoma, 1.48 for hepatocellular carcinoma, 1.3 for natural killer/T-cell lymphoma, respectively. Such a wide range of cutoff values for AGR suggests that different malignancies may have their specific AGR cutoff value and the utilization of different AGR cutoff values in particular cancer cohorts may result in different conclusions. Thus, more investigations should be performed to identify an ideal AGR cutoff value for UCB patients as well as other particular malignancies.
While it has been illustrated that albumin is an effective predictor of the effects of chemotherapy in nonsmall cell lung cancer patients (a lower level of AGR is associated with poor chemotherapy results), investigations on the parameters for their predictive value of survival outcomes of UCB mainly focused on tumor-related factors. However, the effect of patient-related factors in predicting the survival outcomes of cancer patients is drawing more and more attention, among which AGR acts as a promising blood-based biomarker due to its advantages of low cost, easy application, and broad availability.
Moreover, AGR, which is defined as a ratio of serum albumin to nonalbumins, would not be affected by the presence of dehydration which often affects the predictive value of other blood-based biomarkers. Above all, these features make AGR a potential biomarker through which clinicians are able to improve the risk stratification of UCB before any treatments.
The main limitations of this study were the retrospective single-center design, a limited study cohort, a relatively short follow-up period and lack of measurement of other specific inflammatory markers such as cytokine levels. However, the use of PSM analysis led to a balanced the baseline of each variable which is of great influence on survival outcomes of UCB and prevented a biased evaluation of the prognostic value of AGR for UCB patients. Thus, our findings further suggested that low AGR presents to be an independent risk factor for the survival outcomes of UCB patients.
| > Conclusion|| |
The utilization of PSM analysis further confirmed that low AGR is an independent risk factor for survival outcomes of UCB patients, including OS, PFS, and TSS. Moreover, AGR is a potential biomarker of great value in improving pretreatment risk stratification of UCB patients.
We would like to thank all of the treating physicians of Peking University First Hospital for allowing us to include their patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]