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Systemic Inflammatory Response Based on Neutrophil-to-Lymphocyte Ratio as a Prognostic Marker in Bladder Cancer

A growing body of evidence suggests that systemic inflammatory response (SIR) in the tumor microenvironment is closely related to poor oncologic outcomes in cancer patients. Over the past decade, several SIR-related hematological factors have been extensively investigated in an effort to risk-stratify cancer patients to improve treatment selection and to predict posttreatment survival outcomes in various types of cancers. In particular, one readily available marker of SIR is neutrophil-to-lymphocyte ratio (NLR), which can easily be measured on the basis of absolute neutrophils and absolute lymphocytes in a differential white blood cell count performed in the clinical setting. Many investigators have vigorously assessed NLR as a potential prognostic biomarker predicting pathological and survival outcomes in patients with urothelial carcinoma (UC) of the bladder. In this paper, we aim to present the prognostic role of NLR in patients with UC of the bladder through a thorough review of the literature.


Introduction
Cancer is a leading cause of morbidity and mortality presenting multifactorial features affected by a variety of factors, including tumor-related and host (patient)-related factors. Until recently, predicting outcomes in cancer patients have mainly depended upon tumor characteristics, such as pathologic tumor stage and tumor grade. However, various hostrelated factors, including weight loss (cachexia), performance status, and systemic inflammatory response (SIR), have been suggested as potential prognostic indicators in cancer patients.
UC is the second-most frequently diagnosed urologic malignancy. Clinical outcomes vary. A majority of UCs (90∼ 95%) originate in the bladder, and UC of the UUT only accounts for 5∼10% of all UCs. Radical cystectomy (RC) and radical nephroureterectomy (RNU), respectively, are applied 2 Disease Markers as the gold standard local treatment for muscle-invasive or high-risk, non-muscle-invasive UC of the bladder and UUT. However, in spite of these aggressive local approaches, longterm prognosis remains poor due to disease recurrence accompanied by local and/or distant metastasis [61][62][63]. These poor outcomes suggest a need for ongoing risk stratification and proper selection of multimodal treatment approaches, such as chemotherapy in the neoadjuvant or adjuvant setting. To address these issues, a number of studies have explored SIR-related biomarkers as potential predictors of oncologic outcomes in UC. Among these, NLR, defined as the ratio of absolute neutrophils to absolute lymphocytes, has recently gained considerable attention as a biomarker in urothelial carcinoma (UC) arising from the bladder or upper urinary tract (UUT).
In this paper, we reviewed the clinical studies dealing with SIR-related biomarkers in association with oncologic outcomes in UC, with a special focus on NLR.

SIR-Based Prognostic Scoring System
Potential hematological biomarkers representing SIR in cancer patients include C-reactive protein (CRP), albumin, Glasgow Prognostic Score (GPS), modified GPS (mGPS), and neutrophil-to-lymphocyte ratio (NLR). The association of these SIR-related biomarkers with oncological outcomes has been extensively studied by many investigators in many types of nonurologic cancers (Table 1). Because hematological tests are routinely performed in most cancer patients, these biomarkers may be used as easily measurable, objective, reproducible, robust, and inexpensive parameters able to express the severity of SIR in cancer patients.
CRP is a nonspecific but sensitive marker of the acute phase response and is expressed in selected tumor cells [64]. The biological basis for the correlation between expression of this marker, cancer risk, outcome, and survival is not completely understood. Several proinflammatory cytokines, such as interleukin-1 (IL-1), IL-6, and TNF-a, expressed by the tumor environment induce CRP synthesis from the liver and other tissues [1,2]. Based on many recent studies, it is now widely accepted that an elevated CRP value is a reliable indicator of poor prognosis in a variety of types of cancers [4,8,14,16,23,28,29,31,32,65,66].
Serum albumin, another marker of acute phase response to an inflammatory state, is generally used to assess nutritional status, severity of disease, disease progression, and prognosis [64]. Malnutrition and inflammation suppress albumin synthesis. In an adult, the normal range of serum albumin level is 3.5-5.0 g/dL. When levels drop below 3.5 g/dL, the condition is called hypoalbuminemia. The lower serum albumin concentration may be due to the production of cytokines such as IL-6, which modulate the production of albumin by hepatocytes [64]. Alternatively, TNF-a may increase the permeability of the microvasculature, thus allowing an increased transcapillary passage of albumin. Presence of micrometastatic tumor cells in the liver may induce the Kupffer cells to produce a variety of cytokines (IL-1, IL-6, and TNF-a), which may modulate albumin synthesis by hepatocytes [1,2]. Thus, hypoalbuminemia is uncommon in earlystage cancer but as the disease progresses, albumin levels drop significantly and serve as good prognostic indicators in patients with various cancers [7,19,22,67].
GPS and mGPS are inflammation-based prognostic scores developed by combining CRP and albumin to predict the clinical outcomes in cancer patients [68,69]. GPS and mGPS, as routinely available, easily measured, and well standardized worldwide hematologic biomarkers, have subsequently been the subject of prognostic studies in wide variety of operable [13,15,18,25,27,34] and inoperable [9,10,17,20,33] cancers. Indeed, these scoring systems have been extensively validated in various clinical scenarios and are now recognized to have prognostic value independent of tumorbased factors, such as pathologic tumor stage, tumor grade, lymphovascular invasion, and lymph node involvement.
It is also well recognized that SIR is related to changes in circulating white blood cells, especially an abnormal increase in neutrophils (neutrophilia) along with an abnormal decrease in lymphocytes (lymphocytopenia) [2,64]. In light of this phenomenon under inflammatory conditions, NLR, being the ratio of neutrophils to lymphocytes, has gained considerable interest over the past decade not only as a potential prognostic factor associated with outcomes in a variety of cancers but also as a means of refining risk stratification of patients to treatment and predicting survival rates.

SIR in Bladder Cancer
Prognosis in bladder cancer utilizes the same factors utilized for other types of cancers, including tumor-related factors, such as tumor stage, grade, lymphovascular invasion (LVI), and lymph node involvement (LNI) [61,63]. However, all of these factors feature postoperative parameters. Given that SIR-related hematological biomarkers are easily obtained through pretreatment routine blood examination and have provided reliable prognostic information in other types of cancers, these biomarkers have been investigated in risk stratification for recurrence and mortality of patients with bladder cancer in both pre-and posttreatment settings. Several clinical studies have found an association between SIR-related hematological biomarkers, including CRP, albumin, and GPS, and oncologic outcomes of UC of the bladder (Table 3). In each different treatment setting, elevated CRP, defined as different cut-off (1.0 or 0.5 mg/dL),was significantly related to worse cancer-specific-survival (CSS) [35,36]. One study demonstrated that in muscle-invasive bladder cancer (MIBC) patients with elevated CRP levels showed significantly more adverse pathologic features, such as extravesical disease (≥pT3), larger tumor size, lymph node involvement, and positive surgical margin prior to undergoing RC compared to patients with normal CRP levels. In addition, one-unit elevation in pre-RC CRP levels was significantly associated with a 20% increased risk of cancer-related death after RC [37]. In inoperable advanced bladder cancer, hypoalbuminemia and GPS 2 measured prior to chemotherapy were independently associated with shortened progression-free survival (PFS) and overall survival (OS), respectively [39]. Recently, Ku et al. developed a nomogram incorporating albumin, lymphocyte count, and platelet count to predict the probability of 5year OS and disease-specific survival (DSS) after RC that demonstrated higher predictive accuracy than the existing staging system [46].

NLR in Non-Muscle-Invasive Bladder Cancer (NMIBC)
To date, few studies have assessed the association between NLR and the prognosis of NMIBC initially treated with transurethral resection of the bladder tumor (TURBT). Indeed, the evaluation of the prognostic role of NLR has been conducted with focus on MIBC patients undergoing RC or a mixed cohort of muscle-invasive and non-muscle-invasive tumors ( Table 2). One recent study assessed the predictive value of preoperative NLR in 107 patients initially diagnosed with NMIBC following TURBT [47]. When applying each different cut-off point for NLR using the standardized cutoff finder algorithm, NLR > 2.41 and NLR > 2.43 were significantly associated with unfavorable disease progression and recurrence. Owing to the limited sample size of this study, further studies will be required to validate the role of NLR as a predictor for recurrence and progression in NMIBC.

NLR in Muscle-Invasive Bladder Cancer (MIBC)
In the past five years, the prognostic role of NLR in MIBC has been actively investigated in association with various oncological outcomes, including pathologic outcome, post-RC recurrence, and survival (Table 2). Several studies evaluated the association between NLR and post-RC survival outcomes [38,40,41,44]. The cut-off point chosen to define an elevated NLR differed across studies, ranging from 2.5 to 3. Although one study reported no significant association between elevated NLR and OS [40], elevated NLR has been regarded as an independent predictor of RFS (recurrence-free survival), OS, and CSS in most studies [38,41,44]. One study reported that higher NLR values were observed in MIBC patients compared with NMIBC patients [42]. In addition, several studies demonstrated a significant correlation between a higher NLR and adverse pathologic outcomes, such as larger tumor size, pathological upstaging to locally advanced disease (pT3), and LNI after RC [41][42][43][44]. In locally advanced MIBC treated with neoadjuvant chemotherapy (NACH) prior to RC, continuous NLR decrease from before NACH to before RC was observed only in patients showing a pathological response after RC; therefore, sustained NLR decrease during NACH was suggested as a potential surrogate marker reflecting the effect of NACH [48]. The aforementioned studies mainly dealt with the prognostic value of NLR in the pretreatment setting. Interestingly, one recent study elucidated the influence of posttreatment NLR measured in the early post-RC period on oncologic outcomes [45]. The cut-off point of pre-and post-RC NLR (2.1 and 2.0, resp.) was differently determined according to each receiver operating characteristics (ROC) curve analysis. Similar to the aforementioned study results, elevated NLR after RC was also significantly associated with adverse pathologic outcomes, such as pT3/T4 disease, LVI, and LNI, and was an independent predictor of OS and CSS. Moreover, patients with perioperative continuous elevated NLR (2.1 ->2.0) showed worse OS and CSS compared with other change groups. Therefore, pre-and posttreatment NLR might have prognostic value in predicting postoperative survival outcome in patients with MIBC.

NLR in Upper Urinary Tract Urothelial Carcinoma (UTUC)
Similar to bladder cancer, the prognostic significance of other SIR-related hematological biomarkers, including CRP, albumin, and neutrophil count, has been proven to be reliable in terms of predicting adverse pathologic and survival outcomes following definitive surgery in UTUC [49,51,52,55,58]. In recent years, the prognostic role of NLR has also been vigorously assessed in UTUC [50,53,56,57,60] ( Table 3). Although all of the studies involved cohorts of patients with operable UTUC, the threshold to determine elevated NLR levels was not uniform, ranging from 2.5 to 3. However, irrespective of the choice of NLR threshold, elevated NLR over the threshold was consistently correlated with adverse postoperative pathologic findings (high tumor grade, advanced tumor stage, LVI, and LNI) and worse survival outcomes following RNU.

Clinical Implications of SIR in Bladder Cancer
NMIBC can primarily be treated with TURBT. However, frequent recurrence (50∼70%) and progression (10∼20%) rates after TURBT are a major concern [61,73]. Management of NMIBC might involve lifelong surveillance and place a considerable economic burden on patients. Currently, cystoscopy is the standard of care during the surveillance period. It is, however, invasive, and repeated cystoscopic examinations can cause substantial discomfort and pain to patients. Although investigators have developed various models to predict recurrence and progression after TURBT for NMIBC including nomogram, scoring systems, and risk tables [74][75][76][77], these models mainly incorporated tumor-related factors, such as tumors number, tumor diameter, T category, World Health Organization (WHO) tumor grade, and carcinoma in situ (CIS). Considering the significant correlation of elevated NLR with disease recurrence and progression in NMIBC [47], the addition of NLR to the existing prediction model may contribute to more accurate stratification of patients with NMIBC according to risk of recurrence and progression. Also, according to risk stratification based on pretreatment NLR values, selective cystoscopic examination and additional treatment, including intravesical Bacillus Calmette-Guérin (BCG) immunotherapy or chemotherapy, will be possible 6 Disease Markers     in patients with high-risk NMIBC, thereby reducing their economic burden and the potential discomfort caused by repeated cystoscopy. In terms of MIBC, one significant challenge has been the limited, pretreatment, risk-stratification data that exists for patients undergoing RC. The well-established risk factors for recurrence and survival in MIBC included tumor-related factors, including pathologic tumor stage, pathologic tumor grade, CIS, LVI, and LNI [78][79][80]. Moreover, most predictive models (nomogram) predicting recurrence and survival in bladder cancer have been heavily based on postoperative pathologic factors, such as pathologic tumor stage, pathological grade, LVI, and LNI [81][82][83], with minimal consideration for associated host-related factors. Meanwhile, the accuracy of clinical staging in bladder cancer remains poor, reporting upstaging rate of 50% at RC specimen [84]. Thus, not enough data exists to facilitate appropriate patient counseling and guide clinical trial enrollment. As such, it is required to identify biomarkers that can assist with preoperative patient risk stratification and counseling. To achieve these goals, SIR-related hematological biomarkers can be a potential and promising factor. Assessment of SIR-related biomarkers in bladder cancer may be particularly relevant, because the inflammatory process seems to play an important role in the genesis and progression of, as well as mortality from, bladder cancer [1,2]. Based on the previous study result [43], demonstrating a significant association between pretreatment elevated NLR and pathologic upstaging after RC, the performance of early cystectomy or NACH prior to RC might be considered in patients with pretreatment high NLR to attain tumor downstaging and improve postoperative survival. In addition, the pattern of change in NLR during NACH will be a valuable surrogate marker for monitoring and predicting pathological response to NACH [48]. Several studies reported the incorporation of SIR-related hematological biomarkers, such as CRP, NLR, albumin, and lymphocyte and platelet count, with a predictive model for survival outcomes in MIBC [37,38,46] or UTUC [50,55,57], improved predictive accuracy of the model, and consequently discriminated patients well according to risk stratification. It follows that pretreatment evaluation of NLR will be helpful in counseling patients about their prognosis.
A recent study revealed that the NLR value measured during the early postoperative period (from 1 to 3 months) after RC had a significant correlation with adverse oncological and survival outcomes [45]. Thus, postoperative NLR and the pattern of NLR change in the perioperative period may also provide valuable information in determining which patients should be referred for additional multimodal treatment, such as radiation and adjuvant chemotherapy.
The limitations of current NLR-associated studies in cancer are as follows. First, as mentioned earlier, there was no uniform cut-off point for NLR; each threshold was adopted according to a variety of statistical methodologies. Unlike tumor-related prognostic factors, including pathologic tumor stage and grade, NLR as a host-related factor can be affected by a variety of physiologic conditions, such as patients' comorbidities (hypertension and diabetes mellitus) and type of cancer, which can trigger immune response to cancer so that the establishment of definite NLR threshold may be difficult in consideration of these changeable physiologic conditions among cancer patients. Second, nearly all of the studies were both clinical and retrospective. Further largescale prospective clinical or experimental animal (preclinical) research using a unified and robust statistical methodology will be required to determine the definite cut-off value of NLR and to discover the biological mechanisms supporting the correlation between NLR and oncologic outcomes in cancer patients.

Conclusion
Elevated NLR has shown a significant association with adverse oncologic and survival outcomes in patients with UC. Thus, NLR as a potential marker of SIR may become a promising tool in the management of patients with UC of the bladder and UUT, in terms of improved risk assessment for prognosis and guidance for treatment. Moreover, the ease and convenience of routine blood examinations in the clinical setting mean that NLR can be an objective, inexpensive, reproducible, and cost-effective measurement for the prediction of prognosis in UC. However, current NLRrelated studies have not applied uniform NLR thresholds and thus require cautious interpretation because of many statistical methodological limitations. For the introduction of NLR into the clinical practice, rigorous attempts should be made in proper prospective study design.