Stesura Seveso Archivio Italiano di Urologia e Andrologia 2025; 97(2):13880 1 REVIEW the patient’s tumor stage, grade, comorbidity, and per- formance. When the disease progresses to unresectable, locally advanced, or metastatic UCs (mUC), the adminis- tration of systemic therapy is generally recommended (3). For many years, cisplatin-based cytotoxic chemotherapy has been the standard treatment for mUC. However, as the disease advances, up to 50% of patients requiring chemotherapy may be considered unfit for cisplatin- based treatment due to the presence of comorbidities (4). Recently, immunotherapy using immune checkpoint inhibitors have emerged as alternative treatment options for individuals with mUC (5). One notable example of this class of drugs is pembrolizumab, a PD-1 inhibitor agent that functions by inhibiting the interaction between programmed cell death protein-1 (PD-1) and its ligand (PD-L1) (6). Numerous ongoing studies are investigating these agents as first- and second-line therapies, both alone and in combination with chemotherapy or in a maintenance regimen, thereby signaling their steadily increasing importance (7). Consequently, the European Association of Urology (EAU) has recently recommended the use of Enfortumab vedotin (EV) in combination with pembrolizumab as a first-line treatment for patients considered suitable for combination therapies, irrespective of their cisplatin eligibility, which significantly reduces treatment-related toxicity (3, 8). Despite these recommendations, EV may not be accessible in various countries. Furthermore, certain patients may be ineligible for EV treatment, including those with uncon- trolled diabetes, peripheral neuropathy, and significant skin disorders (9). Therefore, for this patient population - comprising those who are either (1) ineligible for combi- nation therapy or EV, (2) eligible for combination therapy but without access to EV, or (3) ineligible for both combi- nation therapy and unfit for platinum-based chemothera- pies - there exists uncertainty concerning the optimal treat- ment options available to them. For patients who are inel- igible for platinum-based chemotherapies, current guide- lines recommend assessing PD-L1 positivity status through immunohistochemistry. The European Medicines Agency (EMA) has approved pembrolizumab and atezolizumab for first-line treatment in patients with positive PD-L1 stain- ing, while the U.S. Food and Drug Administration (FDA) has Introduction: Recent studies have shown the therapeutic benefits of pembrolizumab in locally advanced or metastatic urothelial carcinoma (mUC). However, its high cost and variable patient responses remain challenges. This study aims to investigate the prognostic value of pre-treatment hematologic and clinical parameters in predicting outcomes in mUC patients. Methods: A comprehensive search was conducted across five databases for relevant articles. Studies that assessed the rela- tionship between pre-treatment hematological and clinical parameters and either progression free survival (PFS) or overall survival (OS) were included and evaluated for bias. Results: The literature search identified 27 studies encompassing a total of 4,731 patients. Several prognostic factors linked to OS were identified, with the most adverse survival outcomes associ- ated with hypoalbuminemia (HR 3.13, 95% CI: 2.52-3.88), ECOG-PS ≥2 (HR 2.94, 95% CI: 2.65-3.26), and the presence of liver metastasis (HR 2.44, 95% CI: 2.16-2.76). Additionally, the presence of bone, liver, or lung metastases, ECOG-PS ≥ 2, surgi- cal excision of the primary tumor, elevated C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR), and low hemo- globin levels were all correlated with unfavorable PFS and OS. Conclusions: Patients with metastatic urothelial carcinoma and poor performance status, visceral metastases, high NLR or CRP, or low hemoglobin may have poorer survival, even with pem- brolizumab. These factors may help guide clinical decisions for patients with advanced/metastatic urothelial carcinoma. KEy wORDS: Urothelial; Pembrolizumab; Survival. Submitted 9 April 2025; Accepted 14 April 2025 INTRODUCTION Urothelial carcinoma (UC), also known as transitional cell carcinoma, is a type of cancer that originates in the urothelium. UC includes all tumors found in the bladder, upper urinary tract (including the renal pelvis and ureters), and proximal urethra, with bladder cancer con- stituting approximately 90% to 95% of these cases (1). It is the second most prevalent urological malignancy in men, with an estimated global mortality exceeding 200,000 (2).Current treatment options are dependent on Predicting outcomes with pembrolizumab: A meta-analysis of pre-treatment hematological and clinical prognostic factors in advanced/metastatic urothelial carcinoma Kevin Yuwono 1, Junjungan Nimasratu Rahmatsani 1, Nadhifah 1, Revina Maharani 2, Zakaria Aulia Rahman 3 1 Faculty of Medicine, Airlangga University, Indonesia; 2 Faculty of Medicine, Brawijaya University, Indonesia; 3 Department of Urology, Faculty of Medicine, Airlangga University, Indonesia. DOI: 10.4081/aiua.2025.13880 Summary Archivio Italiano di Urologia e Andrologia 2025; 97(2):13880 K.. Yuwono, J. Nimasratu Rahmatsani, Nadhifah, et al. 2 approved pembrolizumab for use regardless of PD-L1 sta- tus (3). Despite these recommendations, the historical out- comes for this patient group have been unfavorable. Often, best supportive care is preferred over systemic therapy. This highlights the need for a biomarker to better predict which patient populations will benefit from these treat- ments. Several biomarkers have been proposed, including PD-L1 expression (10), tumor mutational burden (TMB), microsatellite instability (MSI), and mismatch repair defi- ciency (11). However, these biomarkers have been found to lack sufficient predictive accuracy. By systematically reviewing existing literature, we aim to identify the several hematological and clinical parameters that can better pre- dict the population of mUC patients who are likely to ben- efit from pembrolizumab monotherapy. METHODS This systematic review followed PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and the Cochrane handbook for systemat- ic reviews of interventions. Our full protocol was registered in PROSPERO (registration number CRD42024608476). Search strategy A systematic literature data search was conducted in PubMed, Scopus, ProQuest, Cumulative Index to Nursing and Allied Health Literature (CINAHL) via EBSCO, and Cochrane Central Register of Controlled Trials (CENTRAL) for studies published up to November 2, 2024. We addi- tionally performed a manual hand-search on Google and the reference lists of the included studies to maximize the search results. The following main keywords were initially established: “pembrolizumab”, “urothelial carcinoma”, along with prognostic factors such as “hemoglobin”, “neutrophil”, “c reactive protein” and “lactate dehydrogenase”. We subse- quently added several Medical Subject Headings (MeSH) and other free-text terms to construct database-specific search terms. The full search strings for each database are provided in Supplementary Table S1. No publication date and language restrictions were set in all searches. Eligibility criteria We included clinical studies that examined the associa- tion between hematological parameters and outcomes in patients with advanced/metastatic UCs. To be included in this systematic review and meta-analysis, studies had to meet the following criteria: (1) the study population con- sisted of adults aged 18 years or older; (2) the study exclusively included UC patients receiving pembrolizum- ab monotherapy; (3) it assessed the relationship between prognostic factors and outcomes; and (4) it was either a clinical trial or an observational study (case-control or cohort studies). We accepted studies published in any language. Studies were excluded if: (1) the study was a review article, case report, case series, or conference abstract; (2) the full-text was irretrievable; or (3) raw data could not be separated. Data extraction and quality assessment Two independent investigators performed data extraction from each included study and recorded it within the pre- specified form, with discrepancies resolved by the con- sensus with an independent third investigator. The data extracted include the name of the first author and year of publication, study location (country and region), study design, sample size, pembrolizumab dose used, patients characteristics (age, sex), follow up duration, clinical characteristics (ECOG PS ≥ 2, site of primary tumor, metastatic sites), overall response rate (ORR), and relation- ship between prognostic factor and outcomes. Risk of bias assessment For the risk of bias assessment, Quality in Prognosis Studies (QUIPS) tool was used to assess the methodological quali- ty of each study and subsequently judged to be yielding low, moderate, or high risk of bias (12). The visualization of the bias assessment’s summary was generated using the Robvis tool (13). The methodological quality assessment of the included studies was conducted by two independent reviewers (NDF and JNR). Discordance in judgements was resolved simultaneously in a consensus with a third reviewer (KYU). We planned to conduct a funnel-plot and Egger’s test to assess the possibility of publication bias across studies. Statistical analysis For the primary outcome of overall survival, we reported pooled hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs). The initial quantitative synthesis was performed by comparing each prognostic factor, applying the generic inverse variance method within a DerSimonian-Laird fixed-effects model. In cases where significant heterogeneity was detected, a random-effects model was subsequently applied. In the case where two or more studies involved overlapping populations, analy- sis was prioritized to studies with larger sample sizes. The presence of heterogeneity was analyzed using Cochran’s Q and I2 statistics, where heterogeneity was classified as negligible, low, moderate, or high to I2 values of 0%, 25%, 50%, and 75%, respectively (14). Whenever appropriate (n ≥ 10), potential publication bias was eval- uated visually by contour-enhanced funnel plot and quantitatively by Egger’s and Begg’s tests. Whenever available, subgroup analyses were carried out based on the risk of bias. On the other hand, sensitivity analyses were conducted by leave-one-out analysis and the exclusion of studies with high-risk of bias. Meta- regression analyses were carried out for (1) year of publi- cation, (2) % of males, (3) sample size; (4) mean age, (5) % of upper tract primary tumor site, and (6) follow up duration whenever possible. All analysis was conducted with R ver. 4.3.0 (R Foundation for Statistical Computing, Vienna, Austria). Conventional meta-analysis was con- ducted using the meta package, while meta-regression analyses were performed using the metafor package. RESULTS Study selection A PRISMA flowchart of the study selection process is depicted in Figure 1. Initial searches of the five databases yielded 4449 records. We identified duplicates, and a Archivio Italiano di Urologia e Andrologia 2025; 97(2):13880 3 Pembrolizumab in advanced/metastatic urothelial carcinoma total of 577 records were removed. Of the remaining 3872 records, 3818 records were excluded. One confer- ence abstract with unavailable full-text and six other arti- cles were not retrieved. We then thoroughly reviewed forty-seven studies and further excluded twenty-one studies, due to the following: (1) combined with other chemotherapies (n = 10), missing outcome of interest (n = 7), data cannot be extracted (n = 3), and use of intravesical pembrolizumab (n = 1). Ultimately, the entire screening process led to the inclusion of twenty-six eligi- ble studies in this systematic review. Study characteristics In our review, we analyzed a total cohort of 4,679 patients, with a median age ranging from 68.9 to 76 years. Among the total population, 3,092 patients were male, accounting for 71.5% of the participants. The majority of the research was conducted in Japan, with only one study taking place in the Netherlands. All stud- ies used a retrospective comparative design. The median follow-up duration was quite variable, ranging from 5.7 to 34 months. Regarding ECOG performance status (PS), five studies did not disclose the percentage of patients with PS ≥ 2, while four studies only disclosed those with a PS of ≥ 1. In total, 604 patients (18.3%) were identified with a PS of ≥ 2. Among the studies that reported primary tumor sites, 1,863 patients (43.1%) had tumors in the upper urinary tract, while 2,212 patients (51.7%) had tumors originating from the bladder. The primary out- comes of our review were ORR, PFS, and OS. The values for each outcome are further reported in Table 1. Quantitative analysis (meta-analysis) Twenty-six studies with a total sample of 4,679 patients Figure 1. PRISMA flowchart of the study selection process. Archivio Italiano di Urologia e Andrologia 2025; 97(2):13880 K.. Yuwono, J. Nimasratu Rahmatsani, Nadhifah, et al. 4 Table 1. Characteristics of included studies. No Author; Year Location Study Sample Age Male Follow up ECOG PS Site of Outcome Design size (years) duration (months) ≥ 2 Primary ORR PFS OS Tumour (%) (median) (median) 1 Akashi; 2023 (40) Japan Retrospective study 41 75 (58-81) 35 (85.4) 16.5 (1.0-47.8) 4 (10) UTUC: 16 (40) 29.3 4.9 (1.2-8.6) 17.8 (11.5-24.0) BC: 25 (60) 2 Fukata; 2022 (41) Japan Retrospective study 44 70 (54-80) 30 (68) 13.2 (1-40.8) 7 (16) UTUC: 16 (36) 54.5 NR NR BC: 28 (64) 3 Furubayashi; 2021 (42) Japan Retrospective study 105 72 (67-77) 75 (71.4) 8.4 (4.1-15.7) 10 (9.5) UTUC: 41 (39) 36.2 NR NR BC: 42 (40) Both: 22 (21) 4 Ito; 2020 (43) Japan Retrospective study 755 ECOG 0-1: 72.09 568 (75.2) 7.2 153 (20.26) UTUC: 373 (49.4) 26.2 NR NR (66.3-77.23) BC: 382 (50.6) ECOG 2: 72.01 (66.49-76.21) ECOG 3-4: 70.18 (63.5-75.72) 5 Kawashima; 2021(a) (44) Japan Retrospective study 165 73 (28-93) 117 (70.9) 6.71 (0.26-37.0) 27 (16.3) UTUC: 99 (60) 21.8 (2.32-2.88) 2.6 NR BC: 61 (37) Both: 5 (3.0) 5 Kawashima; 2021(b) (45) Japan Retrospective study 103 73 (30-86) 76 (73.8) 6.67 (0.99-36.1) 23 (22.3) UTUC: 58 (56.3) 30.1 (1.79-5.31) 3.55 NR BC: 45 (43.7) 6 Kita; 2022 (45) Japan Retrospective study 739 NR 554 (75) 34 150 (20.3) UTUC: 352 (47.63) 27.2 3.5 NR BC: 384 (51.9) Unknown: 4 (0.4) 7 Kobayashi; 2020 (46) Japan Retrospective study 463 71 (31-88) 357 (77.1) 17.7 (12.9-21.4) 90 (19.4) UTUC: 179 (38.7) 30.5 NR 10.2 (8.2-11.7) BC: 230 (49.7) Both: 27 (5.8) Unknown: 1 (0.2) 8 Komura; 2023 (47) Japan Retrospective study 100 70.30 (9.03) 78 (78) NR NR UTUC: 18 (18) 22 NR NR BC: 77 (77) Both: 5 (5) 9 Kurashina; 2023 (18) Japan Retrospective study 75 NR NR 7.3 (0.47-47.6) NR NR 21.3 NR 8.5 (6.4-10.7) 10 Miyama; 2022 (48) Japan Retrospective study 50 71.9 (1.69) 31 (62) NR NR UTUC: 23 (46) BC: 27 (54) 30 3.62 10.97 11 Nagasaka; 2024 (49) Japan Retrospective study 48 76 (47-88) 31 (64.58) NR 2 (4.17) UTUC: 48 (100) 27.1 2.2 5.47 12 Nishio; 2024 (50) Japan Retrospective study 220 NR 154 (70) 7.3 123 (56)* UTUC: 85 (39) 29.1 NR NR BC: 135 (61) 13 Ogihara; 2020 (51) Japan Retrospective study 78 72.16 (9.29) 54 (69.23) 7.42 (0.9-17.9) 18 (23.07)* UTUC: 35 (44.9) 29.5 NR NR BC: 43 (55.1) 14 Rijnders; 2023 (52) Netherlands Retrospective study 71 NR 51 (71.8) NR NR UTUC: 21 (29.6) NR NR NR BC: 44 (61.9) Both: 6 (8.5) 15 Sato; 202353 Japan Retrospective study 101 71 (33-85) 71 (70.3) 19 (3-54) 17 (16.8) UTUC: 35 (34.7) 19.8 NR 13 BC: 66 (65.3) 16 Shimizu; 202054 Japan Retrospective study 27 71.48 (7.51) 23 (85) 7.88 (4.76) 12 (44) UTUC: 12 (44) 37.0 4 7 BC: 15 (56) 17 Tamura; 202055 Japan Retrospective study 41 68.91 ± 8.08 29 (70) 6.2 (4.4) 6 (15) UTUC: 22 (54) 14.6 2.5 (1.4-6.2) 11.9 BC: 19 (46) 18 Tanabe; 202415 Japan Retrospective study 331 73 (68-78) 241 (73) 7.3 (3.4-16.5) 57 (17) UTUC: 154 (47) 32.3 3.3 (2.6-4.3) 9.6 (7.3-13.2) BC: 177 (53) 19 Tomioka-Inagawa; 202216 Japan Retrospective study 211 72.1 (1.63) 121 (57.3) 10 28 (13.4) UTUC: 49 (23.2) 25.1 5 (3-5) 17 (15-26) BC: 89 (42.2) Archivio Italiano di Urologia e Andrologia 2025; 97(2):13880 5 Pembrolizumab in advanced/metastatic urothelial carcinoma were included for meta-analysis. Pooled PFS and OS were measured using hazard ratios (HRs). Demographic factors The demographic factors chosen for this analysis are age and gender. Among these factors, age ≥ 70-75 years old are found to be associated with worse progression free survival (HR 1.21, 95%CI 1.04-1.41, n = 8 studies). Furthermore, our investigation revealed a lack of signifi- cant heterogeneity regarding these outcomes. Clinical factors Ten clinical factors are included in this analysis, consisting of metastasis sites (bone, liver, lung, and lymph node), ECOG-PS ≥ 2, UTUC primary site, prior surgical removal for primary site, pure UC pathological type, smoking, < 90 days from previous chemotherapy (Table 2). For PFS, we detected one factor with moderate amount of heterogene- ity, which is UTUC primary site (I2 = 58%). For OS, we detected three factors with moderate to high amounts of heterogeneity, including presence of bone (I2 = 64%) or lymph node metastasis (I2 = 73%), and ECOG-PS ≥ 2 (I2 = 86%). All heterogeneity tests are performed using REM. Based on the HRs, there are six clinical factors that can be considered as prognostic factors. For PFS, five factors are linked with worse survival are as follows: (1) ECOG-PS ≥ 2 (HR 2.30, 95%CI 1.91-2.76); (2) pure UC pathological type (HR 2.33, 95%CI 1.20-4.54); (3) presence of liver metastasis (HR 1.70, 95%CI 1.35-2.14); (4) lung metasta- sis (HR 1.34, 95%CI 1.10-1.64); and (5) bone metastasis (HR 1.29, 95%CI 1.02-1.64). On the contrary, surgical removal of primary site (HR 0.80, 95%CI 0.65-0.99) is associated with better survival. Sensitivity analysis of PFS factors suggest that the provided overall effects are robust and not affected by any single study. For OS, five factors are also associated with worse survival: (1) Presence of bone metastasis (HR 1.94, 95%CI 1.25- 3.0); (2) Liver metastasis (HR 2.44, 95%CI 2.16-2.76); (3) Lung metastasis (HR 1.35, 95%CI 1.18-1.56); (4) ECOG- PS ≥ 2 (HR 3.38, 95%CI 2.17-5.28); (5) Time from previ- ous chemotherapy < 90 days (HR 1.42, 95%CI 1.22- 1.64). A leave-one-out sensitivity analysis was conducted for all prognostic factors showing significant heterogene- ity. The analysis revealed that the presence of bone metas- tasis, upon removal of one study by Tanabe et al. (15) resulted in a shift of the pooled effect from significant to nonsignificant, and significant reduction of heterogeneity. The same result is found for C-reactive protein level. In contrast, the effects of all other clinical factors remained robust (Supplementary Figures S2B, S2D). Hematological factors We identified four potential hematological markers as prognostic factors: albumin, CRP, hemoglobin, and NLR. Most outcome analyses demonstrated nonsignificant het- erogeneity, except for CRP’s association with OS, which exhibited high heterogeneity (I² = 94%). For PFS, three markers showed a significant effect: elevated CRP (HR 1.94, 95%CI 1.54-2.45), low hemoglobin (HR 1.80, 95%CI 1.51-2.14), and high NLR (HR 1.65, 95%CI 1.44- 1.89). For OS, we found four markers associated with poorer survival: hypoalbuminemia (HR 3.13, 95%CI 2.52-3.88), high CRP (HR 2.18, 95%CI 1.07-4.42), low hemoglobin (HR 2.08, 95%CI 1.85-2.35), and high NLR (HR 1.93, 95%CI 1.71-2.18). Sensitivity analysis was performed for all outcomes. For CRP, removing one study by Tomioka-Inagawa significantly reduced hetero- geneity (16), while excluding a study by Tanabe et al. made the effect size nonsignificant (15). Given this, we advise interpreting these results with caution, while all other hematological markers showed stable outcomes. Subgroup and meta-regression analyses We performed subgroup and meta-regression analyses for prognostic factors with a sufficient number of studies: (1) age, (2) gender, (3) presence of liver metastasis, (4) ECOG-PS ≥ 2, and (5) UTUC primary site associated with OS. For most factors, we found no significant differences between subgroups. For ECOG-PS, results of the sub- group analysis of risk of bias are presented in the supple- mentary materials. Meta-regression analyses on the per- centage of male (p = 0.01) suggest that this factor influ- enced the effect of ECOG-PS ≥ 2 on overall survival (Supplementary Table S3 and Figure S4). Additionally, subgroup comparisons based on risk of bias revealed no statistically significant differences in effect sizes between 20 Uchimoto; 202156 Japan Retrospective study 212 72 (8.95) 151 (71.2) 8 120 (56.6)* UTUC: 82 (38.7) 26.4 NR 11.7 BC: 130 (61.3) 21 Uchimoto; 202257 Japan Retrospective study 177 72 (66-78) 125 (70.6) 6 100 (56.5)* UTUC: 68 (38.4) 26.6 NR 14 BC: 109 (61.6) 22 Umeda; 202258 Japan Retrospective study 115 75 (70-79) 29 (65.9) 7.4 (4.6-16.4) NR UTUC: 22 (50) 25.2 NR NR BC: 21 (47.7) Both: 1 (2.3) 23 Yamamoto; 202259 Japan Retrospective study 31 74 (70-82) 22 (71) 5.7 (3.4-16.3) 3 (10) UTUC: 9 (29) 35.5 NR NR BC: 22 (71) 24 Yamashita; 202360 Japan Retrospective study 96 74 (70-79) 69 (72) 7 (4-17) 15 (15.6) UTUC: 46 (48) 23 2 NR BC: 41 (43) Both: 9 (9) Categorical data are shown as n (%), while numerical data are presented as mean (SD) or median (IQR). NR: Not reported; ECOG-PS: Eastern Cooperative Oncology Group Performance Status Scale; UTUC: Upper urinary tract urothelial carcinoma; BC: Bladder urothelial carcinoma. *ECOG PS >= 1. Archivio Italiano di Urologia e Andrologia 2025; 97(2):13880 K.. Yuwono, J. Nimasratu Rahmatsani, Nadhifah, et al. 6 studies classified as low risk versus moderate-high risk (Supplementary Figure S5). Publication bias and quality assessment of included studies For outcomes with included studies ≥ 10, we performed publication bias assessment by generating funnel plots. For overall survival, one study each by Tanabe et al. (15), Kobayashi et al. (17), and Kurashina et al. (18) appeared as outliers in the funnel plots for age, gender, and liver metastasis, respectively. In contrast, a total of three stud- ies assessing ECOG-PS fell outside the funnel plot, sug- gesting that ECOG-PS results may be particularly affected by publication bias. Nonetheless, Egger’s test did not show statistically significant bias for any of the evaluated risk factors (Supplementary Table S2 and Figure S3). Three reviewers assessed the risk of bias within individ- ual studies using the QUIPS tool, given that all the included studies were studies evaluating prognostic fac- tors (Figure 2). Among the studies reviewed, six were identified as having a high risk of bias due to attrition. All the included studies were retrospective in nature, and the high risk of attrition bias stemmed from either a lack of reporting on missing data or the exclusion of a significant portion of data (> 10%) from the final analysis. We iden- tified three studies with a moderate risk of bias, while the remaining studies had a low risk of bias. Some studies were rated as having a moderate risk of bias related to participation, primarily because they failed to report details such as the study location or the recruitment peri- od. Additionally, a few studies exhibited a moderate risk of bias due to confounding, as significant confounders were neither addressed in the study design nor adjusted for in the statistical analysis. Figure 2 and 3 provides an in-depth visualization of the risk of bias assessment for each study. Table 2. Pooled hazard ratios of demographical, clinical, and hematological factors associated with PFS and OS. Factors Definition Number Hazard ratio Heterogeneity Overall effect of studies (95%CI) I2 p-value Z-score p-value Progression free survival Demographic factors Age ≥ 70-75 years old 8 1.21 (1.04-1.41) 0 0.84 2.44 0.01 Gender Male vs. female 8 0.99 (0.84-1.17) 1 0.42 -0.14 0.89 Clinical factors ECOG-PS ≥ 2 vs. < 2 8 2.30 (1.91-2.76) 39 0.12 8.9 < 0.01 Pathological type Pure vs mixed UC 3 2.33 (1.20-4.54) 3 0.36 2.49 0.01 Liver metastasis Yes vs. no 5 1.70 (1.35-2.14) 13 0.33 4.52 < 0.01 Lung metastasis Yes vs. no 4 1.34 (1.10-1.64) 0 0.73 2.93 < 0.01 Lymph node metastasis Yes vs. no 5 0.84 (0.70-1.01) 0 0.78 -1.82 0.07 Bone metastasis Yes vs. no 3 1.29 (1.02-1.64) 0 0.89 2.12 0.03 Primary site UTUC vs BC 8 1.05 (0.73-1.52) 58 0.02 0.32 0.76 Surgical removal of primary site Yes vs. no 5 0.80 (0.65-0.99) 5 0.38 -2.07 0.04 Hematological parameters CRP High vs. low 4 1.94 (1.54-2.45) 21 0.28 5.62 < 0.01 Hemoglobin Low vs. high 5 1.80 (1.51-2.14) 0 0.69 6.52 < 0.01 NLR High vs. low 6 1.65 (1.44-1.89) 13 0.33 7.22 < 0.01 Overall survival Demographic factors Age ≥ 70-75 years old 10 1.00 (0.99-1.01) 43 0.07 0.16 0.87 Gender Male vs. female 10 0.97 (0.87-1.08) 30 0.17 -0.58 0.57 Clinical factors Bone metastasis Yes vs. no 5 1.94 (1.25-3.00) 64 0.03 4.2 0.01 Liver metastasis Yes vs. no 10 2.44 (2.16-2.76) 31 0.16 14.39 < 0.01 Lung metastasis Yes vs. no 7 1.35 (1.18-1.56) 34 0.17 4.29 < 0.01 Lymph node metastasis Yes vs. no 7 0.94 (0.67-1.33) 73 < 0.01 -0.4 0.7 ECOG-PS ≥ 2 vs. < 2 10 3.38 (2.17-5.28) 86 < 0.01 6.68 < 0.01 Pathological type Pure vs. mixed UC 5 1.17 (0.88-1.55) 21 0.28 1.07 0.29 Primary site UTUC vs BC 10 1.07 (0.97-1.18) 7 0.38 1.36 0.17 Smoking Yes vs. no 6 1.03 (0.93-1.14) 0 0.44 0.57 0.57 Surgical removal of primary site Yes vs. no 4 0.71 (0.58-0.88) 0 0.6 -3.21 < 0.01 Time from previous chemotherapy < 90d vs. ≥ 90d 4 1.42 (1.22-1.64) 0 0.66 4.66 < 0.01 Hematological parameters Albumin < 3.5-3.7 3 3.13 (2.52-3.88) 0 0.7 10.4 < 0.01 CRP High vs. low 5 2.18 (1.07-4.42) 94 < 0.01 3.05 0.04 Hemoglobin Low vs. high 8 2.08 (1.85-2.35) 23 0.24 12.05 < 0.01 NLR High vs. low 8 1.93 (1.71-2.18) 46 0.07 10.52 < 0.01 ECOG-PS: Eastern Cooperative Oncology Group Performance Status Scale; UC: Urothelial carcinoma; UTUC: Upper urinary tract urothelial carcinoma; BC: Bladder urothelial carcinoma; CRP: C-reactive protein. Archivio Italiano di Urologia e Andrologia 2025; 97(2):13880 7 Pembrolizumab in advanced/metastatic urothelial carcinoma Figure 2. Traffic plot of the included studies risk of bias assessed by QUIPS tool. Archivio Italiano di Urologia e Andrologia 2025; 97(2):13880 K.. Yuwono, J. Nimasratu Rahmatsani, Nadhifah, et al. 8 DISCUSSION Given that only a small percentage of patients derive bene- fits from immunotherapy, numerous predictive biomarkers have been developed to improve outcome predictions. Current evidence indicates that PD-L1 expression serves as the most reliable biomarker for predicting which patients with advanced UC are likely to respond to anti-PD-1 or anti-PD-L1 therapies (19-21). However, pembrolizumab monotherapy showed comparable survival to platinum- based chemotherapy regardless of PD-L1 combined positive score (CPS) (22). That is why in this study, we identified several potential hematological and clinical risk factors linked to unfavorable outcomes in patients with advanced UC receiving pembrolizumab monotherapy. The metastatic sites significantly associated with worse pro- gression free survival and overall survival are the liver, lung, and bone. Lymph nodes are the most common site of metastasis in urothelial carcinoma, with other studies reporting an incidence of 69%-90% (23). In accordance with this study, patients with lymph-node-only metastasis tend to have better PFS and OS compared to those with visceral metastases. This better prognosis may be explained by the presence of immune cells within the lymph nodes, which may enhance the efficacy of immune checkpoint inhibitors (ICIs) and other therapies. Additionally, lymph-node-only metastasis may represent an earlier stage of cancer progression, with less tumor heterogeneity or clonal evolution compared to visceral metastasis (24). In contrast, liver metastasis occurs less frequently, with an incidence ranging from 19% up to 47%, but is associated with the worst survival outcomes among metastatic sites, as this research demonstrates (25). Patients with liver metastases have a median over- all survival of only seven months, highlighting its poor prognosis compared to other metastatic patterns (26). Liver metastases are often multiple and diffuse, indicat- ing systemic disease with high tumor burden Hypotheses for the poor prognosis of liver metastases include the immunosuppressive microenvironment of the liver, increased tumor mutation burden, clonal evolution, and poor response to chemotherapy and ICIs (24, 25). Furthermore, small metastases in the liver might not be detected by imaging techniques and are only revealed later on during autopsy, such as in the study performed by Wallmeroth (27). Liver-directed therapies such as radiofrequency ablation may offer some survival benefit on top of systemic chemotherapy (26). Bone metastases are reported in 32%-47% of patients with mUC (23, 27). Recent studies have reported a higher inci- dence of bone metastases, potentially due to advanced imaging techniques like bone scintigraphy and MRI, which have improved the detection of osseous lesions. Bone metastases often coexist with other metastatic sites and contribute to significant morbidity, including pain and fractures, further complicating the disease course (23). Lung metastases, present in 37%-45% of cases, are anoth- er common manifestation of advanced urothelial carcino- ma (25). These metastases typically appear as pulmonary nodules, consolidation, or lymphangitic spread. Although lung metastases are less associated with poor survival out- comes than liver metastases, their presence often indicates advanced disease progression (25). The differences in prognosis among metastatic sites may be attributed to sev- eral factors. Organotropism and tumor biology likely play significant roles, as metastases to organs like the liver may reflect advanced clonal evolution, greater tumor hetero- geneity, and a more unfavorable tumor microenvironment (24, 25). Immune heterogeneity across metastatic sites, such as variations in tumor-infiltrating lymphocytes, PD- L1 expression, and immune response, can further influ- ence prognosis and treatment outcomes. Additionally, molecular factors, such as MTAP-deficient tumors, have been associated with an increased likelihood of visceral metastases and worse outcomes with ICIs (28). Patients with an ECOG PS of ≥ 2 are clearly at a higher risk of poor outcomes. This is particularly significant as patients with a PS > 2 are typically considered unfit for platinum-based chemotherapy. In such cases, the European Association of Urology suggests that best sup- portive care may be the most appropriate approach to optimize quality of life and minimize treatment-related harm (3). For patients with a PS of 2, careful considera- tion of additional risk factors and overall organ function is essential, e.g. glomerular filtration rate (GFR) of less than 60mL/min. This decision should be made in close collaboration with experts to ensure a tailored and bal- Figure 3. Summary plot of the included studies risk of bias assessed by QUIPS tool. Archivio Italiano di Urologia e Andrologia 2025; 97(2):13880 9 Pembrolizumab in advanced/metastatic urothelial carcinoma anced approach that takes into account the patient’s comorbidities, disease burden, and treatment goals. In contrast, patients with a PS of 0-1 represent a subgroup that may be better suited for more active treatment strate- gies. For these individuals, pembrolizumab monotherapy could be considered in two specific scenarios: (1) when enfortumab-vedotin (EFV) and platinum-based chemother- apy are unavailable, or (2) when the patient is deemed ineligible for platinum-based chemotherapy due to other contraindications. While pembrolizumab monotherapy may not be the first-line option in many cases, its role as an alternative should be weighed carefully, particularly in light of emerging evidence supporting its efficacy and safe- ty in select patient populations. In a phase II single-arm trial involving 370 participants with cisplatin-ineligible urothelial carcinoma, pembrolizumab monotherapy achieved an objective response rate of 26% among 69 patients with metastatic UTUC (29). Several prognostic blood- or serum-based parameters have been reported in advanced UCs, including CRP, LDH, platelet-to-lymphocyte ratio (PLR), and neutrophil-to- lymphocyte ratio (NLR). In our study, low hemoglobin and high NLR consistently demonstrated worse PFS and OS. Hemoglobin (HGB) level is one of the parameters that has been used as inclusion criteria in the original trials assess- ing pembrolizumab for advanced urothelial carcinoma (20). Several studies of other types of cancers have shown significantly longer OS and PFS in patients with higher HGB levels undergoing immunotherapy (30, 31). In one study, HGB levels were positively correlated with clinical outcomes in cancer patients receiving immunotherapy, but not in those not undergoing such treatment, suggest- ing a positive association between HGB levels and response to immunotherapy. Additionally, it was found that this effect was independent of other clinicopatholog- ical factors, including sex, age, tumor stage, and tumor mutational burden (TMB), as well as established bio- markers like PD-L1 expression and microsatellite instabili- ty (MSI) (32). It is thought that hypoxia induced by HGB reduction stimulates tumor growth and progression and decreases their sensitivity to anticancer treatments, even- tually contributing to poor patient outcomes (33). Pretreatment NLR and lymphocytopenia have been linked to increased mortality rates in patients with solid tumors, as well as in the general population (34, 35). This suggests that NLR is not a specific biomarker for patients with UCs. One study found that after adjusting for other prognostic factors, patients with a decrease in post-chemotherapy NLR experienced longer OS compared to those with mere- ly low pretreatment NLR levels. These findings suggest a unique association between response to 1st-line chemotherapy with efficacy of pembrolizumab treatment (17). Furthermore, a trend was observed suggesting that high NLR is associated with worse OS, particularly in metastatic diseases. This suggests either a greater tumor burden or more prolonged chronic inflammatory process (36). The mechanisms linking high NLR to poor outcomes in cancer patients remain poorly understood. Research has indicated that neutrophils, along with other cells like macrophages, secrete various factors that promote tumor growth, likely contributing to an environment that stimu- lates tumor progression (34). A range of inflammatory cytokines play a role in the systemic inflammatory response. Notably, IL-6 specifically enhances the produc- tion of acute-phase proteins, such as C-reactive protein, while simultaneously reducing albumin synthesis in the liver (37). In this review, we also identified an association between high CRP levels and hypoalbuminemia with poor OS, although this was supported by fewer studies and sig- nificant heterogeneity. Interestingly, varying cutoff points for both hemoglobin and NLR across studies were docu- mented. Despite these differences, given the relatively nar- row range of hemoglobin and NLR cutoffs used in our analysis, we do not expect this variability to significantly affect the interpretation of our findings. In our study, we found that higher CRP levels are associ- ated with worse outcomes, although there is considerable heterogeneity. This variability may be attributed to the different cutoff values used in the studies included. The relationship between CRP and cancer prognosis is a com- plex interplay of cytokines. Tumor cells release cytokines and chemokines such as IL-6 and IL-8, which result in elevated serum CRP levels. Moreover, tumor growth and invasion can cause inflammation, contributing to further rise in CRP (38). High CRP levels have also been demon- strated to cause DNA damage and weaken immune func- tion, further facilitating carcinogenesis and tumor pro- gression (39). To our knowledge, this is the first systematic review and meta-analysis that comprehensively assess prognostic value of pre-treatment hematologic and clinical parame- ters in predicting outcomes of patients with locally advanced or metastatic urothelial carcinoma. While we have made every effort to ensure the highest quality in this study, we recognize several limitations. First, the studies included in this review were quite heterogeneous, as they encompassed patients with different lines of chemothera- py. Second, most of the studies that met our inclusion cri- teria originated from Japan. These limitations underscore the necessity for standardized protocols and more rigor- ous studies to enhance our understanding of the predic- tive value of these prognostic factors in immunotherapy. CONCLUSIONS Our research revealed a number of important prognostic variables linked to survival in pembrolizumab-treated mUC patients. 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Prognostic value of the fluctuation in the neutrophil-lymphocyte ratio at 6 weeks of pem- DECLARATIONS Ethical approval: Not applicable. Consent for publication: Not applicable. Availability of data and material: All data generated or ana- lyzed during this study are included in this published article. Competing interests: The authors declare that they have no competing interests. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sec- tors. Authors' contributions: KYU: study concept, data collection, statistical analyses, manuscript original drafting; JNR: study con- cept, data collection, manuscript original drafting; NDF: study concept, data analysis, contribution to manuscript writing and editing; REV: study concept, data analysis, contribution to manu- script writing and editing; ZAR: study concept, data interpreta- tion, critical revision of manuscript.All authors have read and approved the final version of the manuscript. Acknowledgments: The authors would like to thank Dr. Zakaria Aulia Rahman for his guidance and assistance in the study. Further information: Parts of this study were presented at the 2024 Bandung Urological Meeting held in Bandung, Indonesia. Archivio Italiano di Urologia e Andrologia 2025; 97(2):13880 K.. Yuwono, J. Nimasratu Rahmatsani, Nadhifah, et al. 12 brolizumab treatment is specific to the clinical response in metastat- ic urothelial carcinoma. Urol Oncol Semin Orig Investig. 2022; 40:344.e11-344.e17. 58. Umeda K, Tanaka N, Yasumizu Y, et al. Site-Specific Differences in PD-1 Blockade Success and Biomarkers in Urothelial Carcinoma Treated with Pembrolizumab. Clin Genitourin Cancer. 2023; 21:128-35. 59. Yamamoto S, Fukushima H, Fukuda S, et al. Early cancer cachexia phenotype predicts survival of advanced urothelial cancer patients treated with pembrolizumab. Asia Pac J Clin Oncol. 2022; 18:410-8. 60. Yamashita S, Wada T, Deguchi R, et al. Prognostic significance of pre-treatment albumin-bilirubin grade in metastatic urothelial carcino- ma receiving pembrolizumab. Jpn J Clin Oncol. 2023; 53:845-50. Correspondence Kevin Yuwono yuwonokvn@gmail.com Junjungan Nimasratu Rahmatsani junjungan.nr@gmail.com Nadhifah Nadhifah nadhifahmahfudi@gmail.com Revina Maharani 10maharanirevina@gmail.com Faculty of Medicine, Brawijaya University, Indonesia Zakaria Aulia Rahman zakariaaulia04@gmail.com Department of Urology, Faculty of Medicine, Airlangga University, Indonesia Mayjen Prof. Dr. Moestopo, 47, 60131, Indonesia