Preoperative Anemia and Low Hemoglobin Level Are Associated With Worse Clinical Outcomes in Patients With Bladder Cancer Undergoing Radical Cystectomy: A Meta-Analysis

doi:10.1016/j.clgc.2016.08.017

Clinical Genitourinary Cancer

Volume 15, Issue 2, April 2017, Pages 263-272.e4

https://doi.org/10.1016/j.clgc.2016.08.017 Get rights and content

Abstract

Purpose

The aim of this study was to determine the effect of preoperative anemia status and hemoglobin level on clinical outcomes in patients with bladder cancer undergoing radical cystectomy.

Materials and Methods

A systematic review of literature with meta-analyses of predefined outcomes based on a search of PubMed and EMBASE was performed. Hazard ratios (HRs) measuring the association between preoperative anemia/hemoglobin and all-cause mortality, cancer-specific mortality, and disease recurrence were calculated with random effects model. Study heterogeneities were quantified by I² tests. Publication bias was assessed with funnel plots.

Results

A total of 17 studies evaluating the impact of preoperative anemia status (categorical, 11 studies) and hemoglobin level (continuous, 7 studies) on clinical outcomes were included. The cutoff value of anemia varied among studies (10.5-13.5 g/dL for male, 10.5-13.4 g/dL for female). Meta-analyses showed that compared with non-anemia, anemia was associated with increased all-cause mortality (HR, 1.75; 95% confidence interval [CI], 1.48-2.05; P < .00001; I² = 30%), cancer-specific mortality (HR, 1.80; 95% CI, 1.45-2.25; P < .00001; I² = 26%), and disease recurrence (HR, 1.37; 95% CI, 1.16-1.62; P = .0002; I² = 9%). Meta-analyses showed that higher level of hemoglobin was associated with decreased all-cause mortality (HR, 0.90; 95% CI, 0.87-0.92; P < .00001; I² = 13%), cancer-specific mortality (HR, 0.90; 95% CI, 0.85-0.95; P = .0003; I² = 61%), and disease recurrence (HR, 0.95; 95% CI, 0.91-0.99; P = .01; I² = 53%). No obvious publication bias was observed.

Conclusions

Preoperative anemia and low hemoglobin level are associated with earlier recurrence and shorter survival of patients with bladder cancer undergoing radical cystectomy. However, well-designed prospective studies with large sample size and limited confounding factors are needed to confirm and update our findings.

Introduction

Bladder cancer is a major health problem in the United States. In 2016, an estimated 76,960 new cases of bladder cancer will be diagnosed, and 14,880 patients will die from the disease.¹ Level 1 evidence supports the use of neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) with pelvic lymph node dissection (PLND) for patients with muscle-invasive bladder cancer (MIBC).² However, the 5-year survival rate after RC only ranges from 40% to 60%.³ Treatment decision-making for MIBC is of great significance but sometimes challenging. More specifically, clinical, radiologic, and pre-RC pathologic information has significant accuracy limitations and currently is a limitation for optimal clinical decision making.4, 5, 6 There is still a glaring need to identify other potential prognostic markers, in particular, preoperative ones, to improve the stratification of patients with MIBC.

Recently, there has been increasing interest in the prognostic role of hematologic biomarkers in patients undergoing RC. Neutrophil-lymphocyte ratio has been widely reported as an efficient biomarker to predict oncologic outcomes in patients undergoing RC for bladder cancer.7, 8, 9 Other biomarkers, including lymphocyte-monocyte ratio, lymphocyte-monocyte ratio, and platelet count, have also been reported.10, 11, 12 Most of the biomarkers focused on the leukocytes, and the prognostic role of hemoglobin have not been clearly defined. Anemia and low hemoglobin level are quite common in patients with malignant tumors, including bladder cancer.13, 14, 15 Although the number of studies exploring the prognostic role of anemia and hemoglobin level has been increasing, the results are inconsistent and often based on small samples.16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 Here, we performed a meta-analysis to pool currently available evidence on this topic and further define the prognostic role of anemia status and hemoglobin level in patients with MIBC undergoing RC.

Section snippets

Literature Search

This meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.³³ A systematic search of the literature was conducted on May 13, 2016 using the PubMed and EMBASE database. The following search strategy was employed to both PubMed and EMBASE: (radical cystectomy) AND (anemia OR hemoglobin OR hematocrit OR transfusion OR blood cell OR hematology). No restrictions on publication type, publication language, or publication year

Literature Search

Figure 1 shows the flow diagram of the selection of studies. A total of 1222 references were identified in the preliminary search. After excluding 209 duplicate publications, 1013 references were identified for screening. By reviewing the titles and abstracts, 899 references were excluded and 114 studies were identified for full-text review. After reading the full-text, 97 studies were excluded. Finally, 17 studies fulfilled the inclusion criteria and provided the data for meta-analyses.16, 17,

Main Findings

In this comprehensive meta-analysis of 17 cohort studies, we identified a possible association between preoperative anemia/hemoglobin and clinical outcomes in patients with MIBC undergoing RC. Our meta-analysis firstly shows that compared with non-anemia status, preoperative anemia is associated with increased ACM (HR, 1.75; 95% CI, 1.48-2.05), CSM (HR, 1.80; 95% CI, 1.45-2.25), and DR (HR, 1.37; 95% CI, 1.16-1.62) in patients undergoing RC. Our meta-analysis also indicates that higher

Conclusions

Preoperative anemia and low hemoglobin level are associated with earlier recurrence and shorter survival of patients with MIBC undergoing RC. However, well-designed prospective studies with large sample size and limited confounding factors are still needed to confirm and update our findings.

Disclosure

The authors have stated that they have no conflicts of interest.

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Cited by (33)

The impact of chemotherapy-naïve open radical cystectomy delay and perioperative transfusion on the recurrence-free survival: A perioperative parameters-based nomogram
2024, Asian Journal of Urology
To develop and internally validate a nomogram to predict recurrence-free survival (RFS) including the time to radical cystectomy (RC) and perioperative blood transfusion (PBT) as potential predictors.
Patients who underwent open RC and ileal conduit between January 1996 to December 2016 were split into developing (n=948) and validating (n=237) cohorts. The time to radical cystectomy (TTC) was defined as the interval between the onset of symptoms and RC. The regression coefficients of the independent predictors obtained by Cox regression were used to construct the nomogram. Discrimination, validation, and clinical usefulness in the validation cohort were assessed by the area under the curve, the calibration plot, and decision curve analysis.
In the developing dataset, the 1-, 5-, and 10-year RFS were 83.0%, 47.2%, and 44.4%, respectively. On multivariate analysis, independent predictors were TTC (hazards ratio [HR] 1.07, 95% confidence interval [CI] 1.05–1.08, p<0.001), PBT (one unit: HR 1.40, 95% CI 1.03–1.90, p=0.03; two or more units: HR 1.72, 95% CI 1.29–2.29, p<0.001), bilateral hydronephrosis (HR 1.54, 95% CI 1.21–1.97, p<0.001), squamous cell carcinoma (HR 0.60, 95% CI 0.45–0.81, p=0.001), pT3-T4 (HR 1.77, 95% CI 1.41–2.22, p<0.001), LN status (HR 1.53, 95% CI 1.21–1.95, p<0.001), and lymphovascular invasion (HR 1.28, 95% CI 1.01–1.62, p=0.044). The areas under the curve in the validation dataset were 79.3%, 69.6%, and 76.2%, for 1-, 5-, and 10-year RFS, respectively. Calibration plots showed considerable correspondence between predicted and actual survival probabilities. The decision curve analysis revealed a better net benefit of the nomogram.
A nomogram with good discrimination, validation, and clinical utility was constructed utilizing TTC and PBT in addition to standard pathological criteria.
Bloodless surgery in urologic oncology: A review of hematologic, anesthetic, and surgical considerations
2023, Urologic Oncology: Seminars and Original Investigations
Citation Excerpt :
Prospective studies on management of preoperative anemia within oncology primarily focus on colorectal cancer patients, but data remains limited in GU malignancies. High prevalence rates of preoperative anemia (∼30–45%), extensive postoperative blood transfusion rates, and association with worse clinical outcomes have most commonly been reported in patients with bladder cancer undergoing radical cystectomy [36–41]. Preoperative anemia rates are approximately 35 to 40% for patients with kidney cancer requiring nephrectomy and 8% of patients requiring radical prostatectomy [13,24,42,43].
The urologic oncology patient who refuses blood transfusion can present unique challenges in perioperative blood management. Since blood loss and associated transfusion can be expected in many complex urologic oncology surgeries, a multidisciplinary approach may be required for optimal outcomes. Through collaboration with the hematologist, anesthesiologist, and urologist, various techniques can be employed in the perioperative phases to minimize blood loss and the need for transfusion. We review the risks and benefits of these techniques and offer recommendations specific to the urologic oncology patient.
Implementation of a comprehensive prehabilitation program for patients undergoing radical cystectomy
2023, Urologic Oncology: Seminars and Original Investigations
Citation Excerpt :
This visit was scheduled to coordinate with the patient's postoperative check-up to reduce additional patient burden. Malnutrition is prevalent in patients undergoing RC, and data supporting preoperative correction of malnutrition, anemia, and vitamin deficiency is more robust [20–23]. As part of the preoperative assessment, participating patients had standardized lab work performed.
Coordinated preoperative optimization programs for radical cystectomy (RC) are limited and non-comprehensive. We evaluated the feasibility and acceptability of a coordinated, multi-faceted prehabilitation program for RC patients at a high-volume bladder cancer referral center.
We performed a narrative literature review for prehabilitation in bladder cancer management as of December 1, 2020, with specific emphasis on examining higher-level evidence sources. We selected domains with the highest level of evidence and recruited a multidisciplinary team of experts to design our program. We implemented a comprehensive prehabilitation program with a pre-defined order set as standard of care for all patients undergoing RC beginning February 1, 2021. Demographic and clinicopathologic data were collected prospectively. Rates of adherence to the prehabilitation program services were analyzed using Stata version 13.
A total of 82 patients were enrolled between February – December 2021, of which 67 (81%) had undergone RC at data cutoff. Mean age was 68 years (SD 11) and 63 (76%) identified as male. Neoadjuvant chemotherapy (NAC) was utilized in 48 (59%) patients. The mean Charlson Comorbidity Index was 3.8 (SD 2.3). 100% of patients were screened for malnutrition, with 82% consuming nutritional supplements. Fifty-two percent of patients attended physical therapy pre-op. The 30-day and 30- to 90-day rates of complications were 56% and 40%, respectively. Resource length of stay (RLOS) declined after implementation of prehabilitation.
Implementation of a comprehensive prehabilitation program at a high-volume bladder cancer referral center is feasible and has a modest effect on resource consumption and complications in our early experience.
Hemoglobin, albumin, lymphocyte, and platelet (HALP) score and cancer prognosis: A systematic review and meta-analysis of 13,110 patients
2023, International Immunopharmacology
Citation Excerpt :
Pretreatment low hemoglobin (anemia) is a common clinical feature in cancer patients and might contribute to hypoxia [49], which could drive cancer progression and therapeutic resistance [50]. Clinical studies have shown that anemia is closely related to poor survival [51–54]. In addition, serum albumin is a component of serum total proteins, and its level represents host inflammation and nutritional status [55,56].
We sought to explore the prognostic role of the hemoglobin, albumin, lymphocyte, and platelet (HALP) score on survival outcomes in patients with solid tumors by performing a systematic review and meta-analysis.
PubMed, EMBASE and Web of Science were searched for relevant articles through 02 Nov 2022. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were extracted and pooled to assess the association of the HALP score with survival outcomes in solid tumors using Stata 15.0. The primary outcome was overall survival (OS), and the secondary outcomes were cancer-specific survival (CSS) and progression/disease/recurrence-free survival (PFS/DFS/RFS).
A total of 28 studies (31 cohorts) comprising 13,038 patients were enrolled. A low HALP score was associated with decreased OS (HR, 1.61; 95 % CI, 1.44–1.81; P < 0.001), CSS (HR, 1.80; 95 % CI: 1.54–2.09; P < 0.001) and PFS/DFS/RFS (HR, 1.61; 95 % CI: 1.45–1.80; P < 0.001). The prognostic value of HALP on OS was observed across various tumor types and tumor stages. meta-regression found that tumor stage was the major source of the heterogeneity for OS.
A low pretreatment HALP score is a reliable and negative prognostic biomarker for survival outcomes in patients with cancer.
Patterns and timing of perioperative blood transfusion and association with outcomes after radical cystectomy
2021, Urologic Oncology: Seminars and Original Investigations
Citation Excerpt :
Thus, conflicting evidence on PBT and clinical outcomes may in part be due to lack of specificity of PBT timing. Other confounding factors should be considered, such as preoperative anemia, which could predispose patients to increased need for PBT, and has been associated with poor survival and recurrence outcomes in urothelial carcinoma [19]. In this manuscript, we explore the association of PBT with 90-day postoperative morbidity and oncologic outcomes among patients undergoing RC for bladder cancer.
Perioperative blood transfusion (PBT) has been associated with worse outcomes across tumor types, including bladder cancer. We report our institutional experience with PBT utilization in the setting of radical cystectomy (RC) for patients with bladder cancer, exploring whether timing of PBT receipt influences perioperative and oncologic outcomes.
Consecutive patients with bladder cancer treated with RC were identified. PBT was defined as red blood cell transfusion during RC or the postoperative admission. Clinicopathologic and peri and/or postoperative parameters were extracted and compared between patients who did and did not receive PBT using Mann Whitney U Test, chi-square, and log-rank test. Overall (OS) and recurrence-free survival (RFS) were estimated with the Kaplan Meier method. Univariate/multivariate logistic and Cox proportional hazards regression were used to identify variables associated with postoperative and oncologic outcomes, respectively.
The cohort consisted of 747 patients (77% men; median age 67 years). Median follow-up was 61.5 months (95% CI 55.8–67.2) At least one postoperative complication (90-day morbidity) occurred in 394 (53%) patients. Median OS and RFS were 91.8 months (95% CI: 76.0–107.6) and 66.0 months (95% CI: 48.3–83.7), respectively. On multivariate analysis, intraoperative, but not postoperative, BT was independently associated with shorter OS (HR: 1.74, 95% CI: 1.32–2.29) and RFS (HR: 1.55, 95%CI: 1.20–2.01), after adjusting for relevant clinicopathologic variables. PBT (intra- or post- operative) was significantly associated with prolonged postoperative hospitalization ≥10 days.
Intraoperative BT was associated with inferior OS and RFS, and PBT overall was associated with prolonged hospitalization following RC. Further studies are needed to validate this finding and explore potential causes for this observation.
Impact of anemia on the survival of patients undergoing radical cystectomy for bladder cancer
2020, Actas Urologicas Espanolas
Evaluar la prevalencia de anemia preoperatoria y su impacto sobre los resultados oncológicos de pacientes intervenidos de cistectomía radical (CR) por tumor vesical.
Estudio retrospectivo de 176 CR realizadas entre mayo de 2008 y julio de 2018 en un mismo centro. La anemia fue definida según los criterios de la OMS (hemoglobina < 130 mg/dl en hombres y < 120 mg/dl en mujeres). Mediante el método de Kaplan-Meier analizamos la supervivencia global, la supervivencia específica de cáncer y la supervivencia libre de recurrencia. Utilizamos la regresión logística multivariante para identificar los factores pronósticos de mortalidad global.
Del total, 89 (50,6%) pacientes eran anémicos preoperatoriamente y 44 de ellos (49,4%) recibieron quimioterapia neoadyuvante. Los pacientes anémicos tuvieron un ASA mayor (ASA > 2: 54,6 vs. 27,5%, p = 0,003), más ectasia prequirúrgica (41,6 vs. 19,5%; p = 0,002), peor estadio patológico (pT > 2: 49,4 vs. 33,3%; p = 0,03), realizaron más quimioterapia neoadyuvante (49,4 vs. 19,5%; p < 0,001) y requirieron más transfusiones sanguíneas (25,8 vs. 11,5%; p = 0,015). La mediana de seguimiento fue de 27,2 meses (RIC 11,12-72,28). La supervivencia global (105 vs. 34 meses; p = 0,001), la supervivencia específica de cáncer (89 vs. 61 meses; p = 0,004) y la supervivencia libre de recurrencia (85 vs. 57 meses; p = 0,002) fueron peores en las CR anémicas. En el estudio multivariante, la anemia, un estadio pT > 2 y tener afectación ganglionar fueron identificados como factores predictores independientes de mortalidad.
La anemia previa a CR es común y asocia un peor pronóstico oncológico. Siendo esta una variable modificable, la implementación de programas de Patient Blood Management durante la prehabilitación puede tener un papel importante para mejorar la supervivencia de estos pacientes.
To evaluate the prevalence of preoperative anemia and its effect on oncological outcomes in patients undergoing radical cystectomy (RC) due to bladder cancer.
Retrospective single-center study with 176 RCs between May 2008 and July 2018. Anemia was defined according to the WHO classification (male < 130 mg/dL, female < 120 mg/dL). Kaplan-Meier test was used to estimate recurrence-free, cancer-specific and overall survival rates. Multivariate logistic regression was used to identify factors associated with overall mortality rates.
Overall, 89 (50.6%) patients had preoperative anemia, and 44 of them (49.4%) received neoadjuvant chemotherapy. Anemic patients resulted in higher rates of ASA (ASA > 2: 54.6 vs. 27.5%; P = .003), ectasia rate previous to RC (41.6 vs. 19.5%; P = .002), treatment with neoadjuvant chemotherapy (49.4 vs. 19.5%; P < .001), blood transfusion rate (25.8 vs. 11.5%; P = .015) and pathological stage (pT > 2: 49.4 vs. 33.3%; P = .03) compared to non-anemic patients. Median follow-up was 27.2 months (IQR 11.12-72.28). Median overall survival (105 vs. 34 months, log-rank; P = .001), cancer-specific survival (89 vs. 61 months; P = .004) and recurrence-free survival (85 vs. 57 months; P = .002) were significantly lower in anemic patients compared to the non-anemic group. In multivariable Cox analysis, preoperative anemia, pT > 2 and N ≥ 1 were independently associated with overall mortality.
Preoperative anemia was common in patients undergoing RC for bladder cancer, and it is related with a worse cancer prognosis. Anemia is a preoperative modifiable factor; we believe that the implementation of Patient Blood Management programs during prehabilitation may have a relevant role in improving the oncological outcomes in these patients.

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Original StudyPreoperative Anemia and Low Hemoglobin Level Are Associated With Worse Clinical Outcomes in Patients With Bladder Cancer Undergoing Radical Cystectomy: A Meta-Analysis

Abstract

Purpose

Materials and Methods

Results

Conclusions

Introduction

Section snippets

Literature Search

Literature Search

Main Findings

Conclusions

Disclosure

Eur Urol

Eur Urol

Eur Urol

Eur Urol

Urol Oncol

Clin Oncol (R Coll Radiol)

Cancer Treat Commun

Urology

Clin Genitourin Cancer

Urol Oncol

Urol Oncol

Urol Oncol

Clin Genitourin Cancer

J Urol

Clin Genitourin Cancer

Urology

Ann Oncol

Cancer statistics, 2016

CA Cancer J Clin

Clinicopathological outcomes after radical cystectomy for clinical T2 urothelial carcinoma: further evidence to support the use of neoadjuvant chemotherapy

BJU Int

Discrepancy between clinical and pathologic stage: impact on prognosis after radical cystectomy

Eur Urol

Identification of the best complete blood count-based predictors for bladder cancer outcomes in patients undergoing radical cystectomy

Br J Cancer

Pretreatment parameters obtained from peripheral blood sample predicts invasiveness of bladder carcinoma

Urol Int

Original Study
Preoperative Anemia and Low Hemoglobin Level Are Associated With Worse Clinical Outcomes in Patients With Bladder Cancer Undergoing Radical Cystectomy: A Meta-Analysis