Introduction
Gliomas account for ~80% of malignant brain tumors, with an incidence of 6 per 100,000 annually (1). Despite advances in treatment, prognosis remains poor, particularly for glioblastoma, with a median survival of 14–16 months (2). At present, the comprehensive treatment of glioma is based mainly on surgical resection combined with radiotherapy and chemotherapy (3). Surgery can relieve patients' symptoms, prolong survival and obtain tumor tissue to confirm the pathological diagnosis. For adjuvant therapy, the Stupp regimen-which consists of maximal safe resection, followed by concurrent radiotherapy (60 Gy in 30 fractions) with daily temozolomide (75 mg/m2), and then at least six cycles of adjuvant temozolomide (150–200 mg/m2 for 5 days every 28 days)-has been the standard treatment regimen for gliomas since 2005 (4).
Red blood cell distribution width (RDW) is a part of the complete blood count test and reflects the heterogeneity of red blood cell sizes (5). This parameter is derived using the following formula: (Standard deviation of the mean corpuscular volume/mean corpuscular volume) ×100. RDW is initially used to identify anemia, but it can also reflect the nutritional status of the body. Elevated RDW may reflect tumor-associated systemic inflammation and altered erythropoiesis, both of which are poor prognostic indicators in glioma patients (6–8). The prognostic value of RDW for some cancers including laryngeal cancer, endometrial cancer, esophageal cancer, and colorectal cancer has also been increasingly discussed (9–13). Moreover, previous studies have reported that a high RDW is associated with poor outcomes in patients with glioma. Schneider et al (14) reported that RDW was an independent prognostic factor for glioma, but other studies reported no association (15–21). Therefore, the present meta-analysis aimed to evaluate the prognostic effect of RDW for patients with glioma.
Discussion
The present meta-analysis included 8 studies involving 1,468 patients. Patients were divided into high and low RDW groups according to different cut-off values. After analysis of the data, patients in the high RDW group were found to have worse survival. Moreover, after pooling the HRs and 95% CIs for OS, RDW was demonstrated to be an independent prognostic factor for gliomas.
Gliomas are an invasive brain malignancy, and prognosis is poor. Moreover, gliomas place a considerable mental and economic burden on patients and their families (27,28). Therefore, prognostic factors including age, initial neurological status, degree of resection, postoperative complications and duration of intensive care are important (29–31). However, a large proportion of these prognostic indicators are postoperative indicators, and only a few indicators are known before surgery.
Previous studies have reported that patients with glioma with a high preoperative RDW have poor survival. Schneider et al (14) and Kaisman-Elbaz et al (20) demonstrated that RDW was an independent prognostic factor for OS in patients with glioblastoma. Liang et al (16) also examined patients with glioblastoma and revealed that the pretreatment RDW was superior to the mean cell volume and mean corpuscular hemoglobin concentration as a prognostic factor. Several previous studies on patients with glioma reported that a low RDW led to improved clinical outcomes and contributes to patients follow-up optimization (14,16,18,21). Xu et al (18) reported that RDW was a sex-specific predictor of tumor grade and progression in female patients with high-grade glioma, but not in male patients (17).
The present findings should be interpreted in the context of potential confounding factors. RDW is influenced by a variety of physiological and pathological conditions, including systemic inflammation, anemia, nutritional deficiencies and chronic diseases. Since most of the included studies were retrospective and did not include individual patient-level data, adjustments for these potential confounders through multivariate analysis were not feasible. Consequently, the observed association between RDW and survival in patients with glioma might be partially attributed to these unmeasured variables. Future studies with detailed clinical data are needed to validate the independent prognostic value of RDW after adjusting for such factors.
The exact mechanisms underlying the relationship between RDW and gliomas have yet to be fully elucidated. We hypothesize that inflammation may be a key factor. Previous studies have demonstrated that an increase in the RDW is notably associated with increases in other inflammatory markers, including C-reactive protein, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) (32,33). Therefore, RDW is considered to be associated with an inflammatory response. Previous studies have reported an association between chronic inflammation and tumors (34–37). The development of cancer is accompanied by the complex action of inflammatory cells in the local microenvironment where the tumor site and the environment can stimulate tumor cell proliferation and infiltration (38–40). Although gliomas do not tend to metastasize outside of the central nervous system, exosomes serve an important role in the systemic inflammatory response (41). Glioma-derived exosomes can transmit local inflammation throughout the body, by converting M1 macrophages into tumor-associated macrophages (TAMs) through transcription regulation. In addition, reprogrammed TAMs can produce exosomes, which further leads to a systemic inflammatory response (42).
Elevated RDWs may reflect underlying chronic inflammation and immune dysregulation, both of which serve important roles in glioma progression (34–37). Proinflammatory cytokines such as IL-6 and TNF-α can impair erythropoiesis and increase anisocytosis, indirectly increasing the RDW (32,33). Additionally, glioma cells and TAMs can release exosomes that modulate systemic inflammatory responses and promote immune escape (42). These exosomes may reprogram macrophages and other immune cells to support tumor cell proliferation and invasion. Thus, the RDW may serve as a surrogate biomarker of tumor-promoting inflammation and immune evasion, contributing to poor clinical outcomes in patients with glioma.
The potential mechanisms are still unclear; however, to the best of our knowledge, the present meta-analysis is the first to summarize the current studies on the prognostic value of RDW for gliomas, and all the included studies were published since 2016. Although the cut-off values for RDW varied across studies (ranging from 12.5 to 14.1%), meta-regression analysis did not reveal a statistically significant impact of these differences on the pooled survival outcomes. These findings suggest that the prognostic value of RDW in patients with glioma is relatively consistent regardless of the specific cut-off thresholds used. However, only OS was reported in the included studies, and additional survival indicators, including disease-free survival and cancer-specific survival, are needed. Furthermore, subgroup analysis of histological subtypes was limited because most of the included studies did not report subtype-specific outcomes. In the future, studies should stratify survival outcomes by tumor grade and molecular classification.
In conclusion, the prognosis of patients with glioma could be predicted and the appropriate treatment chosen according to low-cost blood tests. Meanwhile, high preoperative RDW levels may be associated with poor prognosis and warrant further clinical attention.