Prognostic value of hemoglobin to red blood cell distribution width ratio in pancreatic ductal adenocarcinoma: a retrospective study

Abstract

Background

Previous studies have identified the hemoglobin (Hb) to red blood cell distribution width (RDW) ratio (HRR) is associated with the prognosis of a variety of malignant tumors. However, the relationship between HRR and pancreatic ductal adenocarcinoma (PDAC) prognosis remains unexplored. This study aims to ascertain the prognostic significance of HRR in PDAC patients.

Methods

In a retrospective analysis, 128 PDAC patients undergoing initial surgical resection at Ningbo Medical Center Lihuili Hospital between January 2016 and September 2021 were included. Based on receiver operating characteristic curve-derived cut-off values, participants were categorized into low and high HRR groups. The correlation between HRR and patient prognosis was subsequently examined.

Results

Significant disparities in age, Hb levels, RDW, tumor locality, surgical intervention, and postoperative chemotherapy were observed between the two groups (P < 0.05). Notably, the low HRR cohort exhibited inferior disease-free survival (DFS) and overall survival (OS) rates (P = 0.002 for both). Univariate analysis indicated that male gender, adjacent tissue invasion, TNM stages III/IV, non-O blood types, low HRR, and lack of postoperative chemotherapy were linked to adverse DFS and OS outcomes (P < 0.05). Multivariate analysis further delineated low HRR as an independent predictor of poor DFS and OS outcomes (HR: 1.520, 95% CI: 1.028–2.247, P = 0.036; HR: 1.537, 95% CI: 1.034–2.284, P = 0.034, respectively).

Conclusion

Our findings suggest that a lower HRR is indicative of poorer DFS and OS in PDAC patients, underscoring its potential utility as a prognostic biomarker for this population.

Introduction

Pancreatic ductal adenocarcinoma (PDAC), the predominant form of pancreatic cancer, ranks as the fourth leading cause of cancer mortality globally, with a dismal 5-year overall survival rate below 10% [1, 2]. Predicting survival outcomes in PDAC patients remains a considerable challenge.

Hemoglobin (Hb) and red cell distribution width (RDW) are both readily available and routinely measured by automated laboratory instruments. The Hb level in patients with cancer is often considered a marker of nutritional status, and these patients may exhibit anemia in chronic disease [3]. Anemia results in low oxygen levels in the blood, and hypoxia helps release factors involved in tumor angiogenesis and metabolism. Angiogenesis in turn increases tumor tolerance to therapeutic interventions and adversely affects survival [4]. RDW, as a specific indicator reflecting the change of red blood cell volume, is closely related to the progression of tumor-related inflammation. The high expression level of inflammatory factors can inhibit the maturation of bone marrow red blood cells, resulting in a large number of immature red blood cells entering the blood, which will increase the level of RDW [5]. Elevated RDW has been shown to be a prognostic biomarker for a variety of diseases, including malignancies [6, 7]. Given the promising prognostic value of both Hb [8,9,10] and RDW [7, 11, 12], it is possible to combine the two as a predictor of prognosis in cancer patients.

Recent years have seen the emergence of a novel biomarker, Hb-to-RDW ratio (HRR) [13,14,15], which is associated with the prognosis of various cancers, including small cell lung cancer [16], liver cancer [17], nasopharyngeal carcinoma [18], and non-small cell lung cancer [19], among others. However, the relationship between HRR and the prognosis of PDAC remains unclear.

This study endeavors to elucidate the prognostic value of HRR in PDAC patients through a retrospective analysis conducted at Ningbo Medical Center Lihuili Hospital.

Materials and methods

Date collection and study design

A comprehensive collection of 149 patients with PDAC, who underwent their initial surgical resection at Ningbo Medical Center Lihuili Hospital between January 2016 and September 2021, was conducted retrospectively. The inclusion criteria encompassed: (1) patients aged 18 years or older; (2) those who had never undergone surgical resection previously; (3) a pathological diagnosis of PDAC. The exclusion criteria encompassed: (1) a history of primary malignancies or the presence of a secondary primary malignancy; (2) patients who had received allogeneic red blood cell transfusions within 120 days prior to surgery; (3) the coexistence of other systemic hematological diseases; (4) incomplete follow-up data. After applying the exclusion criteria, a total of 128 patients were ultimately enrolled in this study (refer to Fig. 1).

Fig. 1

Study flow diagram

The latest demographic and clinical information of the patients before surgery, including age, gender, body mass index (BMI), hemoglobin (Hb), red blood cell distribution width (RDW), Carbohydrate antigen 19 − 9 (CA199), ABO blood group, and imaging results were obtained from electronic medical records (EMR) provided by Ningbo Jintang Software Co., Ltd, China. Additionally, postoperative pathological results and postoperative adjuvant chemotherapy data were also obtained through the EMR system. The HRR values were calculated as the ratio of Hb (g/dL) to RDW (%).

Survival data were collected through outpatient visits, inpatient records, or telephone follow-up until death or the end of follow-up (October 31, 2023). Disease-free survival (DFS) was calculated from the date of initial surgery for PDAC until recurrence. DFS was censored at the last confirmed date of freedom from recurrence. Overall survival (OS) was calculated from the date of initial surgery for PDAC to the date of death from any cause or the end of follow-up.

Tumor staging was performed according to the 8th edition tumor-node-metastasis (TNM) staging criteria for PDAC, as defined by the American Joint Committee on Cancer (AJCC).

All procedures involving human participants in this study were conducted in accordance with the ethical standards set forth by the ethics committee of Ningbo Medical Center Lihuili Hospital (Approval No: Li Huili Hospital Ethics Review 2023 Research No. 350) and in compliance with the 1964 Declaration of Helsinki and its subsequent amendments or comparable ethical standards. As this study was observational and retrospective in nature, informed consent was waived by the ethics committee.

Statistical analysis

Categorical variables were presented as counts and percentages, and their significance was assessed using the chi-square test or Fisher’s exact test. Continuous variables with non-normal distributions were described as medians with interquartile ranges, and their significance was evaluated using the Mann-Whitney U test. The cut-off value for HRR was determined using receiver operating characteristic (ROC) curve analysis based on OS outcomes. Survival curves were generated using the Kaplan-Meier method and between-group comparisons were made using the log-rank test. Univariate and multivariate analyses utilized the Cox proportional hazards regression model to identify independent risk factors associated with DFS and OS. A two-sided P value of less than 0.05 was considered statistically significant for all analyses. Statistical computations were carried out using SPSS statistical software, version 24.0 (IBM, Armonk, NY, USA), and GraphPad PRISM 6.0 software (GraphPad Software, San Diego, CA, USA).

Results

Patient characteristics

Table 1 presents the clinical and demographic characteristics of the 128 patients with PDAC included in this study. Of these patients, 72 (56.3%) were male. The median age (interquartile range) was 67.00 (60.00, 71.75) years, and the median follow-up time (interquartile range) was 16.1 (8.9, 31.5) months. During the follow-up period, 114 patients (89.1%) experienced relapse, and 107 patients (83.6%) passed away. The median DFS and OS were 8.42 months and 16.07 months, respectively.

Table 1 Basic clinical and demographic characteristics of the study population categorized by the HRR*

Comparison of each variable between low HRR and high HRR groups

Based on the ROC cut-off value, patients were divided into the low HRR group (≤ 0.88) and the high HRR group (> 0.88). In the low HRR group, several differences were observed compared to the high HRR group. Specifically, the average age was older (P = 0.026), Hb levels were lower (P < 0.001), RDW levels were higher (P < 0.001), and there was a higher proportion of tumor location in the head (P < 0.001), pancreaticoduodenectomy (P < 0.001), and postoperative non-adjuvant chemotherapy (P = 0.043). However, no significant differences were found in the other variables between the two groups (P > 0.05) (Table 1).

Low HRR is independently associated with poor DFS

Figure 2 (A) illustrates the difference in DFS between the low HRR and high HRR groups, showing worse DFS in patients with low HRR (P = 0.002). Table 2 presents the univariate and multivariate analyses of predictors of DFS in patients with PDAC. In the univariate analysis, male gender (hazard ratio [HR]: 1.453; 95% confidence interval [CI]: 1.000-2.112; P = 0.0498), surrounding tissue invasion (HR: 1.994; 95% CI: 1.136-3.500; P = 0.016), TNM stage III/IV (HR: 1.920; 95% CI: 1.232–1.991; P = 0.004), non-O blood group (HR: 0.650; 95% CI: 0.445–0.950; P = 0.026), low HRR (HR: 1.834; 95% CI: 1.254–2.683; P = 0.002), and postoperative adjuvant chemotherapy (HR: 0.620; 95% CI: 0.421–0.912; P = 0.015) were identified as prognostic factors. Further multivariate analysis revealed that low HRR was independently associated with poor DFS (HR: 1.520; 95% CI: 1.028–2.247; P = 0.036).

Fig. 2

Comparison of disease‑free survival (DFS) and overall survival (OS) between Low HRR and High HRR groups. (A) Kaplan-Meier curve for DFS; (B) Kaplan-Meier curve for OS

Table 2 Univariate and multivariate statistical analyses of disease-free survival

Low HRR is independently associated with poor OS

Figure 2 (B) demonstrates the difference in OS between the low HRR and high HRR groups, indicating worse OS in patients with low HRR (P = 0.002). Table 3 displays the univariate and multivariate analyses of predictors of OS in patients with PDAC. In the univariate analysis, male gender (HR: 1.753; 95% CI: 1.184–2.596; P = 0.005), surrounding tissue invasion (HR: 1.981; 95% CI: 1.106–3.550; P = 0.022), TNM stage III/IV (HR: 2.110; 95% CI: 1.343–3.316; P = 0.001), non-O blood group (HR: 0.638; 95% CI: 0.432–0.941; P = 0.023), low HRR (HR: 1.855; 95% CI: 1.258–2.736; P = 0.002), and postoperative adjuvant chemotherapy (HR: 0.508; 95% CI: 0.342–0.754; P = 0.001) were identified as prognostic factors. Multivariate analysis further revealed that low HRR was independently associated with poor OS (HR: 1.537; 95% CI: 1.034–2.284; P = 0.034).

Table 3 Univariate and multivariate statistical analyses of overall survival

Discussion

This retrospective study was conducted at Ningbo Medical Center Lihuili Hospital in Ningbo, China. To the best of our knowledge, this is the first study to investigate the prognostic value of HRR in patients with PDAC. Our findings indicate that low preoperative HRR is not only associated with poor DFS, but also poor OS in PDAC patients. These results suggest that controlling preoperative HRR may present a new therapeutic target for PDAC patients in the future.

Two important parameters related to red blood cells, namely Hb and RDW, are included in routine blood tests. Apart from reflecting the anemia status of patients, Hb has been reported to be associated with the prognosis of various cancers such as esophageal cancer [8], cervical cancer [9], and gastric cancer [10]. RDW measures the variability in red blood cell size and elevated RDW has been linked to the prognosis of several cancers including oral squamous cell carcinoma [7], gastric cancer [11], and non-small cell lung cancer [12]. Sun et al. [20] combined the significance of Hb and RDW in 2016 to report the prognostic value of HRR in esophageal squamous cell carcinoma.

Since then, HRR has become a research focus in recent years [13,14,15,16,17,18,19]. Most studies have found that low HRR is associated with overall survival, disease progression, or relapse in the studied cancers [21]. This aligns with our results in PDAC patients for the first time, suggesting that this phenomenon or pattern may also apply to PDAC patients. However, the only published study on HRR in pancreatic cancer showed that low HRR was associated with disease progression but not OS in advanced pancreatic cancer [22].

In the present study, CA199 grouping with a reference value of 37 U/mL as a cut-off value was found to be of no significance for the prognosis of PDAC, which was consistent with the results of some studies [23, 24], but inconsistent with the results of others [25,26,27]. However, the cut-off value of CA19-9 varies in some reports of the prognosis of surgically resectable pancreatic cancer, although 37 U/mL is most commonly used [26,27,28]. As reported in some studies [23, 25], the cut-off value of CA199 may greatly affect the results. At the same time, some studies have suggested that the observation of preoperative and postoperative CA199 changes may be more significant for the prognosis of PDAC [23, 29].

Blood transfusions can increase Hb levels [30]. However, the infusion of allogeneic red blood cells can also affect the homogeneity of red blood cells, leading to increased RDW [31]. The direct impact of blood transfusion on HRR is currently unclear. To minimize bias, we excluded two patients who had received blood transfusions within 120 days prior to surgery. Nevertheless, the effect of transfusion on HRR and its duration will likely be an important area for future research.

In this study, variables that showed statistical significance in univariate analysis were included in the final multivariate analysis. However, there may be other potentially relevant measures, particularly those with univariate P values between 0.05 and 0.1. Due to the limited number of cases and numerous indicators in this study, these potentially meaningful indicators were not included in the multivariate analysis, which may introduce bias into the results.

The OS in PDAC patients was calculated from the day of surgery, consistent with previous studies [32, 33]. Although most patients did not undergo major treatment, a few may have received some form of preoperative treatment, such as chemotherapy, which could influence the results. Unfortunately, similar to previous studies [32, 33], variables related to preoperative treatment were not considered or collected in the design of this study.

The cut-off value of HRR determined by ROC analysis in this study was 0.88, consistent with the range of 0.7-1.0 reported in most previous studies [16,17,18, 34, 35]. However, an ideal and definitive cut-off value for HRR has yet to be established, requiring further clarification through additional follow-up studies.

There are several limitations in our study. Firstly, some indicators, such as serum iron and ferritin, were not completely collected, which may affect HRR and introduce bias into the results. Secondly, the sample size was relatively small. Thirdly, this study was conducted at a single center and was retrospective in nature. Therefore, prospective studies with multiple centers and larger sample sizes are warranted to validate our findings.

Conclusion

Our findings confirm that low HRR is independently associated with poorer survival in PDAC patients, advocating for its integration into future prognostic models to enhance clinical decision-making and patient care.