Abstract
The prognostic value of peripheral blood hemoglobin/red blood cell distribution width ratio (HRR) in colorectal cancer (CRC) is unclear. The aim of this study was to analyze the correlation between peripheral blood HRR and the prognosis of CRC. A retrospective study analyzed the medical records of 284 CRC patients who attended Linyi People Hospital between June 1, 2017 and June 1, 2021. The optimal diagnostic cutoff value for hemoglobin (Hb)/erythrocyte distribution width was determined by ROC curve as 3.098, and patients were divided into high- and low-level groups for comparative analysis of clinical data. Kaplan–Meier method was used for survival analysis, and logrank test was used to assess survival differences. In univariate and multifactorial analyses, Cox proportional risk regression models were used to assess independent risk factors for overall survival (OS) and progression-free survival (PFS). All statistical tests were bilateral probability tests with α = 0.05, and P < .05 was considered statistically significant. There were 284 patients who were finally included in the statistical analysis. Gender, tumor stage, Hb, platelets, and CEA were associated with PFS and OS. Tumor stage, Hb, and HRR (P < .05) were independent risk factors for PFS and OS. Low-level HRR was associated with poor patient prognosis. Low-level HRR is associated with poor patient prognosis and is a potential tumor prognostic marker.
Keywords: colorectal cancer, hemoglobin, prognosis, red blood cell distribution width
1. Introduction
Colorectal cancer (CRC) currently ranks third in the global cancer incidence rate and second in cancer-related mortality.[1] In China, the incidence and mortality of CRC are still increasing year by year, and most patients are already in the middle and late stages at the time of diagnosis. Current early treatment options include surgical resection therapy and neoadjuvant radiotherapy-chemotherapy for patients with recurrence and metastasis. Although the advent of more accurate early screening methods and personalized treatment has stabilized the number of CRC cases in developed countries, the incidence and mortality rates in developing countries, including China, continue to increase significantly, and there is a need to find new potential indicators to identify the prognosis of CRC.
The inflammatory microenvironment affects many stages of CRC development and promotes tumorigenesis and metastasis,[2,3] and a large number of inflammatory and immune cells, such as neutrophils, T lymphocytes, monocytes, and natural killer cells, are present in the tumor microenvironment.[4] Neutrophil count to lymphocyte count ratio, platelet count to lymphocyte count ratio, and red blood cell distribution width (RDW) have been shown to be strongly associated with the survival prognosis of CRC patients,[5] and hemoglobin (Hb), albumin, lymphocytes, and platelets are associated with the prognosis of CRC patients treated surgically.[6] Hb can reflect the nutritional status of the body, the immune status of the organism, and decreased Hb has been shown to be associated with poor prognosis in pancreatic neuroendocrine tumors, esophageal cancer, and oral cancer,[7–9] and erythrocyte distribution width is a parameter that reflects the heterogeneity of erythrocyte volume, and previous studies have found that it may be a potential predictor of osteosarcoma, CRC, and breast cancer.[10–12] The hemoglobin/erythrocyte distribution width ratio (HRR) is a new marker with higher sensitivity and specificity compared to Hb and RDW alone, and better predicts the level of inflammation in patients at an early stage. Recently, a retrospective study confirmed a positive correlation between HRR and prognosis of patients with primary liver cancer.[13] However, the role of HRR in the survival prognosis of CRC patients is not yet known; therefore, the aim of this study was to analyze the correlation between HRR and survival prognosis of CRC patients.
2. Ethical statement
This study was approved by the Medical Ethics Committee, Linyi People Hospital with the waiver of informed written consent in view of the retrospective nature of the study.
2.1. Research subjects
This retrospective study analyzed 284 CRC patients who attended Linyi People Hospital between June 1, 2017, and June 1, 2021. Inclusion criteria were: Patients with a first colonoscopic pathological diagnosis of CRC. Age > 18 years. Patients who underwent CRC-related investigations one week before surgery. No history of antitumor therapy. No severe liver or kidney dysfunction or other hematologic disorders. Exclusion criteria are: secondary CRC preoperative neoadjuvant radiotherapy, chemotherapy, immunotherapy patients hormone therapy, blood transfusion and treatment affecting the physical and chemical properties of peripheral blood within 6 months complicated by serious infection complicated by blood diseases or other autoimmune diseases.
2.2. Research method
General clinical characteristics of patients, including gender, age, body mass index, and routine blood tests after first diagnosis, were collected from eligible patients according to the inclusion criteria. Tumor staging was performed according to the Union for International Cancer Control Colorectal Cancer 2017 8th edition TNM method. All patients underwent surgical treatment and were confirmed by postoperative pathological tissue. HRR was the HRR. The optimal diagnostic cutoff value of Hb/erythrocyte distribution width was determined by ROC curve as 3.098 (Fig. 1), and patients were divided into high- and low-level groups for comparative analysis of clinical data.
Figure 1.
ROC curve of HRR in CRC patients. CRC = colorectal cancer, HRR = hemoglobin/red blood cell distribution width ratio.
2.3. Follow-up
Survival data were obtained by outpatient review or telephone for patients who died or until the follow-up cutoff date (December 30, 2022). Patients who survived at the follow-up endpoint were recorded as alive and those who died were recorded as dead. PFS is progression-free survival time, which is the time from randomization to the first occurrence of disease progression or death from any cause. Overall survival (OS) is the time from the start of randomization to death from any cause.
2.4. Statistical analysis
SPSS 26.0 statistical software was used for data analysis. Data involving 2 groups were compared using t test, chi-square test, Fisher precision test, and Wilcoxon Mann Whitney test. Kaplan–Meier method was used for survival analysis, and logrank test was used to assess survival differences. In univariate and multifactorial analyses, Cox proportional risk regression models were used to assess independent risk factors for OS and PFS. All statistical tests were bilateral probability tests with α = 0.05, and P < .05 was considered statistically significant.
3. Results
3.1. Baseline clinical features of patients
A total of 284 CRC patients with a mean age of 65.16 ± 11.85 years were included in this study, of whom 132 were women and 152 were men. The percentage of patients who were overweight was 38.7%. Patients with tumor stages I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb, and IVc accounted for 15.14%, 34.51%, 2.11%, 2.11%, 2.82%, 30.99%, 7.04%, 4.23%, 0.7%, and 0.35%, respectively. Statistical analysis of complete blood count of 284 CRC patients showed that the percentage of patients with Hb ≤ 131 g/L was 52.1%, platelets ≤ 230 × 109/L was 48.6%, lymphocytes ≤ 1.63 × 109/L was 50.4%, monocytes ≤ 0.36 × 109/L was 51.1%, 62.0% for patients with CEA ≤ 5ug/L, 87.0% for patients with CA199 ≤ 37, and 97.2% for patients with CA125 ≤ 35. According to the optimal diagnostic cutoff value of HRR level in CRC patients (3.098, Fig. 1), 137 patients belonged to the low level HRR group and 147 patients belonged to the high level HRR group.
Comparing all clinical characteristics of the 2 groups, the analysis showed that there were significant differences between the low level HRR group and the high level HRR group in terms of age, gender, Hb, and BPC (P < .05). The baseline clinical characteristics of the 2 groups are shown in Table 1.
Table 1.
Relationship between HRR and baseline clinical characteristics of CRC patients.
| All patients (N = 284) | HRR ≤ 3.098 (N = 137) | HRR > 3.098 (N = 147) | |||||
|---|---|---|---|---|---|---|---|
| Parameters | N | % | N | % | N | % | P value |
| Age | 65.16 ± 11.85 | 67.34 ± 13.00 | 63.13 ± 10.31 | .003 | |||
| Gender | <.001 | ||||||
| Male | 152 | 53.5 | 53 | 38.7 | 99 | 67.3 | |
| Female | 132 | 46.5 | 84 | 61.3 | 48 | 32.7 | |
| BMI | .595 | ||||||
| ≤24 | 174 | 61.3 | 87 | 63.5 | 87 | 59.2 | |
| >24 | 110 | 38.7 | 50 | 36.5 | 60 | 40.8 | |
| Tumor stages | .141 | ||||||
| I | 43 | 15.14 | 22 | 16.06 | 21 | 14.29 | |
| IIa | 98 | 34.51 | 44 | 32.12 | 54 | 36.73 | |
| IIb | 6 | 2.11 | 4 | 2.92 | 2 | 1.36 | |
| IIc | 6 | 2.11 | 6 | 4.38 | 0 | 0.00 | |
| IIIa | 8 | 2.82 | 4 | 2.92 | 4 | 2.72 | |
| IIIb | 88 | 30.99 | 44 | 32.12 | 44 | 29.93 | |
| IIIc | 20 | 7.04 | 7 | 5.11 | 13 | 8.84 | |
| IVa | 12 | 4.23 | 4 | 2.92 | 8 | 5.44 | |
| IVb | 2 | 0.70 | 2 | 1.46 | 0 | 0.00 | |
| IVc | 1 | 0.35 | 0 | 0.00 | 1 | 0.68 | |
| Hemoglobin | <.001 | ||||||
| ≤131 | 148 | 52.1 | 121 | 88.3 | 27 | 18.4 | |
| >131 | 136 | 47.9 | 16 | 11.7 | 120 | 81.6 | |
| Platelet | .002 | ||||||
| ≤230 | 138 | 48.6 | 56 | 40.9 | 82 | 55.8 | |
| >230 | 146 | 51.4 | 81 | 59.1 | 65 | 44.2 | |
| Lymphocyte | .092 | ||||||
| ≤1.63 | 143 | 50.4 | 74 | 54.0 | 69 | 46.9 | |
| >1.63 | 141 | 49.6 | 63 | 46.0 | 78 | 53.1 | |
| Monocyte | .887 | ||||||
| ≤0.36 | 145 | 51.1 | 71 | 51.8 | 74 | 50.3 | |
| >0.36 | 139 | 48.9 | 66 | 48.2 | 73 | 49.3 | |
| CEA | .958 | ||||||
| ≤5 | 176 | 62.0 | 80 | 58.4 | 96 | 65.3 | |
| >5 | 108 | 38.0 | 57 | 41.6 | 51 | 34.7 | |
| CA199 | .615 | ||||||
| ≤37 | 247 | 87.0 | 118 | 86.1 | 129 | 87.8 | |
| >37 | 37 | 13.0 | 19 | 13.9 | 18 | 12.2 | |
| CA125 | .108 | ||||||
| ≤35 | 276 | 97.2 | 131 | 95.6 | 145 | 98.6 | |
| >35 | 8 | 2.8 | 6 | 4.4 | 2 | 1.4 | |
BMI = body mass index, CRC = colorectal cancer.
3.2. Cox regression of OS and PFS
Univariate COX proportional risk regression model survival analysis showed that sex (HR = 1.570, 95% CI: 0.796–1.914, P = .049), tumor stage (HR = 5.120, 95% CI: 2.965–8.843, P < .001), Hb (HR = 4.274, 95% CI: 0.138–0.396, P < .001), platelets (HR = 2.116, 95% CI: 1.360–3.292, P = .001), CEA (HR = 1.732, 95% CI: 1.112–2.67, P = .015), HRR (HR = 3.268, 95% CI: 0.185–0.565, P < .001) were associated with OS (Table 2); gender (HR = 1.525, 95% CI: 1.031–2.254, P = .034), tumor stage (HR = 3.163, 95% CI: 2.072–4.829, P < .001), Hb (HR = 3.922, 95% CI:0.162–0.399, P < .001), platelets (HR = 2.100, 95% CI: 1.425–3.095, P < .001), and HRR (HR = 2.725, 95% CI: 0.240–0.562, P < .001) were associated with PFS (Table 2).
Table 2.
Univariate cox regression analysis of CRC patients.
| Overall survival (OS) | Progression-free survival (PFS) | |||
|---|---|---|---|---|
| Parameters | HR (95%CI) | P | HR (95%CI) | P value |
| Age | .347 | .171 | ||
| ≤65 | 1 | 1 | ||
| >65 | 1.234 (0.796,1.914) | 1.309 (0.890,1.924) | ||
| Gender | .049 | .034 | ||
| Male | 1 | 1 | ||
| Female | 1.570 (1.001,2.461) | 1.525 (1.031,2.254) | ||
| BMI | .684 | .712 | ||
| ≤24 | 1 | 1 | ||
| >24 | 1.096 (0.704,1.708) | 0.928 (0.625,1.379) | ||
| Tumor stages | <.001 | <.001 | ||
| I,II | 1 | 1 | ||
| III,IV | 5.120 (2.965,8.843) | 3.163 (2.072,4.829) | ||
| Hemoglobin | <.001 | <.001 | ||
| >131 | 1 | 1 | ||
| ≤131 | 4.274 (0.138,0.396) | 3.922 (0.162,0.399) | ||
| Platelet | .001 | <.001 | ||
| ≤230 | 1 | 1 | ||
| >230 | 2.116 (1.360,3.292) | 2.100 (1.425,3.095) | ||
| Lymphocyte | .997 | .895 | ||
| ≤1.63 | 1 | 1 | ||
| >1.63 | 1.001 (0.650,1.541) | 1.026 (0.703,1.497) | ||
| Monocyte | .989 | .376 | ||
| >0.36 | 1 | 1 | ||
| ≤0.36 | 1.003 (0.646,1.537) | 1.188 (0.575,1.233) | ||
| CEA | .015 | .086 | ||
| ≤5 | 1 | 1 | ||
| >5 | 1.732 (1.112,2.670) | 1.404 (0.953,2.069) | ||
| CA199 | .071 | .385 | ||
| ≤37 | 1 | 1 | ||
| >37 | 1.704 (0.955,3.040) | 1.275 (0.737,2.207) | ||
| CA125 | .152 | .100 | ||
| ≤35 | 1 | 1 | ||
| >35 | 2.331 (0.732,7.423) | 2.320 (0.851,6.326) | ||
| HRR | <.001 | <.001 | ||
| >3.098 | 1 | 1 | ||
| ≤3.098 | 3.268 (0.185,0.506) | 2.725 (0.240,0.562) | ||
BMI = body mass index, CRC = colorectal cancer, HRR = hemoglobin/red blood cell distribution width ratio.
Multifactorial COX proportional risk regression model survival analysis showed that tumor stage (HR = 5.585, 95% CI: 3.173–9.835, P < .001), Hb (HR = 3.448, 95% CI: 0.116–0.724, P = .008), HRR (HR = 3.135, 95% CI: 0.266–1.441, P = .026) were associated with OS and were independent factors affecting OS in CRC patients (Table 3); tumor stage (HR = 3.239, 95% CI: 2.111–4.970, P < .001), Hb (HR = 4.000, 95% CI: 0.119–0.529, P < .001), and HRR (HR = 2.083, 95% CI:0.054–1.341, P = .037) were associated with PFS and were independent factors affecting PFS in CRC patients (Table 3).
Table 3.
Multifactorial cox regression analysis in CRC patients.
| Overall survival (OS) | Progression-free survival (PFS) | |||
|---|---|---|---|---|
| Parameters | HR (95%CI) | P | HR(95%CI) | P |
| Gender | .580 | .509 | ||
| Female | 1 | 1 | ||
| Male | 1.153 (0.523,1.438) | 1.160 (0.554,1341) | ||
| Tumor stages | <.001 | <.001 | ||
| I,II | 1 | 1 | ||
| III,IV | 5.585 (3.171,9.835) | 3.239 (2.111,4.970) | ||
| Hemoglobin | .008 | <.001 | ||
| >131 | 1 | 1 | ||
| ≤131 | 3.448 (0.116,0.724) | 4.000 (0.119,0.529) | ||
| Platelet | .211 | .079 | ||
| ≤230 | 1 | 1 | ||
| >230 | 1.345 (0.845,2.142) | 1.433 (0.959,2.140) | ||
| CEA | .884 | - | ||
| ≤5 | 1 | - | ||
| >5 | 1.034 (0.659,1.623) | - | ||
| HRR | .026 | .037 | ||
| >3.098 | 1 | 1 | ||
| ≤3.098 | 3.135 (0.266,1.441) | 2.083 (0.554,1.341) | ||
CRC = colorectal cancer, HRR = hemoglobin/red blood cell distribution width ratio.
3.3. Survival Analysis
The median OS of the 284 CRC patients was 25.4 months, and the median PFS was 24.2 months. For OS, the OS survival rate was significantly higher in the high level HRR group than in the low level HRR group; the median OS survival rate was 15.27 months longer in the high level HRR group than in the low level HRR group (HR = 0.385, 95% CI: 0.242–0.612, P < .001, Fig. 2A). For PFS, OS survival was significantly higher in the high level HRR group than in the low level HRR group; the median PFS survival was 17.3 months longer in the high level HRR group than in the low level HRR group (HR = 0.432, 95% CI: 0.289–0.640, P < .001, Fig. 2B).
Figure 2.
K-M curves of PFS and OS of CRC patients in the high- and low-level groups. (A) K-M curves of OS in CRC patients in the high- and low-level groups. (B) K-M curves of PFS in CRC patients in the high level and low level groups. CRC = colorectal cancer, OS = overall survival, PFS = progression-free survival.
4. Discussion
The present study showed that low levels of HRR were positively associated with poor prognosis in CRC patients. It has been shown that the state of the inflammatory environment in the tumor microenvironment is associated with tumor growth, invasion and metastasis.[14] In addition, it has been shown that some inflammatory factors such as some inflammatory factors such as interleukin-6 and neutrophil to lymphocyte ratio can predict the prognosis of cancer patients.[15,16] In this study, multifactorial COX proportional risk regression model survival analysis showed that tumor stage, HRR and poor prognosis of CRC patients were independently associated, and we should pay more attention to patients with lower preoperative HRR.
Hb is a common test that responds to the patient is responds to the patient systemic nutritional status, immunity, and resistance. Anemia is the most common hematologic abnormality in cancer patients.[17] YingJun Zhang et al[18] compared preoperative Hb levels in 2123 breast cancer patients and showed that preoperative anemia was independently associated with poor prognosis in breast cancer patients.S R Majumda et al[19] studied symptoms, duration, and location clues in 194 CRC patients and found that majority had anemia (57%) and occult bleeding (77%). As consistent with previous studies, our study found a poor prognosis for patients with Hb ≤ 131g/L. Cancer patients are frequently anemic. More commonly, anemia is due to the cancer itself or to the myelosuppressive effects of cancer treatment. Anemia of chronic disease in cancer patients is associated with a diminished response of endogenous erythropoietin (EPO) to anemia, resulting in a state of relative EPO deficiency. In addition, patients with anemia of chronic disease often show a diminished hematopoietic response to EPO, leading to relative EPO resistance.[20] Anemia causes the formation of a hypoxic environment in the body, which promotes the secretion of angiogenic factors such as VEGF, the formation of neovascularization, and accelerates the proliferation and metastasis of tumor cells.[21]
RDW is the main response to impaired erythropoiesis and abnormal erythrocyte survival.[22] As a routinely available indicator of systemic inflammatory response, RDW is thought to be associated with poor outcomes in patients with different cancers. Ze-Lin Wen et al[23] performed a meta-analysis of whether RDW is a prognostic factor in CRC patients undergoing radical surgery. The study involved 5411 patients, and after combining the overall risk ratios, red cell distribution width-standard deviation was found to be an independent prognostic factor for OS and DFS, and RDW-coefficient of variation was an independent prognostic factor for DFS. Deshun Yao et al[12] conducted a retrospective cohort study including 825 breast cancer patients and found that RDW was positively associated with tumor stage positively correlated with tumor stage; multifactorial COX regression analysis showed that the high RDW group had poorer OS compared to the low RDW group. RDW may be a potential predictor of poor patient prognosis.
The relationship between Hb and RDW and prognosis of cancer patients is well established, but both parameters are susceptible to diseases other than cancer, such as autoimmune diseases, hematologic diseases, and systemic inflammatory diseases. HRR, the ratio of Hb and RDW, is a new inflammatory marker that is also more sensitive and specific and reflects more consistently the degree of oxidative stress and systemic inflammatory response of the body.[24] HRR may be a more reliable parameter for determining the prognosis of cancer patients. In recent years, different studies have shown that HRR is a valid prognostic factor for disease-free survival in patients with resected lung adenocarcinoma[25]; HRR may be an important indicator for the adjuvant diagnosis of nasopharyngeal carcinoma.[26] In our study, we found that the survival prognosis of CRC patients in the high level HRR group was better and was positively correlated with the tumor stage of CRC. These results suggest that HRR is a good predictor of prognosis for CRC patients.
This study has many drawbacks and limitations. First, this is a retrospective study and factors affecting patients’ Hb and RDW such as age, autoimmune diseases, and hematologic diseases cannot be excluded. Second, we extracted the most relevant factors in this study, and other factors affecting CRC were not included. Third, the relatively small sample size and the single-center retrospective design of this study may increase statistical bias and require further large-scale studies for validation. In conclusion, this study explored the role of HRR in predicting the prognosis of CRC patients, and survival analysis using the COX proportional risk regression model demonstrated that HRR was an independent predictor of OS and PFS in CRC patients.
5. Conclusion
HRR is an independent predictor of OS and PFS in CRC patients, and is a potentially valuable prognostic factor for CRC patients.
Author contributions
Conceptualization: Haifeng Zhang.
Data curation: Kang Li, Jing Yan.
Investigation: Kang Li, Jing Yan.
Software: Kang Li.
Supervision: Kang Li.
Writing – original draft: Kang Li.
Writing – review & editing: Haifeng Zhang.
Abbreviations:
- CRC
- colorectal cancer
- Hb
- hemoglobin
- HRR
- hemoglobin/red blood cell distribution width ratio
- OS
- overall survival
- PFS
- progression-free survival,
- RDW
- red blood cell distribution width
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
The authors have no conflicts of interest to disclose.
How to cite this article: Li K, Yan J, Zhang H. Correlation between peripheral blood hemoglobin/erythrocyte distribution width ratio and prognosis of patients with primary colorectal cancer. Medicine 2023;102:23(e34031).
Contributor Information
Kang Li, Email: 3264277939@qq.com.
Jing Yan, Email: 2430077188@qq.com.
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