Abstract
Objective: To determine the correlation of the systemic immune-inflammatory response index (SIRI) with clinical data in patients with malignant ovarian tumor. Methods: The clinical data of 118 patients with ovarian cancer (OC) treated in Ningbo Women’s and Children’s Hospital from February 2016 to January 2018 were retrospectively studied. Patients were divided into high and low SIRI expression groups according to the receiver operator curve (ROC) optimal cut-off (Cut-off) value, and the association of SIRI with the patient’s clinical data was analyzed. Cox regression was adopted for the analysis of prognostic factors impacting the patients’ 5-year survival. The associations of SIRI with tumor markers were also analyzed. A risk prediction model was constructed based on the Cox regression coefficient. Results: The group of patients who died showed notably higher neutrophil (NEUT) and SIRI levels than the surviving group, and also showed a significantly lower lymphocyte (LYM) level than the surviving group (P < 0.001). The areas under the ROC curves (AUC) for CA125, NEUT, LYM, and SIRI for predicting death from OC were 0.779, 0.754, 0.776, and 0.848, respectively. In addition, the AUC of each index was ranked CA125 > SIRI > LYM > NEUT. The high-expression group had a higher proportion of patients with stage III-IV and lymph node metastasis (LNM) than the low-expression group (P < 0.05). SIRI showed a positive correlation with serum carbohydrate antigen 125 (CA125), CA153, and HE4 (all P < 0.05), but had no correlation with CA199, AFP, or CEA (all P > 0.05). According to multivariate Cox regression analysis, age, FIGO stage, SIRI, and therapeutic regimen were independent prognostic factors for the 5-year survival of OC patients (all P < 0.05). The risk score was significantly higher in the death group than that in the surviving group (P < 0.001), and the AUC of this risk score for predicting 5-year survival was 0.876. Conclusion: Patients with an increased SIRI level account for a large proportion of OC patients with a high FIGO stage and LNM. The 5-year survival rate of patients with a high SIRI level is unfavorable, suggesting the use of SIRI as an observation index for the prognosis of OC.
Keywords: Systemic immune-inflammatory response index, ovarian cancer, 5-year survival, prognosis, Cox regression
Introduction
Ovarian cancer (OC) is a frequent female malignant tumor, ranking the eighth most common cancer and the fifth leading cause of cancer-associated death among women worldwide [1]. According to data from the World Health Organization [2], in 2020, there were approximately 313,959 new cases of OC and 207,252 deaths from OC. Although the incidence of OC varies by region and population, most cases are diagnosed among women over 50 years old [3]. There are several different types of OC, but the most frequent is epithelial OC, which begins with cells arranged on the surface of the ovary, accounting for 85-90% of all OCs [4]. Some common symptoms of OC include abdominal or pelvic pain, abdominal distension, changes in bowel or bladder habits, and a quick sense of fullness after eating [5]. These symptoms may also be triggered by other diseases, such as irritable bowel syndrome, which challenges doctors to identify OC.
The prognosis of OC is bound up with the cancer stage at diagnosis, the type of OC, and the overall health status of the patient [6]. Because of the occult symptoms, OC usually has entered a late clinical stage at the time of diagnosis, which makes the treatment more challenging and prognosis poor [7]. According to statistics, the five-year survival rate of OC patients is approximately 49%, which means that about half of the women diagnosed with OC survive for at least five years after diagnosis [8]. However, the survival rate may vary greatly due to the different stages of cancer at diagnosis [9]. The systemic immune-inflammatory response index (SIRI) is a marker to measure the host’s immune response to a tumor [10]. It is calculated by dividing the absolute neutrophil count by the absolute lymphocyte count, which reflects a balance between pro-inflammatory and anti-inflammatory processes in vivo [11]. Increasing SIRI levels were found to be associated with poor prognosis in multiple cancers [12]. A high SIRI level may represent a weakened immune response and a more aggressive cancer phenotype, which probably results in an unfavorable prognosis [13]. Additionally, as a simple and cost-effective marker, SIRI shows good prospects in various clinical environments including cancer, autoimmune disease, and infectious disease [14]. However, whether SIRI has prognostic value in OC is still controversial.
This study analyzed the influence of SIRI, clinical data, and prognosis of patients with malignant ovarian tumor, with the purpose of providing markers for clinical diagnosis and prognosis.
Methods and materials
Patient information
A total of 118 patients with OC treated in Ningbo Women’s and Children’s Hospital from February 2016 to January 2018 were retrospectively enrolled. This study was conducted with permission from the Ethics Committee of Ningbo Women’s and Children’s Hospital (EC2022-008).
Inclusion and exclusion criteria
Inclusion criteria: Patients diagnosed and confirmed with primary OC by pathologic examination; patients whose pathologic staging met the International Federation of Gynecology and Obstetrics (FIGO) staging criteria [5], patients without a history of ovarian surgery, radiotherapy, or chemotherapy before admission; patients with detailed case data; and patients with estimated survival > 6 months.
Exclusion criteria: Patients who had undergone a blood transfusion recently or had received antibiotics within 2 weeks before the operation; patients with diseases associated with pregnancy or the blood system, patients with thrombotic disease, immune disease, severe liver or kidney damage, or malignant tumors in other parts.
Collection of clinical data
The following case information of each patient was collected: neutrophil percentage (NEUT%), lymphocyte percentage (LYM%), serum carbohydrate antigen 125 (CA125), CA153, CA199, alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), human epididymal protein 4 (He4), and patient’s age, FIGO staging, histological classification, tumor diameter, lymph node metastasis (LNM), and ascites. The SIRI condition of each patient was calculated by Eq.
Collection of follow-up data
Each patient was followed up since the patient was discharged from the hospital after surgery, once every three months for the first two years, and once every six months or one year after two years, until the termination date of follow-up (January 30, 2023) or the death date of the patient. The main follow-up methods included outpatient service and telephone follow-up.
Outcome measures
Primary outcome measures
The SIRI in surviving patients was determined. According to the cut-off value of the receiver operating characteristic (ROC), the patients were assigned to high and low SIRI groups to understand the association of SIRI with the patient’s clinical data.
Secondary outcome measures
Cox regression was used for analysis of the prognostic factors impacting the patients’ 5-year survival. The association of SIRI with tumor markers was also analyzed. The difference in the area under the ROC curve for each index was compared. A risk prediction model was constructed based on the Cox regression coefficient.
Statistical analyses
This study used SPSS 26.0 and GraphPad Prism 8 software for data analyses. The optimal cut-off of SIRI was determined based on the ROC curve. Based on this value, the patients were assigned to a high SIRI group or a low SIRI group. The Kaplan-Meier (K-M) method was used to draw the survival curve, and the log-rank test was adopted for inter-group comparison of the 5-year survival. Counted data were described by frequency (percentage), and their inter-group comparison was done by χ2 test. Measured data were described by mean ± SD, and their inter-group comparison was done by independent-samples t test. The Pearson test was used to test the correlation between the data. Differences in the area under the ROC curve of each index were analyzed using the pairwise test by ROC curve analysis. Cox proportional hazard regression model was used for analysis of independent risk factors affecting the OC patients’ prognosis. P < 0.05 was considered significant.
Results
Levels of NEUT, LYM, and SIRI in surviving OC patients
The clinical data and vital status of the 118 patients were analyzed. Up to the end of follow-up, 51 patients survived, showing a 5-year survival rate of 43.65%. The patients were assigned to a surviving group (n=51) or a death group (n=67) on this basis. According to inter-group comparison of NEUT, LYM, and SIRI between the two groups, the death group showed significantly higher NEUT and SIRI levels but a lower LYM level than the surviving group (all P < 0.001, Figure 1).
Figure 1.
NEUT, LYM, and SIRI levels of surviving OC patients and dead patients. A. Comparison of NEUT level between surviving OC patients and dead patients. B. Comparison of LYM level between surviving OC patients and dead patients. C. Comparison of SIRI level between surviving OC patients and dead patients. Note NEUT%: Neutrophil percentage; LYM%: Lymphocyte percentage; SIRI: Systemic immune-inflammatory response index. ***P < 0.001.
ROC curves of NEUT, LYM, and SIRI in predicting patients’ death
The predictive values of CA125, NEUT, LYM, and SIRI for death in OC patients was analyzed by ROC curves. According to the results, the areas under the ROC curve of CA125, NEUT, LYM, and SIRI in predicting death from OC were 0.779, 0.754, 0.776, and 0.848, respectively (Figure 2; Table 1). Further analysis revealed that the areas under the curve of the four indices were ranked CA125 > SIRI > LYM > NEUT (Table 2).
Figure 2.
ROC curves of NEUT, LYM and SIRI for predicting the death of OC patients. A: ROC of NEUT in forecasting the death of OC patients. B: ROC of LYM in forecasting the death of OC patients. C: ROC of SIRI in forecasting the death of OC patients. D: ROC of CA125 in forecasting the death of OC patients. Note NEUT%: Neutrophil percentage; LYM%: Lymphocyte percentage; SIRI: Systemic immune-inflammatory response index; CA125: carbohydrate antigen 125; ROC: receiver operating characteristic.
Table 1.
Values of ROC curves
| Predictor variable | Area under the curve (AUC) | Confidence interval (CI) | Cut-off | Sensitivity | Specificity | Youden index |
|---|---|---|---|---|---|---|
| NEUT | 0.754 | 0.667-0.841 | 58.32 | 92.54% | 45.10% | 37.64% |
| LYM | 0.776 | 0.693-0.859 | 31.65 | 65.67% | 84.31% | 49.99% |
| SIRI | 0.848 | 0.780-0.915 | 1.900 | 76.11% | 84.31% | 60.43% |
| CA125 | 0.779 | 0.693-0.865 | 321.00 | 83.58% | 60.78% | 44.36% |
Note: NEUT%: Neutrophil percentage; LYM%: Lymphocyte percentage; SIRI: Systemic immune-inflammatory response index.
Table 2.
Comparison of AUCs of each marker
| Test results | Z value | P value | AUC difference | Standard error difference | 95% CI | |
|---|---|---|---|---|---|---|
|
| ||||||
| Down | Up | |||||
| CA125 - NEUT | 2.105 | 0.035 | 0.025 | 0.291 | 0.002 | 0.048 |
| CA125 - LYM | 9.176 | < 0.001 | 0.555 | 0.294 | 0.437 | 0.674 |
| CA125 - SIRI | -1.463 | 0.144 | -0.069 | 0.279 | -0.161 | 0.023 |
| NEUT - LYM | 8.499 | < 0.001 | 0.530 | 0.295 | 0.408 | 0.653 |
| NEUT - SIRI | -2.094 | 0.036 | -0.094 | 0.279 | -0.182 | -0.006 |
| LYM - SIRI | -8.336 | < 0.001 | -0.624 | 0.282 | -0.771 | -0.477 |
Notes: SIRI: systemic immune-inflammatory response indexes; FIGO: International Federation of Gynecology and Obstetrics.
Association of SIRI level with patients’ clinical data
According to SIRI ≥ 1.90, the patients were assigned to a high SIRI expression group (n=49) or a low SIRI expression one (n=69). Then their differences in clinical data were compared. According to analysis, the high-expression group had a significantly higher proportion of patients with stage III-IV and LNM than the other group (Table 3, P < 0.05).
Table 3.
Association of SIRI expression with patients’ clinical data
| Factor | SIRI | χ2 value | P-value | |
|---|---|---|---|---|
|
| ||||
| High expression group (n=60) | Low expression group (n=58) | |||
| Age (Y) | 0.464 | 0.534 | ||
| ≥ 50 | 33 | 28 | ||
| < 50 | 27 | 30 | ||
| FIGO staging | 8.883 | 0.003 | ||
| Stage I-II | 25 | 40 | ||
| Stage III-IV | 35 | 18 | ||
| Histological type | 0.867 | 0.351 | ||
| Low level | 31 | 25 | ||
| High level | 29 | 33 | ||
| Tumor size | 1.628 | 0.202 | ||
| ≥ 5 cm | 38 | 30 | ||
| < 5 cm | 22 | 28 | ||
| Lymph node metastasis | 5.018 | 0.025 | ||
| Yes | 33 | 20 | ||
| No | 27 | 38 | ||
| Ascites | 0.789 | 0.374 | ||
| Yes | 20 | 15 | ||
| No | 40 | 43 | ||
| Therapeutic regimen | 0.325 | 0.568 | ||
| Simple surgery | 29 | 25 | ||
| Surgical combination chemotherapy | 31 | 33 | ||
Notes: SIRI: systemic immune-inflammatory response indexes; FIGO: International Federation of Gynecology and Obstetrics.
Association of SIRI with tumor markers
The associations of SIRI with CA125, CA153, CA199, AFP, CEA, and HE4 were analyzed. According to the results, SIRI showed a positive correlation with CA125, CA153, and HE4 (all P < 0.05, Figure 3), but had no correlation with CA199, AFP, or CEA (all P > 0.05, Figure 3).
Figure 3.
Scatter plot of SIRI and tumor markers. A. Association analysis of SIRI and CA125 in OC patients. B. Association analysis of SIRI and CA153 in OC patients. C. Association analysis of SIRI and CA199 in OC patients. D. Association analysis of SIRI and AFP in OC patients. E. Association analysis of SIRI and CEA in OC patients. F. Association analysis of SIRI and HE4 in OC patients. SIRI: Systemic immune-inflammatory response index; CA125: Carbohydrate antigen 125; AFP: alpha-fetoprotein; CEA: Carcinoembryonic antigen; HE4: Human epididymis protein 4.
Cox regression analysis of prognostic factors in OC patients
Finally, the prognostic factors of patients’ 5-year survival were analyzed based on Cox regression. According to the results, age, FIGO stage, LNM, SIRI, and therapeutic regimen were linked to the patients’ 5-year survival by univariate analysis (all P < 0.01, Table 4). According to multivariate Cox regression analysis, age, FIGO stage, LNM, SIRI, and therapeutic regimen were independent prognostic factors for t patients’ 5-year survival (all P < 0.05, Figure 4).
Table 4.
Cox regression analysis of factors affecting 5-year survival of OC patients
| Factor | Univariate Cox regression | Multivariate Cox regression | ||||
|---|---|---|---|---|---|---|
|
|
|
|||||
| P-value | HR-value | 95% CI | P-value | HR-value | 95% CI | |
| Age | < 0.001 | 2.508 | 1.511-4.163 | 0.019 | 1.924 | 1.113-3.324 |
| FIGO staging | < 0.001 | 3.090 | 1.875-5.094 | 0.010 | 2.215 | 1.208-4.062 |
| Histological type | 0.187 | 1.381 | 0.855-2.231 | |||
| Tumor size | 0.769 | 0.930 | 0.574-1.508 | |||
| Lymph node metastasis | < 0.001 | 2.521 | 1.548-4.108 | 0.049 | 1.845 | 1.003-3.394 |
| Ascites | 0.939 | 0.980 | 0.581-1.654 | |||
| NEUT | 0.056 | 1.877 | 0.983-3.585 | |||
| LYM | 0.258 | 0.758 | 0.470-1.224 | |||
| SIRI | 0.006 | 0.505 | 0.308-0.826 | < 0.001 | 0.272 | 0.159-0.466 |
| Therapeutic regimen | < 0.001 | 3.395 | 2.062-5.592 | 0.010 | 2.191 | 1.211-3.964 |
Notes: SIRI: systemic immune-inflammatory response indexes; FIGO: International Federation of Gynecology and Obstetrics.
Figure 4.
Prognostic factors and 5-year survival curves of patients. A. K-M curve of age and 5-year survival of patients. B. K-M curve of FIGO stage and 5-year survival of patients. C. K-M curve of lymph node metastasis and 5-year survival of patients. D. K-M curve of SIRI and 5-year survival of patients. E. K-M curve of therapeutic regimen and 5-year survival of patients. Note: K-M: Kaplan-Meier; SIRI: Systemic immune-inflammatory response index; FIGO: International Federation of Gynecology and Obstetrics.
Construction of a risk model
According to the Cox regression coefficient, we constructed a risk prediction model. Risk score =0.654 * age + 0.795 * FIGO stage + 0.613 * LNM + (-1.301) * SIRI + 0.784 * therapeutic regimen. By comparison, it was found that the risk score in the death group was significantly higher than that of the survival group (P < 0.001, Figure 5A). In addition, ROC curve analysis showed that the AUC of the risk score for predicting 5-year survival was 0.876 (Figure 5B).
Figure 5.
Risk score construction and predictive value analysis. A. Relationship between risk scores and patient survival. B. Efficacy of risk scores for predicting patient survival. Note: ***P < 0.001.
Discussion
The application of molecularly targeted drugs has prolonged the progression-free survival of OC patients to some extent in recent years, but the mortality of the disease still ranks first among gynecologic malignant tumors [16].
As the two mediators of tumor microenvironment, immunity and inflammation play a crucial role in the development and progression of tumors [17]. The blood routine test is the most basic part of clinical blood examination. When cells, tissues, organs, and systems have abnormal reactions, the indexes of blood routine examination will also change greatly or slightly, so it can predict the occurrence, progression, and outcome of diseases. This is of great significance for the clinical diagnosis of diseases [18,19]. Peripheral blood cells include pro-inflammatory cells such as neutrophils, monocytes, and platelets, and also include anti-tumor immune cells such as lymphocytes, which can indirectly reflect the tumor microenvironment [20].
SIRI is a blood-based biomarker. Reportedly, a higher SIRI level indicates a stronger systemic immune-inflammatory response [21]. For example, Hua et al. [22] have revealed that SIRI can serve as an indicator to independently predict the survival rate of postmenopausal patients with breast cancer. According to one study by Pacheco-Barcia [23], SIRI is linked to survival rate of patients with metastatic pancreatic cancer and could help predict the prognosis of tumors treated with mFOLFIRINOX. All these studies demonstrate a close correlation between SIRI and tumor survival. In this study, the association of SIRI with OC patients’ survival was evaluated. According to the results, compared to NEUT and LYM, SIRI had a higher level in patients who died from OC, and its area under the ROC curve was larger. The results suggest a close association of SIRI with the death of OC patients. Huang et al. [24] have revealed a correlation of SIRI with an ovarian malignant tumor and a role for SIRI in the differentiation between benign and malignant ovarian tumors and in the rough staging of ovarian malignant tumors. In this study, patients were grouped based on the cut-off value, and SIRI was found to be correlated with the clinical stage and LNM in OC patients, which was in agreement with the research finding of Huang et al. [24]. This further verifies the value of SIRI in OC.
Currently, the markers used for diagnosis of OC include CA125, CA153, CA199, AFP, CEA, and HE4. CA125 is a protein on the surface of some OC cells that can serve as a tumor marker in blood [25]. However, it is not unique to OC, and it may be increased by other factors, such as endometriosis, pelvic inflammatory disease, and liver and lung diseases [26]. CA153 is an antigen linnked to breast cancer and a tumor marker frequently used for clinical diagnosis of breast cancer [27]. With a correlation with cancer, it is sometimes combined with other diagnostic tests to monitor the progression of cancer or evaluate effectiveness of treatment [28]. CA199 is a lipid attached to the cell membrane, but is free in human serum in the form of mucin [29]. Although CA199 is not a specific or reliable tumor marker for OC, Li et al. [30] have revealed an association between an increased CA199 level and advanced OC and unfavorable prognosis. AFP and CEA are tumor markers usually associated with other types of cancer. AFP is usually used for liver cancer and germ cell tumors, while CEA is used for colorectal cancer, lung cancer, and breast cancer [31]. However, the two have been found to be elevated in OC patients [32]. HE4, a protein with overexpression in many types of OC, has been discovered to be a more specific tumor marker for OC than CA125 [33]. HE4 is particularly useful in detecting early OC, because the CA125 of OC cases may not increase [34]. In this study, the associations of SIRI with CA125, CA153, CA199, AFP, CEA, and HE4 were analyzed. According to the results, when CA125, CA153, and HE4 increased abnormally, SIRI also increased compared to traditional tumor markers, but SIRI had no correlation with CA199, AFP, or CEA.
OC is the most fatal disease among gynecologic tumors. Finally, this study analyzed the factors impacting the patients’ 5-year survival rate according to Cox regression. According to the results, age, FIGO stage, LNM, SIRI, and therapeutic regimen were independent prognostic factors for their 5-year survival. Age, FIGO stage, LNM, and prognosis of OC patients have been reported in many studies [35,36]. However, this study has verified for the first time that SIRI is linked to the prognosis in OC patients, which provides evidence for SIRI as a prognostic marker in OC. In addition, we concluded this study by constructing a risk model based on a Cox regression model and found that the risk model was highly expressed in patients in the mortality group and had an area under the curve greater than 0.8 for predicting 5-year survival. This suggests its value for clinical prediction.
This study has confirmed the value of SIRI in OC through analysis, but it still has some limitations. First, only the 5-year survival data of patients had been collected, so whether SIRI is bound up the patients’ overall survival requires further research support. Second, in such a single-center study, the samples collected are limited, so whether SIRI has the same prediction effect in other centers needs further verification. Finally, although SIRI demonstrates the prospect as a prognostic factor in OC, it is important to note that it has not been extensively used in clinical practice. Therefore, further research is needed to fully evaluate the clinical application of SIRI for OC and determine how it can be used with other prognostic markers to improve patients’ prognosis.
In sum, patients with an increased SIRI level account for a large proportion of OC patients with a high FIGO stage and LNM, and the 5-year survival rate of patients with a high SIRI level is unfavorable. This suggests SIRI as an observation index for the prognosis of OC.
Acknowledgements
This study was supported by a grant from the Gynecological Disease Treatment and Reproductive Medicine Centre (No. PPXK2018-06) and the Zhejiang Provincial Medical and Health Science and Technology Project (Observation of the efficacy of gene shearing down rondin with ovarian cancer ex vivo chemotherapy, No. 2021S158).
Disclosure of conflict of interest
None.
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