Abstract
Our study aimed to examine the predictive relevance of the Systemic Immune-Inflammation Index (SII) in patients with metastatic castration-resistant prostate cancer (mCRPC). A total of 113 mCRPC patients were assessed. In this descriptive study, SII was calculated using the formula (neutrophil count × platelet count)/lymphocyte count. The optimal threshold for SII, determined via the ROC curve, was 700. Patients with SII ≤ 700 were classified as SII-low, while those with SII > 700 were categorized as SII-high. The median overall survival (mOS) was significantly longer in the low SII group compared to the high SII group (*P = 0.015). In multivariate analysis, Gleason score, albumin levels, CHAARTED volume, and SII were identified as significant prognostic factors. Our findings indicate that SII has a strong correlation with survival and can serve as an independent prognostic marker in mCRPC patients.
Keywords: Cancer of prostate, Biomarkers, Prognosis, Blood test, Inflammation
Introduction
Prostate Cancer (PC), the most common cancer in men, is the second leading cause of cancer-related deaths. At the time of diagnosis, between 6 and 44% of patients are found to have metastatic prostate cancer [1–3]. In the United States, approximately 11% of men are expected to be diagnosed with prostate cancer at some point in their lives, with the incidence rate generally rising with age. The overall five-year survival rate is above 98% [4]. Surgical intervention, radiotherapy, and androgen deprivation therapy (ADT) are effective treatments in controlling the disease at the local stage. However, the progression to a metastatic stage is inevitable for some patients. Patients who experience recurrence after radical treatments are classified as having castration-sensitive prostate cancer (CSPC). In recurrent patients, ADT was initially the only treatment option. Over time, as ADT became ineffective in mCSPC patients, the combined use of systemic therapies was initiated, particularly to improve survival outcomes. These therapeutic modalities include docetaxel or new-generation hormonal agents such as enzalutamide, abiraterone, apalutamide and darolutamide [5]. Although a significant proportion of patients respond to treatment, many progress to a castration-resistant stage. At this stage, patients are considered to have metastatic castration-resistant prostate cancer (mCRPC).
Treatment selection has become a crucial factor in predicting treatment response and prognosis, as demonstrated by clinical studies. The Chemo-hormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer (CHAARTED) study established high-volume and low-volume disease criteria, defining high-volume disease as having four or more bone metastases, with at least one outside the axial skeleton and/or visceral organ metastases [6]. This study showed that docetaxel improved survival in high-volume patients, but not in those with low-volume disease. In the Leuprolide and Abiraterone in High-Risk Metastatic Hormone-Sensitive Prostate Cancer (LATITUDE) study, patients were categorized into high-risk and low-risk groups. High-risk patients were defined as those meeting at least two of the following criteria: I) Gleason score ≥ 8 from prostate biopsy, II) three or more bone metastases, III) visceral organ metastasis. The study found that abiraterone extended survival in high-risk patients [7]. Despite the improvements in survival with new treatments, there remains a need for a biomarker to predict treatment outcomes and prognosis in patients with metastatic disease.
Inflammation has a vital role in PC malignancy by causing DNA damage and activating oncogenic pathways. It can generate "inflammatory storms" that not only foster mutations but also enable tumors to evade detection by the immune system [8].
Inflammation is recognized as a key factor not only in inflammatory disorders but also in cancer progression. It is suggested that certain tumor-derived substances contribute to cancer development by enhancing systemic inflammation. Lymphocytes have been shown to inhibit tumor cell migration and invasiveness by producing interferon-gamma and tumor necrosis factor-alpha. Conversely, an increase in neutrophils has been linked to the promotion of tumor pathogenesis through elevated levels of C-X-C motif chemokine ligand 8, nuclear factor kappa-B (NF-kB), TGF-β1 (Transforming Growth Factor-beta-β1), and VEGF (Vascular Endothelial Growth Factor). Moreover, circulating monocytes differentiate into macrophages, which release proteases that degrade the extracellular matrix, thereby altering the tumor microenvironment [9]. Consequently, both local and systemic inflammation are believed to play a pivotal role in tumor development, cell proliferation, invasion, and metastasis. Previous research has highlighted the prognostic significance of inflammatory markers such as the neutrophil–lymphocyte ratio (NLR), derived neutrophil–lymphocyte ratio (dNLR), lymphocyte-monocyte ratio (LMR), and platelet-lymphocyte ratio (PLR) in PC [10–12]. A poor prognosis for cancer patients is linked to an increased NLR [13]. Additionally, platelets influence tumor cell survival and metastatic potential [14]. It is hypothesized that a prognostic model combining N, L, and P counts would provide greater sensitivity than models based on a single factor. In 2014, Hu and colleagues introduced the SII to predict outcomes in patients undergoing curative resection for hepatocellular carcinoma [15]. The SII is calculated using the following formula, based on preoperative peripheral blood counts of platelets, neutrophils, and lymphocytes: SII = (P x N/L) [16].
Although new agents have extended the survival time in mCRPC, there remains a need for new biomarkers to predict survival. The purpose of this study is to calculate SII's possible prognostic value in patients with mCRPC.
Methods
Patient population
In this study, 157 patients newly diagnosed with mCSPC between January 2015 and January 2023 at the Medical Oncology Clinic of Dokuz Eylül University Hospital were evaluated. Patients were categorized based on the CHAARTED study criteria into high-volume disease (HVD) or low-volume disease (LVD) groups, and according to the LATITUDE study into high-risk disease (HRD) or low-risk disease (LRD) groups. HVD was defined as the presence of visceral metastasis or at least four bone metastases, with at least one outside the vertebrae and pelvis [6]. HRD was defined as meeting at least two of the following criteria: Gleason score (GS) ≥ 8, visceral metastasis, or three or more bone metastases [7]. Every newly diagnosed patient with mCSPC underwent maximal androgen blocking therapy, which included 50 mg of bicalutamide daily in addition to surgical or pharmacological castration. A total of 113 patients who met the criteria for CRPC following follow-up and treatments were identified as the study population. Patients who were at least 18 years old met the inclusion requirements, diagnosed with stage IV prostate carcinoma, having received at least one line of treatment for prostate carcinoma including ADT, and subsequently progressing to castration-resistant clinical status. Exclusion criteria were the inability to access patient data from the hospital database, castration-sensitive patients, and the presence of concurrent malignancies (excluding in situ carcinomas, non-invasive bladder carcinomas, and non-melanoma skin cancers). CRPC is defined as the development of biochemical or radiological progression despite castrate levels of serum testosterone. Castrate testosterone levels are < 50 ng/dl (< 1.7 nmol/L). Biochemical progression occurs if the PSA value is above 2 ng/dl and shows an increase of more than 50% in at least two of three PSA measurements taken one week apart. Radiological progression is defined as the appearance of two or more new metastases on bone scintigraphy or progression of soft tissue metastases according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria [16].
The formula for the SII
Hematological data, including white blood cell count, P, N, and L measurements at the time of CRPC progression, were retrospectively collected for mCRPC patients. The SII, calculated using P, N and L counts as SII = P*N/L, serves as an inflammatory marker. To evaluate its prognostic value for patient survival, SII measurements were analyzed based on cut-off values obtained from Receiver Operating Characteristics (ROC) curve analysis. The average threshold value determined by ROC analysis was 700, categorizing patients into two groups: SII ≤ 700 as SII-low and SII > 700 as SII-high. Additionally, baseline clinical and pathological data were collected, including patient age, PSA levels at initial diagnosis and at the time of CRPC diagnosis, GS, Eastern Cooperative Oncology Group (ECOG) performance status, and the presence of visceral and bone metastases. Patients with PC who were diagnosed with infectious disorders were not allowed to participate in the trial in order to minimize the possible impact of infectious diseases on the predicted accuracy of inflammatory markers. The time between diagnosis and death was referred to as OS.
Ethics approval
The Helsinki Declaration of 1964, its later updates, and comparable ethical principles, as well as institutional and national bodies' ethical standards, were all followed in the research involving human subjects. The study was authorized by Dokuz Eylul University's ethical committee (Approval Number: 2024/27-03).
Statistical analysis
Descriptive statistics for the study population were presented as frequencies and percentages (n (%)) for categorical variables, while numerical variables were summarized using the mean, standard deviation (mean ± SD), minimum, maximum, and median (M) values. Fisher's exact test, chi-square tests, and the Mann–Whitney U test were used to examine patient characteristics and covariates. ROC analysis was conducted to identify the optimal cut-off value for distinguishing patients at high risk of cancer-related mortality. The Kaplan–Meier technique was used to estimate overall survival based on SII, and the log-rank test was used to assess survival differences. The determinants influencing survival were identified using Cox regression analysis. SPSS (version 24.0) was used in all statistical analyses.
Results
Patient characteristics
There were 113 mCRPC patients in our study. The patients were elderly, as evidenced by their median age of 73 ± 8.21 years. At the time of metastasis diagnosis in the castration-sensitive phase, the median PSA value was 65 ng/dl. The median PSA level at the time of mCRPC diagnosis was 17.70 ng/dL. By the end of the study, 72 (63.7%) patients were still alive, while 41 (36.3%) had died. The ROC analysis classified patients into two groups: SII ≤ 700 and SII > 700. The area underneath the curve was 0.647 (*P = 0.031, 95% CI: 0.51–0.57) (Fig. 1).
Fig. 1.
Receiver operating characteristic curve analysis of the optimal cut-off value for systemic inflammation response index (SII) in patients with mCRPC
Based on the combined GS (primary and secondary), 4 (3.5%) patients had a score ≤ 7, 36 (31.9%) patients had a score of 7, and 70 (61.9%) patients had a GS of 8 or higher. Medical castration was preferred in 96 (85%) patients, while surgical castration was chosen for 17 (15%) patients (Table 1 shows the relationship between patient characteristics and SII).
Table 1.
Patients’characteristics
| Parameter | Low SII group (≤ 700 × 109 cells/L) | High SII group (> 700 × 109 cells/L) | Total | P |
|---|---|---|---|---|
| N (%) | N (%) | N (%) | ||
| Age | 0.37 | |||
| ≤ 65 | 12(57.1%) | 9(42.9%) | 21 (25.6%) | |
| > 65 | 28(45.9%) | 33(54.1%) | 61 (74.4%) | |
| Survival | 0.07 | |||
| Alive | 17 (63%) | 10(37%) | 27 (32.9%) | |
| Dead | 23(41.8%) | 32(58.2%) | 55 (67.1%) | |
| Gleason Score | 0.86 | |||
| ≤ 7 | 15(50%) | 15(50%) | 30(48.8%) | |
| > 7 | 24(48%) | 26(52%) | 50(51.2%) | |
| Surgery | 0.20 | |||
| No | 31(45.6%) | 37(54.4%) | 68(82.9%) | |
| Radical prostatectomy | 9(64.3%) | 5(35.7%) | 14(17.1%) | |
| Site of Metastasis | 0.78 | |||
| Non-Visceral | 36(49.3%) | 37(50.7%) | 73(89%) | |
| Visceral | 4(44.4%) | 5(55.6%) | 9(11%) | |
|
Volume According to CHAARTED (at the time of mCSPC) |
0.39 | |||
| Low Volume | 17(54.8%) | 14(45.2%) | 31(37.8%) | |
| High Volume | 23(45.1%) | 28(54.9%) | 51(62.2%) | |
|
Risk According to LATITUDE (at the time of mCSPC) |
0.34 | |||
| Low risk | 26(53.1%) | 23(46.9%) | 49(59.8%) | |
| High risk | 14(42.4%) | 19(57.6%) | 33(40.2%) | |
| PSA Level at the Time of mCRPC Diagnosis | *0.02 | |||
| ≤ 20 | 26(60.4%) | 17(39.6%) | 43(52.4%) | |
| > 20 | 14(35.8%) | 25(64.2%) | 39(47.6%) | |
| Albumin | *0.02 | |||
| ≤ 4 | 11(34.4%) | 21(64.6%) | 32(42.1%) | |
| > 4 | 27(61.4%) | 17(38.6%) | 44(57.9%) |
Bold values highlight statistically significant items
SII, systemic immune-inflammation index; PSA,prostate spesific antigen; mCRPC,metastatic castration-resistant prostat cancer; mCSPC, metastatic castration-sensitive prostat cancer; *p < 0.05 indicates a significant difference., *p > 0.05 indicates no significant difference; chi-square test
Classification according to CHAARTED and LATITUDE Studies
A total of 113 patients were classified according to the CHAARTED study as HVD and LVD, and according to the LATITUDE study as HRD and LRD at the time of castration-sensitive status. According to the CHAARTED study, 37 patients (32.7%) were categorized as LVD and 76 patients (67.3%) as HVD. According to the LATITUDE study, 64 patients (56.6%) were classified as HRD and 49 patients (43.4%) as LRD. Median OS for HVD patients was 75 months compared to 44 months for LVD patients (>**P = 0.003). The OS for HRD patients was 71 months, while for LRD patients it was 35 months (>***P= 0.001).
Treatment characteristics
Docetaxel was the most commonly utilized first-line treatment for CRPC, accounting for 42.5% of all treatments. The second most commonly chosen first-line treatment was enzalutamide at 28.3%, followed by abiraterone as the third choice at 11.3%. In second-line treatment, hormonal options like abiraterone and enzalutamide were preferred more frequently than chemotherapy.
Impact of SII values on survival
When the median OS levels were compared, the median OS was 71 months for the low SII group and 40 months for the high SII group, indicating a statistically significant relationship between SII levels and survival outcomes. (>*P = 0.015). The Kaplan–Meier survival curve illustrating OS based on SII values is presented in Fig. 2.
Fig. 2.
Kaplan–Meier curve for OS according to SII values
In univariate analysis, age, SII, Gleason group, albumin at the time of CRPC diagnosis, visceral involvement, classifications according to the CHAARTED and LATITUDE studies, body mass index (BMI), and PSA value at the time of mCRPC diagnosis were statistically significant for survival. In multivariate analysis, Gleason group, albumin, volume according to CHAARTED, and SII were significant (Table 2).
Table 2.
Univariate and multivariate cox regression analysis for overall survival
| Characteristics | n (%) | Median Overall Survival | Univariate analyzes | P value | Multivariate analyzes | P value |
|---|---|---|---|---|---|---|
| HR (95% CI) | HR (95% CI) | |||||
| Age | ||||||
| ≤ 65 | 25 (22.1) | 29 | 1 | **0.01 | ||
| > 65 | 88 (77.9) | 61 | 1.93 (1.11–3.34) | |||
| Gleason Groups | ||||||
| ≤ 7 | 40 (35.4) | 71 | 1 | 1 | ||
| > 7 | 70 (61.9) | 44 | 1.84 (1.12–3.05) | ** 0.01 | 4.62 (2.0–10.6) | *** < .001 |
| Albumin at CRPC Diagnosis | ||||||
| ≤ 4 | 32 (28.3) | 40 | 1 | *** < .001 | 1 | |
| > 4 | 44 (38.9) | 72 | 0.36 (0.21–0.64) | 0.34 (0.16–0.70) | **0.004 | |
| Visceral Involvement | ||||||
| Non-visceral | 99 (87.6) | 59 | 1 | *0.03 | ||
| Visceral | 14 (12.4) | 34 | 2(1.04–3.84) | |||
| Volume According to CHAARTED | ||||||
| Low Volume | 37 (32.7) | 75 | 1 | **.004 | 1 | |
| High Volume | 76 (67.3) | 44 | 2.21 (1.28–3.82) | 2.27 (1.04–4.94) | *0.03 | |
| Risk According to LATITUDE | ||||||
| Low risk | 64 (56.6) | 71 | 1 | *** < .001 | ||
| High risk | 49 (43.4) | 35 | 2.76 (1.71–4.44) | |||
| PSA Level at CRPC Diagnosis | ||||||
| ≤ 20 | 53 (46.9) | 83 | 1 | *** < .001 | ||
| > 20 | 44 (38.9) | 43 | 2.43 (1.45–4.08) | |||
| BMI | ||||||
| 18.5–24.9 | 29(25.7) | 32 | 1 | |||
| 25–29.9 | 63 (55.8) | 61 | – | **.007 | ||
| ≥ 30 | 21 (18.6) | 75 | 0.60 (0.42–0.87) | |||
| SII | ||||||
| ≤ 700 | 40 (35.4) | 71 | 1 | **0.01 | 1 | *0.04 |
| > 700 | 42 (37.2) | 40 | 1.93 (1.11–3.34) | 1.93 (1.0–3.73) | ||
Bold values highlight statistically significant items
SII, systemic immune-inflammation index.; HR, hazard ratio; CI, confidence interval; BMI, body mass index; mCRPC, metastatic castration-resistant prostat cancer; PSA, prostate spesific antigen
Discussion
The incidence of prostate cancer increases with age and remains lethal in the metastatic stage despite all recent advancements. When patients progress to the castration-resistant stage, the course of the disease changes significantly, and the expected lifespan is considerably shortened [17]. It is increasingly accepted that systemic inflammation initiates and worsens the pathological process of chronic diseases. This study looked at the predictive importance of SII values in patients with mCSPC who later developed mCRPC during follow-up. The data showed that patients with low SII values had significantly better survival outcomes than those with high SII values, implying that SII could be a useful prognostic marker in this patient population.
There is a close relationship between cancer and inflammation. The association of leukocytes infiltrating neoplastic tissues with cancer was first described by Rudolf Virchow in 1863 [18]. In recent years, as the tumor immune microenvironment has been studied in more detail, it has been observed that tumor formation and progression are influenced by the systemic inflammatory response. In cancer, inflammation is triggered by the activation of transcription factors such as NF-kB, Signal Transducer and Activator of Transcription 3 (STAT3), and Hypoxia-Inducible Factor 1a (HIF-1a). These transcription factors regulate the production of cytokines, including Tumor Necrosis Factor-alpha (TNF-α), Interleukin 1β (IL-1β), and Interleukin 6 (IL-6), which contribute to tumor progression by promoting growth and survival. As a result, hematopoietic changes occurring during the inflammation process play a significant role in weakening the immune response and promoting tumor growth. It is now widely accepted that the growth of cancer is affected not only by the tumor's intrinsic features, but also by the host's immune response. Additionally, a heightened systemic inflammatory reaction has been repeatedly associated with worse clinical outcomes, irrespective of tumor stage. This response is distinguished by the presence of white blood cells, neutrophils, lymphocytes, and platelets, as well as acute phase proteins such as C-reactive protein and albumin. These markers can be easily assessed using standardized tests that are broadly available. A major factor contributing to poor prognosis is the ability of tumor cells to metastasize. As they circulate in the bloodstream, circulating tumor cells (CTCs) can interact with platelets, which may help shield them from hemodynamic stress and immune system attacks, particularly from natural killer cells [19]. Moreover, platelets have the ability to secrete chemokines and cytokines that enhance the growth and survival of metastatic tumor cells [20]. In contrast, circulating lymphocytes play a significant role in inhibiting tumor cell proliferation and preventing metastasis. Furthermore, a high preoperative L count has been associated with improved results in individuals with pancreatic ductal adenocarcinoma who underwent surgery [21].
The NLR is one of the most studied inflammatory markers, and high NLR levels are widely accepted as predictors of poor survival, regardless of tumor type, stage, or treatment [22]. The prognostic roles of other inflammatory biomarkers in cancer have also been evaluated [23, 24]. NLR, PLR, and SII have all demonstrated predictive significance in mCRPC patients treated with chemotherapy and new-generation hormonal treatments [25, 26]. In our study, the patients were analyzed in two main groups: SII ≤ 700 and SII > 700 (AUC = 0.647, sensitivity: 42%, specificity: 63%, *P = 0.03) and SII demonstrated prognostic power in both univariate analysis and was independently associated with longer survival in multivariate analysis (HR: 1.93, 95% CI: 1.0–3.73, *P = 0.04). Further studies have shown that SII may be a valuable prognostic marker in various other cancers, including small cell lung cancer, renal cell carcinoma, and esophageal squamous cell carcinoma [27–29]. This implies that SII could be utilized as a prognostic predictor in "basket" trials, which test several cancer types with the same genetic mutation [30]. Thus, by using SII alongside specific targeted therapies, we can treat various tumors. In a meta-analysis of twelve prostate cancer studies, greater SII was related with lower OS (HR = 1.44, 95% CI: 1.23–1.69, ***P < 0.001) [31]. Chen et al. suggested in their meta-analysis of non-squamous lung cancer patients that high SII is associated with a worse prognosis [32]. Similarly, another meta-analysis conducted on colorectal cancer patients showed that those with high SII levels had worse disease outcomes, which were linked to poor overall survival [33]. It is evident that SII is an important marker not only in cancer patients but also in other conditions. A meta-analysis of patients diagnosed with COVID-19, which caused a devastating global pandemic in 2019, showed that high SII at the time of hospital admission may be a potential prognostic indicator for death during hospitalization, especially in individuals categorized as low-risk [34]. In keeping with previous research, our findings showed that the median OS was much longer in the low SII group than in the high SII group. The strong predictive significance of SII seen in these investigations can be attributable to its complete representation of inflammatory components, which includes a variety of immune-inflammatory cells.
The goal of a cancer treatment program is to treat cancer effectively without posing unnecessary risks to the patient. However, this can be challenging in elderly cancer patients, as clinical trials often do not include older patients. Chen et al. suggested in their study that SII might be used as an independent prognostic factor in newly diagnosed elderly cancer patients, with correlations to tumor differentiation and one-year survival [35]. Indeed, our study population was very elderly, with a median age of 73 ± 8.21, and SII may be a highly sensitive prognostic marker for OS in this group. The research contains limited evidence about the relationship between inflammatory indices and poor prognosis mCRPC variants, such as visceral metastases, neuroendocrine differentiation, AR gene amplification, or mutations [36, 37]. In our study, the median survival time was considerably longer in the group without visceral metastases (**P = 0.004).
The LATITUDE and CHAARTED studies' criteria were shown to have prognostic and predictive relevance. At the initial diagnosis in the hormone-sensitive stage, the 113 mCRPC patients in our study population were classified according to these criteria. However, Kawahara et al. argued that there were significant differences in predictions made based on these criteria [38]. For instance, 27.3% of patients classified as low risk according to the LATITUDE criteria were identified as having HVD based on the CHAARTED criteria, while 3.2% of those categorized as high risk according to LATITUDE displayed LVD according to CHAARTED. This highlights a notable discrepancy between the two classification systems. Additionally, no significant correlation was found between SII values and classifications based on the LATITUDE and CHAARTED criteria. In contrast, univariate analysis revealed significant associations between survival and the classifications under both LATITUDE and CHAARTED criteria (HR = 2.21, 95% CI: 1.28–3.82, **P = 0.004; HR = 2.76, 95% CI: 1.71–4.44, **P = 0.001). Additionally, multivariate analysis showed a significant relationship between survival and classifications made according to CHAARTED criteria (HR = 2.27, 95% CI: 1.04–4.94, *P = 0.03). This could be owing to a difference between the LATITUDE and CHAARTED criteria, or an inadequate number of patients. Furthermore, mCRPC encompasses a highly heterogeneous disease spectrum. We believe that the disease burden and risk at the time of initial diagnosis, as classified by these criteria, can provide insight into survival during the hormone-resistant stage. Therefore, the disease burden and risk factors at the time of initial diagnosis are determinant characteristics throughout the disease course.
The importance of balancing the costs and advantages of tumor treatment regimens cannot be overstated, and the ease with which SII may be measured using normal blood tests makes it a practical and cost-effective addition to patient assessments. However, the retrospective nature of this study, the heterogeneous patient population, and the moderate sample size limit the generalizability of the results due to potential selection bias. Consequently, a large-scale, prospective study with a more homogeneous patient cohort is necessary to validate these findings.
Our findings confirm that SII can be utilized as an independent prognostic factor in mCRPC patients, and it has a substantial link with survival. Therefore, SII should be recommended as a practical and cost-effective blood test.
Author contributions
The project was conceptualized by Uzun M., while data curation was handled by S. Semiz H. and formal analysis was also conducted by Uzun M.. The investigation and data collection were carried out by Gökçek S., and the methodology was developed by S. Semiz H.. Visualizations, including graphics and presentations, were prepared by Gökçek S., with the original draft of the writing completed by Uzun M. and the review and editing finalized by Kaya E.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Data availability
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.
Declarations
Conflict of interest
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.