Inflammation-related indicators have a potential to increase overall quality of the prostate cancer management: a narrative review

Introduction

Prostate cancer (PCa) is a common solid tumour in men. According to the World Health Organization (WHO), there were 1,414,259 new cases of PCa and 375,304 PCa-related deaths worldwide in 2020. PCa is the second most common tumour in men worldwide (1). In 2020, China had a cumulative total of 115,426 cases of PCa and 51,094 deaths associated with PCa, ranking 10^th in terms of incidence and 13^th in terms of mortality from malignant tumours (2). Moreover, the cost of treating PCa is currently increasing more quickly than those of any other cancer (3). For doing this, the paradigm change from reactive treatments of the clinically manifested PCa to a predictive approach and personalised prevention is essential (4).

PCa is a systemic multi-factorial disease. Prostate-specific antigen (PSA) is the only biomarker used for the early detection of PCa. PSA is highly specific for prostate but not for PCa. Consequently, predictive diagnostics by liquid biopsy analysis is instrumental for the disease prediction, targeted prevention and curative treatments at early stages (5). It has been shown that a persistent inflammatory state is associated with malignancy and that inflammatory cells and mediators in the tumour microenvironment mediate a pro-inflammatory response, which can in turn act on the tumour and peritumoural cells in an autocrine and/or paracrine manner (6). The interaction between the two ultimately leads to a poorer prognosis and quality of survival. The tumor microenvironment that composed primarily of immune cells surrounding cancer cells could be a potential prognostic biomarker in PCa (7). Therefore, the levels of inflammation-related indicators may predict the diagnosis of patients, guide treatment, and predict prognostic benefit. The study of inflammation-related indicators and tumour development has been widely applied to a variety of tumours, including PCa (8), lung cancer (9), gastric cancer (10), colorectal cancer (11), and liver cancer (12).

Numerous studies have been conducted on the relationship between PCa and inflammation-related indicators; however, there remains a lack of uniform understanding. In this paper, we will review the literature and summarize the inflammation-related indicators that may be related to the diagnosis and prognosis of PCa and describe their value in clinical applications to provide new perspectives for clinical and research work. We present this article in accordance with the Narrative Review reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-23-55/rc).

Methods

The primary objective of our review was to review the inflammation-related indicators that may be related to the diagnosis and prognosis of PCa and describe their value in clinical applications. Table 1 summarizes the search strategy used for our review. The PubMed database was used for the literature review. We searched for literature related to PCa and inflammation-related indicators. A total of 72 articles from English and Chinese journals published mainly from 2015 to 2022 were screened.

Overview of the inflammation-related indicators

With the progressive research on the relevance of inflammation to tumours, Trinchieri et al. (13) classified tumour-associated inflammation as the seventh major biological feature of cancer. In recent years, increasing evidence has indicated that systemic inflammatory response-related markers may be a new direction for tumour diagnosis, stratification, and prognosis-related markers. The commonly used markers of a systemic inflammatory response include lymphocyte-related inflammation indexes [neutrophil-to-lymphocyte-count ratio (NLR), platelet-to-lymphocyte-count ratio (PLR), lymphocyte-to-monocyte ratio (LMR), C-reactive protein (CRP), procalcitonin (PCT), serum albumin (ALB), lymphocyte count ratio (LCR), and the derived NLR (dNLR) (note: the NLR, PLR and LMR are all used to determine the dNLR)]. The NLR, PLR, LMR, and dNLR can be calculated from routine blood parameters, which is easy to obtain, does not create an additional burden on the patient, is easily accepted by the patient, and is highly operational, thus laying the foundation for their clinical application.

NLR and PCa diagnosis and prognosis (Table 2)

The effect of the inflammatory response on leukocyte sorting counts is usually manifested by neutrophilia and lymphocytopenia, so the NLR is widely used in studies involving the diagnosis, staging, and prognosis of malignancies. In men with PSA levels of 4–10 ng/mL, elevated NLR is strongly associated with the detection of PCa (14). The relationship between the NLR and the Gleason score has also been demonstrated in several studies, including the application of the NLR to predict the current Gleason score (15) and its subsequent elevation (16). However, there is also evidence that the NLR does not yet accurately differentiate benign prostatic hyperplasia (BPH) from PCa (17,18) and does not predict positive prostate puncture biopsy results and scores (39). Moreover, the NLR may have a limited role in predicting early-stage PCa (19). The relationship between the NLR and the diagnosis of PCa is relatively small and contradictory, and more research is needed to further explore its clinical value.

In a meta-analysis conducted by Gu et al. (20) that included both Westerners and Asians, the prognostic value of the NLR in patients with PCa was confirmed, and the association of NLR with recurrence-free survival (RFS) and progression-free survival (PFS) in Asians and Caucasians was existed. This suggests that ethnic differences may influence the prediction of PCa prognosis by the NLR. Other meta-analyses (21,22) have demonstrated the relationship between NLR levels and the prognosis of PCa patients. The above studies suggest that the NLR has prognostic value in PCa and that it could be more actively incorporated into the PCa prognostic evaluation system in future studies.

Patients with localized prostate cancer (LPC) can be cured by radical surgery or radical radiotherapy. Preoperative NLR levels in LPC patients affect their overall survival (OS), cancer-specific survival (CSS), and biochemical recurrence-free survival (BCRFS) after radical prostatectomy (RP). OS, CSS (23), BCRFS (24), and postoperative NLR levels were also associated with patient prognosis (25). However, Maeda’s study did not find a relationship between the NLR and prognosis in patients treated with RP (26), which may be related to their small sample size and lack of rigorous classification of patients with PCa by stage. Zanaty et al. (40) examined patients treated with robotic-assisted PCa resection and also did not find an association between the NLR and patient prognosis. The role of the NLR in patients with LPC is controversial. More studies with strict patient classification and adequate sample size are needed to clarify the prognostic value of the NLR.

The treatment of castration-resistant prostate cancer (CRPC) consists of cytotoxic chemotherapy, androgen deprivation therapy (ADT), molecular targeted therapy, and immunotherapy (41). Previous meta-analyses have demonstrated a strong association between the NLR and the prognosis of patients with CRPC (27). In patients with CRPC treated with docetaxel, a high NLR was associated with poorer OS (42), PFS (42), CSS, and radiographic PFS (rPFS) (28). NLR levels were also associated with prognosis in patients with CRPC treated with cabazitaxel (29,30). Androgen receptors in PCa cells are key to the development and progression of CRPC, and ADT remains the basic treatment for CRPC (41). For patients with CRPC treated with enzalutamide (31,32) or abiraterone (33), the NLR plays a corresponding prognostic predictive role. In addition, increased NLR in patients with CRPC treated with radium-233 radiotherapy is also associated with a poor prognosis (34). Studies on CRPC patients treated with different therapies have demonstrated the prognostic value of the NLR in these patients (27-34,41,42).

Metastasis is one of the most important factors affecting the prognosis of PCa. PCa can metastasize via the blood, lymph, or directly to adjacent organs, with lymph nodes and bone being the most common sites of metastasis. The NLR have a significant predictive value towards the development of metastases PCa (35). It can be used to aid in the diagnosis of bone metastases from PCa (36) and to predict the prognosis of patients with bone and lymphatic metastases from PCa (37,38).

PLR and PCa diagnosis and prognosis (Table 3)

The PLR plays an important role in PCa diagnosis. PLR appears to have the greatest accuracy in predicting an initial diagnosis of clinically significant PCa (csPCa) (35). It is significantly higher in patients with bone metastases from PCa, can predict the development of bone metastases, and there is a correlation between PLR and PSA levels (36). The PLR also has the potential to predict the Gleason score (23). A clinical study showed that pre-prostate biopsy PLR was not an independent predictor of csPCa (43). However, the predictive value of PLR for BPH and PCa has been debated in different studies. In a clinical study conducted by Murray et al. (17) that included 1,223 patients, PLR levels were not statistically different between the BPH and PCa groups, while another clinical study that included 873 patients showed a statistical difference between the two (44). Thus, the PLR may be a potential predictor of PCa and in combination with PSA might reduce the need for unnecessary puncture biopsies.

The PLR is also a potential prognostic indicator. Guo et al. (45) suggested that patients with higher PLR levels have a higher risk of death compared to those with a lower PLR. A meta-analysis including Asians and Caucasians illustrated the prognostic value of the PLR for PCa, and a subgroup analysis also showed differences in the relationship between the PLR and disease-free survival (DFS) for different ethnic groups (46), suggesting that ethnic differences need to be considered in subsequent studies of the prognostic value of the PLR. Similar to the NLR, the PLR has a certain prognostic value in patients who progress to the CRPC stage (33) or in those treated with ADT (47). Sun et al. (48) demonstrated the prognostic value of the NLR and PLR and suggested that the NLR was more effective than the PLR as an independent prognostic indicator for PCa. However, more clinical studies comparing the two are needed to verify the reliability of this finding. In a study of PCa patients undergoing robotic-assisted RP conducted by Zanaty et al. (40), the predictive value of the PLR for PCa prognosis was not verified.

Therefore, the current research on the diagnostic and predictive value of the PLR for PCa is still inadequate and needs to be further validated by more retrospective clinical studies and supplemented by prospective studies.

Other inflammation-related indicators and PCa diagnosis and prognosis (Table 4)

PCT and CRP, as non-specific inflammation-related indicators, can reflect the level of inflammation in the body in the event of infection or tissue damage. Elevated PCT is correlated with the development of PCa (49) and may be useful in improving the diagnostic accuracy of PCa (50). Gómez-Gómez et al. (51) found that pre-puncture CRP levels in patients undergoing prostate puncture were associated with csPCa and higher Gleason scores. Similarly, in patients undergoing RP, elevated preoperative CRP (CRP ≥0.5 mg/dL) is correlated with a postoperative pathological diagnosis of aggressive PCa (52).

In terms of prognostic prediction, the association between CRP and the prognosis of patients receiving different treatment modalities, such as RP (52), chemotherapy (53), and radiotherapy (54), has also been demonstrated. In addition, elevated CRP levels were an independent predictor of poorer OS in metastatic PCa (55). In contrast, other studies have not found a correlation between CRP and PCa (56,57), which may be related to the low specificity of CRP; however, further investigation is needed in the future.

Elevated lymphocyte and monocyte counts are associated with high Gleason scores in PCa (58,59) and monocyte counts can also be used to predict the prognosis of PCa patients (60,61). Bahig et al. (61) reported that neutrophil counts are a predictor of prognosis in LPC patients; Vidal et al. (62) found similar findings in White men undergoing RP but did not find them to be associated with the prognosis of Black men undergoing RP. More research is needed on the role of leukocyte sorting counts in PCa, with particular attention to the effect of different ethnicities on the results.

Many studies support the hypothesis that genetic variations in inflammatory response genes, including IL4, IL6, CCL-2, CCL-5, COX-1, COX-2, could affect the level and function of the protein products, resulting in the differential PCa risk among carriers of different variants. Genotyping of the polymorphisms was performed by using evaluating single nucleotide polymorphisms (SNPs) spanning the entire gene on PCa patients and controls, and the association of each polymorphic genotype with PCa risk was evaluated by using logistic regression analysis based on allele, heterozygous, and homozygous comparison models. For example, the COX-2 (-1195G>A) polymorphism was shown to increase PCa risk in both heterozygous and homozygous comparison models (63). The C allele of IL-4 rs2243250 polymorphism could make PCa risk grow while the C allele of IL-6 rs10499563 polymorphism make down (64). However, no relation was observed for COX-1 (50C>T). Therefore, it is highly suggested to pay more attention to the polymorphism of inflammation-related genes, which maybe serve as potential predictive biomarkers for PCa risk in the Chinese population.

In addition to the above inflammation-related indicators, others such as plasma fibrinogen (FBG), the LMR, and the eosinophils-lymphocyte ratio (ELR) have also been shown to be associated with the diagnosis of PCa. A study by Leng et al. (69) found a positive correlation between FBG and the Gleason score, total PSA (tPSA) levels, and clinical T-stage. In a retrospective analysis, Xie et al. (70) reported that FBG and the NLR were both independent risk factors for the development of PCa and that FBG was an independent predictor of International Society of Urological Pathology (ISUP) grade ≥3 and bone metastasis in PCa. The LMR has predictive value in differentiating PCa from prostate enlargement and prostatitis, especially in patients with PSA levels of 4–10 ng/mL, and its combination with free/total PSA (f/tPSA) is more predictive (65). The ELR can be used as a predictor of elevated Gleason score to assess low-risk PCa and guide patients to proactive monitoring (16).

For PCa prognosis, there are also less studied inflammatory factors such as neutrophil count (61), butyrylcholinesterase (66), systemic immune-inflammation index (SII), ALB, FBG (67), etc. In a study on the prognosis of CRPC patients treated with docetaxel, Man et al. (67) suggested that SII, ALB, and FBG levels could also be used as predictors of patient prognosis, providing new ideas for subsequent clinical studies that could be performed to predict the prognosis of patients with PCa at different stages of progression or treatment modalities, as well as for the investigation of other tumours. Serum levels of butyrylcholinesterase are associated with liver injury, inflammation, and malnutrition (66). Conteduca et al. (68) found that metabolic syndrome (MS) was associated with PFS and OS in CRPC patients. MS is a group of metabolic disorder syndromes whose pathogenesis involves patients being in a chronic low-grade inflammatory state for a long time, with inflammatory phenomena such as increased cytokines. This perspective further demonstrates the importance of the inflammatory response in the development of PCa.

The predictive value of the above inflammation-related indicators for the diagnosis and prognosis of PCa has been widely studied but has not yet been applied in clinical practice. Therefore, there is a need to find more meaningful predictors or develop comprehensive predictive models to further guide diagnosis and treatment after screening and to predict the prognosis of patients.

Summary and discussion

Currently ineffective PCa screening

The promotion of PSA screening led to a rapid increase in the incidence of PCa from the late 1980s to the early 1990s (71). However, PSA is less specific and may lead to unnecessary puncture biopsies and consultations. Also, prostate puncture operations, drug treatments, and surgery may result in serious complications for patients. Inflammation-related indicators based on haematological tests have some diagnostic and prognostic value both when used alone and in combination with common clinical indicators such as PSA, and can significantly improve the accuracy of diagnostic results.

Paradigm change from reactive to predictive and preventive PCa management is essential

PCa incidence is permanently increasing in adolescents and young adults (aged 15–40 years). Also, the rates of metastasising PCa are steadily growing up in the young population (4,72). Socio-economic burden is enormous: PCa treatment costs increase more rapidly than for any other cancer (4). To this end, inflammation-related indicators is a promising approach in predicting the diagnosis and prognosis of PCa patients. The relationship between NLR levels and PCa has been extensively reported. The diagnostic value of NLR for PCa lies primarily in its use in combination with PSA for screening patients with suspected PCa, thereby improving the specificity of screening and predicting poor pathological outcomes, among other things. This not only reduces the need for patients to undergo unnecessary tests but also provides guidance regarding whether to undergo aggressive interventions. The prognostic value of the NLR has been studied in a wider variety of patients and in a more detailed way than diagnosis, owing to the different stages of progression and treatment modalities of PCa patients. NLR prognosis has mainly involved LPC, CRPC, metastatic PCa, and its different treatment modalities, including radical surgery, radiotherapy, chemotherapy, and ADT. Numerous studies have shown that NLR has a strong prognostic predictive value; however, some of the findings are controversial and more studies are needed to further confirm them.

Targeted modulation of inflammation for PCa is currently lacking in clinical practice, but one study has shown that the use of NSAIDs such as aspirin is negatively associated with PCa incidence and specific mortality (73). Another study based on dietary inflammatory index suggests that diet may influence the prognosis of patients with more aggressive PCa through its inflammatory potential (74). Dietary interventions aimed at reducing inflammation may be considered to improve the survival of men with PCa (74).

The diagnostic and prognostic value of the PLR and other inflammation-related indicators have also been reported but more research is needed to explore their applicability in clinical work, as there are only a few studies and contradictions between some of the results. We think the possible reason for inconsistent previous research results is the patient stratification that differently. Other possible explanations for the different findings were probably related to the variation in the methodology.

The shortcomings in the existing studies

Many studies have been conducted on the value of inflammation-related indicators in guiding the diagnosis and treatment of PCa; yet, there are still many shortcomings in the existing studies. Firstly, most of the existing studies were only conducted on single factors and on patients with single conditions. There is also a lack of comprehensive studies and a systematic evaluation system has not been developed. Additionally, more studies on patients from different ethnic groups and different geographical areas are needed. Secondly, the conclusions of the existing studies are somewhat divergent, and the value of clinical translation is open to question. Thirdly, retrospective clinical data analysis accounts for the majority of existing research; there are few prospective studies, and the role of inflammation-related indicators has not been fully confirmed.

Conclusions

Although the value of inflammation-related indicators in predicting the diagnosis and prognosis of PCa is now becoming clear, further studies are still needed to validate the present findings. Also, the correlation between relevant inflammation-related indicators and prognosis may suggest mechanisms of tumour progression, and more basic research is needed to support clinical work.

Acknowledgments

Funding: The work was funded by the President Foundation of Nanfang Hospital, Southern Medical University (Nos. 2020B025 and 2022A029).

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-23-55/rc

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(English Language Editor: A. Kassem)