Current state of prostate cancer treatment and future strategies

1. Introduction

Prostate cancer (PCa) is the most prevalent malignant tumor in men worldwide [1, 2, 3]. Prostate has two layers, i.e., basal and luminal epithelial cells with different characteristics. The luminal epithelial cells require androgen signaling for androgen receptor expression and survival, while basal ones are androgen negative and do not need specific orchiectomy. Heterogeneous PCa masses occur in a small number of cases, but they do not give rise to cancer stem cells. However, these cancer cells can metastasize to the lymph nodes and bones. This gives rise to cancer stem cells which metastasize toward the lymph and bone [4, 5]. Genetics account for ~58% PCa cases whereas poor lifestyle increases the PCa risk [6].

Smoking, alcohol, increasing age, black ethnicity, certain gene mutations, family history of insulin-like growth factor (IGF) or malignancy, obesity, diabetes, and radiation exposure contribute to the PCa development [7, 8, 9]. PCa can be localized, progressive, or metastatic. The 10-year PCa-specific survival rate is ~95% for localized disease. The 5-year survival rate for metastasis is ~35% which makes it dangerous for men [10]. It is brought by the androgenic male hormones. Early diagnosis and treatment are vital as it can invade bones if metastasized through the bloodstream, not the lymphatic system [11, 12]. PCa accounts for large proportion of cancer-related deaths. It involves both immutable and modifiable risk factors. Age, race, family history and germline variation are the non-modifiable, while metabolic syndrome, obesity and smoking are the known modifiable risk factors [13]. Resultantly, there are several diagnostic and treatment choices for early PCa detection.

Early detection of metastatic or high-risk prostate cancer is crucial. It includes physical examination, magnetic resonance imaging (MRI), prostate-specific antigen (PSA) test, and biopsy. Most cases of prostate cancer are not aggressive and can be managed with active surveillance [14, 15, 16]. Monitoring is recommended for early diagnosis because of its asymptomatic nature, long latency period, and potential aggressiveness [17, 18, 19, 20]. The approach to treatment is usually through hormones. Hormone replacement therapy interferes with the production of male hormones, i.e., androgen and testosterone. It combines radiation therapy with chemotherapy [14]. If PCa becomes severe, there are therapies to remove testicles for reducing testosterone levels or to replace hormone that kills invasive cancer cells [21]. PCa prognosis is still not conducive despite implementing various diagnostic and therapeutic approaches. Moreover, problems like erectile dysfunction, low libido, obesity and decreased bone mass also arise [22]. Mortality and PCa incidence have been related with human development indices and influenced by the regional differences in epidemiologic characteristics [23]. Epidemiologic reviews, diagnosis, treatment, and prevention need to be systematically organized. This review thus aims to summarize epidemiologic review of PCa, PCa diagnosis at early, intermediate and late stages, and PCa treatment and prevention strategies including surgical and chemotherapeutic. This can predict potential future treatments for PCa and define currently available diagnostic, treatment and prevention methods. Few papers are published on PCa which use multiple modalities for strategic diagnosis, modeling, and analysis of clinical settings. PCa being the leading cause of death in men has many challenges to be addressed.

2. Methods

The content was systematically searched from online databases including PubMed, Science Direct, Scopus and Google Scholar using keywords, “prostate cancer treatment”, “PCa”, “PCA” and “prostate cancer” in the period from 2019 to 2024. Articles were screened based on predefined inclusion and exclusion criteria. Inclusion criteria covered clinical case studies, randomized controlled trials, experiments and longitudinal, epidemiologic and bioactivity studies related to research topic. Exclusion criteria filtered out the non-essential articles including reviews, case analyses, theses, letters, editorials, articles with no full text access, and those having clinical concerns. Literature search yielded total of 1890 articles with 924 from PubMed, 92 from ScienceDirect, 51 from Scopus and 823 from Google Scholar. The duplicates and articles without full-text access were removed. A primary review was conducted to scrutinize the abstracts and full texts for their relevance. This reduced the pool to 1247 articles.

A secondary review was conducted to further refine the selection which resulted in 17 articles. The selected articles were comprehensively evaluated for their adherence to inclusion criteria. The study subjects, methods and results were examined to ensure the robustness and reliability of gathered literature (Fig. 1).

Fig. 1.Flowchart of the articles’ selection process. PCa: Prostate cancer.

3. PCa diagnosis

PCa is categorized as androgen-sensitive or androgen-insensitive. This indicates testosterone stimulation and assists in choosing the treatment strategy. PCa treatment is divided into active surveillance, chemotherapy, radiation therapy, ablative surgery, hormonal therapy, and cryotherapy based on androgen response-based diagnosis. The patient’s tumor level is subdivided according to PSA level, recurrence and metastasis likelihood, and prostatectomy presence [24, 25, 26]. PSA testing is effective for the early detection of PCa, but it does not reliably predict prognosis. Therefore, there is a need to identify new prognostic biomarkers. PCa is diagnosed through PSA testing, rectal examination, tissue biopsy, and standard biochemical testing. However, these diagnostic methods are not suitable for the very early stages of prostate cancer, highlighting the need for the discovery of new biomarkers. PSA levels can be elevated in PCa as well as other conditions such as benign prostatic hyperplasia and prostatitis. The PSA test becomes unreliable in prostate cancer patients with values below 4 ng/mL. Therefore, PSA testing is often performed in conjunction with a rectal examination or biopsy [27].

Tumor, node and metastasis (TNM) classification system considers tumor size, lymph node involvement, and distant metastases to assess tumor staging [28]. This accurately determines the tumor characteristics of PCa. Low-grade PCa have smaller and slow-growing tumors with fewer symptoms. PCa of intermediate malignancy is relatively fast-growing which may invade surrounding tissues. Highly malignant PCa grows rapidly and spreads to surrounding tissues and lymphatic vessels [29]. TNM classification and tumor malignancy influence treatment choices. For instance, low-malignancy PCa may be considered for conservative treatment like surveillance or radiation therapy, while high-grade tumors may require more curative approach, e.g., surgery, chemotherapy and radiation therapy. Clear, and easy-to-understand communication between patient and doctor helps in understanding TNM classification and tumor malignancy [30]. Treatment strategies for PCa are thus individualized by considering tumor pathological characteristics and patient’s overall health status. A conservative treatment is considered for tumors of low- or intermediate-risk [31, 32]. PCa is graded based on the TNM staging system and Gleason score. Monitoring is recommended for early diagnosis because of its asymptomatic nature, long latency period, and potential aggressiveness [33]. This minimizes side effects and maintains patient’s life quality by considering tumor growth and managing treatment accordingly. An intense treatment may be needed for high-risk PCa which includes surgery, radiation therapy, chemotherapy, hormone therapy, and other radical treatments [34]. These treatments remove or control the tumor, prevent recurrence, and improve patient survival. It is important to consider tumor risk and patient’s overall situation for determining appropriate treatment. A non-radical treatment emphasizes on tumor growth and conducted when necessary [35].

Early diagnosis and prompt treatments are crucial for PCa management. Biopsy being a key diagnostic test for PCa requires anesthesia. Anesthesia involves a blend regarding pain management, skin consideration, and muscle relaxation with the intensity depending on approach toward perineal and rectal biopsy. Proper anesthesia is essential for completing the histologic examination [36]. Anesthesia includes postoperative analgesia as the local anesthesia. It also involves neurological, pulmonary, cardiovascular, and hematologic evaluations. Regional anesthesia is safe, however there can be the risks of failure and low incidence of local anesthetic systemic toxicity (LAST), nerve damage, falls, or complications like hematomas, infections and allergic reactions. Therapeutic guidelines, especially for antipsychotic medications, are being followed in the regional anesthesia administration [37].

NOD-like receptor family, pyrin domain containing 1 (NLRP1) and NOD-like receptor family, CARD domain containing 4 (NLRC4) gene expressions are increased in prostate cancer patients, as observed in the clinical diagnosis of PCa by immunohistochemical staining. NLRP1 expression is linearly correlated with interleukin-1β (IL-1β) and IL-18. NLRP1 and NLRC4 are highly expressed in the plasma membrane of PCa patients, which promote the maturation and release of inflammatory cytokines, i.e., IL-1β and IL-18, and promote tumorigenesis. Significant changes are observed in PSA levels, i.e., from 25 to 33 at 29 months and 16 to 24 at 20 months after using metformin. These clinical values have important role in tumor progression, PCa risk assessment, and prognosis [38]. Disease diagnosis via AI (artificial intelligence) is based on data sets’ utilization, which are taken from diagnostic methods such as magnetic resonance scans, computed tomography scans, ultrasound diagnostics, X-rays, or electronic health records, and integrated into new AI models [39]. For instance, there is an online tool (web application) that employs smart AI for rapid PCa diagnosis. It learns deeply and acts as a multi-model for enhanced PCa diagnosis [40]. These treatments separately address localized and metastatic PCa. The methods used to diagnose tumor for localized PCa include PSA testing, digital rectal exam, and biopsy [41]. Non-invasive treatments such as medication or radiation therapy are considered for the early stages. However, a surgical approach may be required to remove tumor in high-risk patients. Metastatic PCa has different treatment strategy as the tumor spreads to bones or intestine [42, 43]. Radical treatments like chemotherapy, hormone therapy, radiation therapy, and colony-targeted therapy are thus considered. Treatments are adjusted based on the patient’s condition and tumor nature [44].

4. Chemotherapy for PCa

Androgen deprivation therapy (ADT) has long been used as chemotherapy regimen to treat PCa which keeps testosterone levels below 50 ng/dL. Medical castration to stop androgens production from testes is accomplished by using agonists or antagonists of gonadotropin-releasing hormone. The study is divided into experimental and control groups for evaluating the tamsulosin impact on bladder function. The experimental group takes 0.4 g tamsulosin daily for 6 months at the start of external beam radiation therapy (EBRT). Control group is used to evaluate the urine amount after urination which remains in bladder after EBRT [45]. Fixed oral dose of dexamethasone (8 mg) is given for the successful treatment [46]. The metformin efficacy as chemotherapeutic agent for PCa has been shown, especially in hormone sensitive prostate cancer (HSPC). It is safe and inexpensive drug to prevent locally advanced or metastatic PCa. This is demonstrated in 124-patient randomized controlled trial (RCT) that depicts improvements in castration-resistant prostate cancer-free survival (CRPC-FS) with no adverse effects on PSA response. Diarrhea is noticed with metformin grade II which confirms the usage of lower doses. In 64-patient study, the modified shenqi dihuang decoction (MSDD) group has lower castration resistance (28.12% vs. 71.87%), new metastases (18.75% vs. 40.63%, p < 0.05), and higher physical status score (79.87 vs. 70.45, p < 0.05) compared to the control group. There is no difference in pain scores or adverse events [47].

In the case of chemotherapy in combination with radiation therapy for PCa patients, a 70-patient clinical trial confirms that chemotherapy improves life quality, increases treatment adherence, and reduces side effects in PCa patients undergoing radiation therapy. In a trial comparing expanded prostate cancer index composite (EPIC) score with the incidence of chemoradiotherapy, the incidence of proctitis and cystitis is lower and EPIC score is higher in the nursing intervention group compared to chemotherapy-treated experimental group or the control group receiving routine care. Dex 0.4 mg is thus effective in mitigating hemodynamic responses and reducing postoperative analgesic requirements [48]. The α-blockers for PCa are the chemical components having prophylactic role in radiation therapy of lower urinary tract. The α-blockers efficacy in preventing acute urinary retention (AUR) in EBRT patients is demonstrated through 108 PCa patients’ clinical trial. The change in international prostate symptom score (IPSS) after 3 months of treatment is correlated with α-blocker alone, and the drug-induced side effects are mild which indicate α-blocker efficacy [49]. Furthermore, steroids are an incomplete regimen in chemotherapeutic armamentarium of PCa treatment, and docetaxel is suggested as an alternative. A 60 PCa patients’ clinical trial demonstrates its impact with fixed dose of 8 mg. This is effective in patients missing steroid premedication with no hypersensitivity reactions or dermatotoxicity [50].

Chemotherapy for PCa is employed as an adjuvant treatment to control negative prognosis after resection surgery. Hormones expressed after castration may negatively impact the bone metastasis. MSDD is used to treat this. RCT of 76 patients with bone metastasis hormone-sensitive PCa exhibits that it improves patients’ quality of life (QoL) scores and memory T cell (TCM) symptom scores. This is confirmed in a comparison with treatment control of maximal androgen blockade (MAB), which suggests that MSDD improves life quality of PCa patients by improving the serum markers and reducing the bone metastatic pain [51]. Chemotherapy is also used to relieve pain after PCa surgery. It is revealed that low-dose usage of dexmedetomidine (DM) combined with hydromorphone (HM) as postoperative analgesia improves serum IL-6 and C-reactive protein (CRP) levels in PCa patients. The combination is thus safe, acts as an effective chemotherapy for postoperative analgesia, and inhibits the expression of inflammatory factors [52]. The clinical case studies have been summarized in Table 1.

5. Hormone replacement therapy for PCa

The outcomes of research and clinical trials over past decade have depicted that androgen receptor and pathway inhibitors such as enzalutamide, abiraterone and apalutamide are the current care standard for hormone-sensitive and treatment-resistant PCa [53, 54]. The hormone replacement therapy and testosterone replacement therapy (TRT) can prevent prostate side effects. TRT is a pharmacological treatment for PCa, acute urinary retention, invasive prostate procedures, and hypo-dose-resistant lower urinary tract symptoms in men. RCT of 5204 men shows that PSA concentrations are higher with TRT compared to placebo [55]. A 6-month trial of TRT treatment reveals that it improves pain and life quality in late-onset hypogonadal (LOH) men having chronic pain from PCa. This is according to the Japanese RCT that compares TRT in 31 experimental and 29 control subjects. It is found that TRT contributes to body pain, mental health and sleep disturbance [56]. TRT is exogenous and often used to treat hypotestosteronism and erectile dysfunction, and associated with 65% improvement in sexual function. Nguyen et al. [57] (2021) depict that 85% patients receiving stereotactic body radiation therapy (SOLAR-P) for low alpha-beta resistant bone metastases get pain relief. However, TRT can have side effects. Andriole et al. [58] (2023) exhibit that TRT leads to 50% decrease in sperm production with increased infertility risk. This study analyzes the impact of 18F-fluciclovine positron emission tomography/computed tomography (PET/CT) on androgen blockade therapy in biochemical recurrent PCa patients [58]. TRT discontinuation is often linked with the medication discomfort, followed by concerns about cost or side effects, lack of efficacy, and return of symptoms. Mean TRT duration is 15.4 ± 7.6 months. Usage of phosphodiesterase-5 (PDE5) inhibitors has been effective treatment [59].

6. Radiation and surgical treatments of PCa

A biochemical response tracking clinical trial of stereotactic body radiation therapy (SBRT) in combination with ADT in men of 70 years and older confirms the safety and curative efficacy of SBRT. SBRT dosage is 35–40 Gy given in five doses. SBRT is a well-tolerated treatment that provides biochemical disease control in older patients with median PSA level of 0.5 ng/mL. Androgen blockade levels possess high prognostic value in localized PCa patients receiving high-dose radiation therapy and ADT [60]. SBRT relieves pain and treats bone metastases. It is more efficient to radiate disease from primary malignancies with low alpha-beta ratios, especially for the pain relief. It relieves pain as shown in a 40-patient clinical trial. It improves patient’s life quality and provides direction for future research regarding its impact on painful bone metastases [61].

Chemotherapy is also associated with PCa recurrence. Biochemical recurrence (BCR) is common, and 18F-fluciclovine PET/CT is used in 317 patients to determine the higher efficacy than ADT. This cures and delays the ADT associated diseases [62]. MRI-guided focal therapy for PCa combines targeted focusing with ultrasound to attain safety and early oncologic and functional outcomes. This can be seen during the monitoring of periprocedural complications. A clinical trial of 44 PCa patients shows no adverse events. Moreover, 41 out of 44 post-ablation patients depict no treatment-related side effects [63]. ADT usage as a general PCa treatment remains controversial. ADT combination with high-dose radiation therapy (HRT) has been effective as shown in the clinical trial of 355 patients with high-risk PCa. The 4-month ADT (lepidlene 11.25 mg, infused every 12 weeks) with HRT (78 Gy/39 fractions) arm do not show lesion metastases, and have reduced biochemical disease-free survival (bDFS) compared to control arm [64]. PET and multiparametric MRI (mpMRI) of prostate membrane specific antigen (PSMA) accurately identify lesions recurring after definitive PCa diagnosis. It employs 18F-PSMA PET/CT and mpMRI for lesion characterization and personalized treatment strategies in patients of biochemical prostatectomy having undergone post-operative radiotherapy (PORT) [65].

Surgery is an alternative PCa treatment. Robotic-assisted laparoscopic prostatecyomy (RALP) is a trending PCa surgical procedure. Patients’ screening after RALP has demonstrated its safety. It is preferred oncologically and functionally regarding preoperative PSA and biopsy results, blood transfusion rates, operative time, and length of hospital stay [66]. However, positive surgical margins (PSMs) are associated with the higher risk of biochemical failure (BCF). In a follow-up of 462 patients undergone robotic-assisted radical prostatectomy (RARP), 13.2% patients have PSMs and 31.7% experience BCF. Patients with PSMs after RARP must receive early treatment interventions such as salvage radiotherapy and ADT [67]. Nonetheless, the prognosis of surgical treatment can reduce mortality. Clinical cases of radiation and surgical treatments are given in Table 2.

7. Prediction of targeted therapies and the biomarker effects

The recent approvals of (poly adenosine diphosphate-ribose polymerase) (PARP) inhibitors have provided new treatments for PCa patients. PARP inhibitors inhibit tumor growth by enhancing the repair of DNA damage. These therapies are important in managing and treating PCa. They are useful for the patients with genetic mutations [68]. PARP inhibitors include olaparib, riparoximab and veliparib. These drugs are effective against tumor cells with genetic or damaged DNA. They are employed in treating variety of tumor types like PCa [69]. The neuroendocrine prostate cancer (NEPC) is a rare but aggressive subtype of PCa. It is resistant to traditional ADT as the cancer cells have acquired neuroendocrine cell characteristics which make them insensitive to androgens [70]. NEPC has poor prognosis and limited treatments. Its clinical management is thus critical. Prostate cells show neuroendocrine differentiation in response to the therapeutic interventions like ADT and chemotherapy. This adaptive mechanism promotes tumor progression [71]. Understanding NEPCs and treatment-induced neuroendocrine differentiation is crucial for managing androgen-insensitive PCa. They are the fundamentals in developing targeted therapies based on molecular mechanisms of neuroendocrine differentiation [72, 73].

PCa is a common genitourinary malignancy in older men. The common treatments include surgery and radiation followed by chemotherapy and androgen deprivation. PCa patients are immune-sensitive and require combination treatment and immunotherapeutic prevention [74]. Current PCa treatments include medical castration with gonadotropin-releasing hormone (GnRH), physical castration with resection, and ADT depending on the progression mechanism of castration-resistant PCa [75, 76]. ADT treatment is androgen receptor (AR) dependent [77, 78], where testosterone is injected into the cell by diffusion and converted to dihydrotestosterone (DHT) by 5-alpha-reductase. AR is then phosphorylated, dimerized and nuclearized where it binds to androgen response elements in host DNA to transcribe genes involved in survival [79].

Lambertianic acid (LA) is a diterpene bioactive compound purified from Pinus species. It is a natural optical isomer. It serves as potential targeted therapy to treat PCa malignancy. LA shows anticancer characteristics by targeting the key signaling components including protein kinase B (AKT), adenosine monophosphate-activated protein kinase (AMPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), cyclooxygenase-2 (COX-2), signal transducer, activator of transcription 3 (STAT3), etc., to inhibit cancer cell proliferation and induce apoptosis [80]. AKT pathway is a signaling pathway associated with obesity and diabetes and known as the targeted therapeutic pathway for obesity [81]. AMPK, NFκB and COX are the signaling pathways with anti-inflammatory and anticancer therapeutic effects [82]. STAT3 is one of the STAT proteins transducing signals from cytokines and growth factors and their receptors inhibit the progression of malignant tumors and shape up the anticancer metabolic process [83]. Prostate cancer stem cells (CSCs) maintain stem-like state and provide microenvironment to the stem cells for responding to any situation in homeostasis and regulate regeneration and balance [84, 85]. CSC microenvironment protects and resists drug-induced apoptosis, and is involved in tumor metastasis and development. The monoclonal antibody bevacizumab targets vascular endothelial growth factor (VEGF) which disrupts CSC microenvironment by reducing angiogenesis. Bevacizumab is a targeted therapy similar to ADT. Patients receiving bevacizumab benefit from change in baseline PSA at maximum tolerated dose (MTD) in 5 of 16 subjects included in immune response evaluation trial. ADT and bevacizumab combination has median survival of 14.5 months, however, excluding bevacizumab decreases survival to 14.3 months [86]. Chimeric antigen receptor (CAR) T cell therapies are also the promising treatments. They proliferate CAR T cells (CARTs) with anti-cancer activity and sustain immune responses for long time. They are involved in immunosurveillance activities to prevent tumor recurrence and attach to prostate stem cell antigen (PSCA), PSMA and epithelial cells as the targets to show preclinical effects in PCa [87, 88, 89]. Harnessing the antitumor immune response of gut microbiome as potential therapeutic agent, and administering gut microbiome prevotella stercorea, are identified as the efficient combination therapy for overcoming endocrine resistance [90, 91]. RNA interference (RNAi) has been investigated for its potential in identifying biomarkers and therapeutic targets for prostate cancer based on gene expression. RNAi technology reduces the tumor’s ability to initiate and metastasize in prostate cancer, playing a critical role in targeting cancer stem cell-like properties [92]. The tumor microenvironment (TME) is linked to carcinogenesis, invasion, and drug resistance. The current preclinical research is focused on immune-based therapies. Understanding the complex TME system in PCa can develop new therapies, design combination treatments, and overcome resistance to existing therapies for improving the lives of PCa patients [93, 94]. Immune checkpoint blockade (ICB) therapies, TME as immunotherapeutic strategy to target immunosuppressive cells in cancer development, progression, and metastasis, and pembrolizumab and ipilimumab are being employed in preclinical studies. The resistance to ICB therapy is conducive for more treatments and combinations when compared to other cancer models. Future targeted therapeutics and biomarker approaches may utilize immunosuppressive cells in TME, microbiota, autophagy, and epigenetic factors which can be extended to RCTs to overcome PCa [95, 96].

8. Conclusions

PCa being a major disease affects only men. Most PCa treatments are based on surgical physical castration, chemical hormonal castration, combinations of chemotherapy, or ADT. PCa can have negative prognosis accompanied by recurrence and pain. The importance of new treatments is thus emphasized. It is vital to choose appropriate treatment for PCa by considering the prognosis and recurrence risk. Early PCa diagnosis is effective, however, it can be difficult because of no symptoms. It is thus important to find and apply appropriate and personalize treatments for preventing side effects and metastasis. Chemotherapeutic and hormonal therapies are used in combination with surgical treatment, radiotherapy, or targeted therapy to improve the survival rates of PCa patients. Today’s emerging usage of stem cells, gut microbiome, autophagy, and acquired genes suggest that they can be safe anticancer, anti-inflammatory, and immunotherapeutic agents. The therapeutic paradigm shifts are expanding pertaining to the microorganisms, genes, and biomarkers in addition to new drugs’ development. It is thus imperative to widen the scope of clinical cases involving animal and human experiments.

Abbreviations

ADT, androgen deprivation therapy; AKT, protein kinase B; AMPK, adenosine monophosphate-activated protein kinase; BCF, biochemical failure; BCR, biochemical recurrence; bDFS, biochemical disease-free survival; CAR, Chimeric antigen receptor; CART, CarT cell; COX-2, cyclooxygenase-2; CRP, C-reactive protein; CRPC-FS, castration-resistant prostate cancer-free survival; CSC, cancer stem cells; DHT, dihydrotestosterone; DM, dexmedetomidine; EPIC, expanded prostate cancer index composite; EBRT, external beam radiotherapy; AUR, acute urinary retention; GnRH, gonadotropin-releasing hormone; HRT, high-dose radiotherapy; HSPC, hormone sensitive prostate cancer; ICB, immune checkpoint blockade; IL, interleukin; IPSS, international prostate symptom score; LA, lambertianic acid; LOH, late-onset hypogonadal; MAB, maximal androgen blockade; HM, hydromorphone; mpMRI, multiparametric magnetic resonance imaging; PORT, post-prostatectomy radiation therapy; MSDD, modified Shenqi Dihuang decoction; MTD, maximum tolerated dose; PCa, prostate cancer; PDE5, phosphodiesterase-5; PET, positron emission tomography; CT, computed tomography; PSA, prostate-specific antigen; PSMA, prostate membrane specific antigen; PSMs, positive surgical margins; QoL, quality of life; RALP, robotic-assisted laparoscopic prostatecyomy; RARP, robotic-assisted radical prostatecyomy; RCT, randomized controlled trail; RNAi, RNA interference; SBRT, stereotactic body radiation therapy; STAT3, signal transducer and activator of transcription 3; TCM, memory T cell; TME, tumor microenvironment; TNM, tumor, nodes and metastasis; TRT, testosterone replacement therapy; VEGF, vascular endothelial growth factor.

Availability of data and materials

Not applicable.

Author contributions

YP and KHK—conceptualization; validation; writing-review. YP—methodology, software; formal analysis, investigation, resources, data curation, writing-original draft preparation; editing, visualization. KHK—supervision. All authors have read and agreed to the published version of the manuscript.

Ethics approval and consent to participate

Not applicable.

Acknowledgment

Not applicable.

Funding

This research received no external funding.

Conflict of interest

The authors declare no conflict of interest.