Navigating the evolving diagnostic and therapeutic landscape of low- and intermediate-risk prostate cancer

Abstract

In this nonsystematic review of the literature, we explored the changing landscape of detection and treatment of low- and intermediate-risk prostate cancer (PCa). Through emphasizing improved cancer assessment with histology classification and genomics, we investigated key developments in PCa detection and risk stratification. The pivotal role of prostate magnetic resonance imaging (MRI) in the novel diagnostic pathway is examined, alongside the benefits and drawbacks of MRI-targeted biopsies for detection and tumor characterization. We also delved into treatment options, particularly active surveillance for intermediate-risk PCa. Outcomes are compared between intermediate- and low-risk patients, offering insights into tailored management. Surgical techniques, including Retzius-sparing surgery, precision prostatectomy, and partial prostatectomy for anterior cancer, are appraised. Each technique has the potential to enhance outcomes and minimize complications. Advancements in technology and radiobiology, including computed tomography (CT)/MRI imaging and positron emission tomography (PET) fusion, allow for precise dose adjustment and daily target monitoring with imaging-guided radiotherapy, opening new ways of tailoring patients’ treatments. Finally, experimental therapeutic approaches such as focal therapy open new treatment frontiers, although they create new needs in tumor identification and tracking during and after the procedure.

INTRODUCTION

Prostate cancer (PCa) presents a spectrum of clinical behaviors. The stratification of patients into risk groups serves as a cornerstone for guiding treatment decisions and optimizing outcomes. Among these risk groups, low-risk PCa and intermediate-risk PCa occupy a critical intersection in the management landscape due to their variable biological behavior and potential for diverse treatment approaches. Over the past decades, the field of PCa research and management has witnessed significant advancements in diagnostic tools and therapeutic strategies, reshaping the paradigm for how clinicians approach and manage these patients.

This nonsystematic review aims to provide a comprehensive overview of the evolving diagnostic and therapeutic landscape in low- and intermediate-risk PCa. By exploring the recent developments in diagnostic modalities, risk assessment, and treatment options, we intend to shed light on the complex decision-making process faced by clinicians and patients. We explore emerging concepts, controversies, and considerations that have emerged as key influencers in tailoring patient-centered approaches for these disease-risk groups.

Developments in medical imaging techniques, such as multiparametric magnetic resonance imaging (mpMRI) and positron emission tomography (PET) using prostate-specific membrane antigen (PSMA) ligands, have transformed the way we stage and pinpoint disease locations. This progress has led to enhanced precision in selecting appropriate treatment options for patients. Alongside imaging, genomic and molecular analyses have provided insights into the underlying biology of PCa, offering opportunities for personalized risk stratification and treatment selection. In parallel with diagnostic innovations, therapeutic strategies have expanded beyond traditional options, offering patients a spectrum of choices, ranging from radical treatments to active surveillance and focal therapies. This review discusses the challenges associated with predicting disease progression within these risk categories, highlights the emerging biomarkers and predictors that are shaping the landscape of precision medicine for low- and intermediate-risk PCa, and addresses the advantages and disadvantages of each approach, examining the implications for long-term cancer control. By exploring the intricacies of treatment decision-making, this review aims to contribute to a deeper understanding of the complexities surrounding low- and intermediate-risk PCa management.

EVIDENCE ACQUISITION

A literature review identified relevant studies on new diagnostic tools and therapeutic techniques for low- and intermediate-risk PCa. PubMed was used as the database, and the collected studies formed the basis for a narrative analysis of the literature published in the last years.

RISK CLASSIFICATION AMONG DIFFERENT GUIDELINES

Various tools are available for classifying the risk of PCa before initiating treatment. Organizations including the European Association of Urology (EAU), the National Comprehensive Cancer Network (NCCN), the American Urological Association (AUA), and the European Society of Medical Oncology (ESMO) have established specific criteria for categorizing low- and intermediate-risk PCa. These criteria incorporate different values for tumor, node, and metastases (TNM) stage, prostate-specific antigen (PSA) levels, and Gleason score/grade group (GG), facilitating the segregation of patients into distinct risk categories. A summarized view of how intermediate-risk PCa is delineated in these guidelines is presented in Table 1. It is important to note that the NCCN and AUA guidelines further divide intermediate-risk PCa into favorable and unfavorable disease groups.1 Conversely, the NICE framework adopts the Clinical Prognostic Grade (CPG) system, which ranges from a score of 1 to 5. CPG 2 and CPG 3 groups encompass medium- or intermediate-risk prostate cancer. When compared directly, the Memorial Sloan Kettering Cancer Center’s nomogram, the Cancer of the Prostate Risk Assessment score, and the CPG system have shown enhanced efficacy in predicting mortality from PCa. While these tools can enhance clinical decision-making, a more unified standardization of guidelines is necessary for a consistent classification approach.1 This alignment is crucial to enable studies and their results to be comparable.

Table 1.

Defining intermediate-risk prostate cancer: a guideline summary

Guideline	Intermediate-risk without further classification	Favorable intermediate-risk	Unfavorable intermediate-risk
NCCN61	All of the following: no high-risk group features no very-high-risk group features has one or more IRFs: cT2b–cT2c, grade group 2 or 3, and PSA 10–20 ng ml−1	All of the following: 1 IRF grade group 1 or 2<50% biopsy cores positive (e.g., <6 of 12 cores)*	Has one or more of the following: 2 or 3 IRFs grade group 3 ≥50% biopsy cores positive (e.g., ≥6 of 12 cores)*
AUA/ASTRO/SUO62		Grade group 1 with PSA 10–20 ng ml−1 or clinical stage T2b–T2c and <50%* biopsy cores positive; or grade group 2 with PSA <10 ng ml−1 and clinical stage T1–T2a and <50% biopsy cores positive	Grade group 1 with PSA 10–20 ng ml−1 and clinical stage T2b–T2c; or grade group 2 with PSA 10–20 ng ml−1 and/or clinical stage T2b–T2c and/or ≥50%** biopsy cores positive; or grade group 3 with PSA <20 ng ml−1
EAU16	PSA 10–20 ng ml−1; or grade group 7 (ISUP Grade 2/3)
ESMO63	T2b and/or grade group 7; and/or PSA 10–20 ng ml−1
Cambridge Prognostic Group64		CPG 2 Gleason score of 3+4=7 (Grade Group 2) or a PSA level 10–20 ng ml−1 and a T stage of 1 or 2	CPG 3 Gleason score of 3+4=7 (grade group 2); and a PSA level between 10 ng ml−1 and 20 ng ml−1; and a T stage of 1 or 2, or a Gleason score 4+3=7 (grade group 3); and a T stage of 1 or 2

^*A targeted lesion that is biopsied more than once and demonstrates cancer (regardless of percentage core involvement or number of cores involved) can be considered as a single positive core. ^** Percent biopsy cores positive is the total number of cores containing cancer divided by total number of cores obtained ×100%. This is not the percentage of cancer within a positive core. CPG: clinical prognostic grade; ISUP: International Society of Urological Pathology; PSA: prostate-specific antigen; NCCN: National Comprehensive Cancer Network; AUA: American Urological Association; EAU: European Association of Urology; ESMO: European Society of Medical Oncology; IRF: intermediate-risk factor; ASTRO: American Society for Radiation Oncology; SUO: Society of Uro-Oncology

HISTOLOGY CLASSIFICATION

In 2013, the classification of PCa underwent a major transformation with the introduction of a new grading system by Pierorazio et al.2 This system was structured around five prognostic grade groups corresponding to specific Gleason scores. The objective of this novel system was to improve the precision in classifying cancer grades. This was further corroborated by a detailed multi-institutional study by Epstein et al.,3 which established the superior predictive capability of the International Society of Urological Pathology (ISUP) 2014 grading system. This system proved particularly effective in forecasting biochemical progression-free survival (bPFS) for patients undergoing radical prostatectomy (RP) and radiation therapy (RT).3 Additionally, Grogan et al.4 have recognized the ISUP 2014 grading system as an independent predictor not only for biochemical recurrence (BCR) but also for clinical recurrence. Among the ongoing debates surrounding the classification of low-grade cancers, prominent experts advocate for the reclassification of Gleason score 6 PCa as “indolent lesions of epithelial origin (IDLE)”, with the intention of alleviating the burden of unnecessary treatments associated with the cancer label.5 Conversely, critics, including Epstein and Kibel,6 assert that retaining the cancer label is crucial due to the wealth of prognostic information it provides, highlighting the historical importance of histologic grading as a complementary element to clinical staging. However, this discussion introduces complex concerns about the boundary between diagnostic and prognostic criteria, which could potentially undermine the fundamental principles of medical diagnosis and complicate treatment decision-making. The proposed reclassification could also impact patients’ access to appropriate treatments and medical insurance coverage, raising questions about patient autonomy and their rights in the decision-making process.

Technological advancements are offering innovative solutions to existing challenges in medical diagnosis. For instance, Ambrosini et al.7 tackled the complexities involved in interpreting microscopic morphology by introducing an advanced deep-learning technique. This technique utilizes a convolutional neural network to autonomously identify cribriform growth patterns in prostate needle biopsies. Such a method holds significant potential in elevating the precision, uniformity, and dependability of pathological analyses. Additionally, the fusion of artificial intelligence with computational pathology is poised to improve the objectivity and replicability of various grading systems. The latest developments in artificial intelligence and computational pathology are recognized for their contribution to the enhancement of efficiency and consistency in grading. This progress could provide solutions to some of the reproducibility challenges commonly associated with the Gleason grading system.8,9,10

GENOMICS

Recent advancements in genomics have unveiled the pivotal role of genetic alterations in shaping the molecular landscape of PCa, particularly within the spectrum of intermediate-risk disease. These genetic changes have provided insights into unique molecular subtypes that carry distinctive prognostic implications. In fact, these underlying genetic signatures have demonstrated superior predictive value for clinical outcomes compared to conventional risk assessment metrics such as GG or PSA levels. Key genetic alterations, including transmembrane protease serine 2 (TMPRSS2)-erythroblast transformation-specific (ETS) gene fusions, MYC oncogene amplification, phosphatase and tensin homolog (PTEN) and tumor protein p53 (TP53) deletions or mutations, as well as androgen receptor amplification or mutation, have emerged as critical determinants of disease behavior. These insights have paved the way for the exploration of serum- and urinary-based biomarkers aimed at predicting tumor aggressiveness. Notably, ongoing trials such as the Prospective Stockholm3 Active Surveillance trial (STHLM3AS) are incorporating genomic biomarkers into active surveillance protocols, leveraging mpMRI to identify suitable patients.11 Moreover, researchers are investigating novel combinations of diagnostic tools, such as the integration of the Decipher PCa test with mpMRI. Recent findings by Falagario et al.12 demonstrate that this combined approach enhances the precision of risk stratification, offering a more nuanced understanding of the adverse and favorable pathologies associated with intermediate-risk PCa.

Currently, commercially available genomic classifiers (GCs) such as Prolaris, Decipher, and Oncotype DX lack validation from prospective clinical trials to confirm their efficacy in improving outcomes for clinically localized PCa. The routine use of these GCs is not recommended due to this lack of validation. Significantly, the current data supporting the prognostic capability of GCs rely predominantly on tissue analysis of RP specimens, which introduces uncertainties related to tissue heterogeneity and undersampling. Nevertheless, there is growing evidence indicating that Decipher scores based on biopsies show a correlation with cancer outcomes. A previous study demonstrates associations with the risks of metastasis and PCa-specific mortality.13 Continuing clinical trials, including NRG GU009 and GU010, are essential for prospectively validating GCs in localized disease. These trials may offer insights into treatment intensification, deintensification, and the personalization of treatment decisions based on GCs results, particularly in intermediate- and high-risk patients. By deciphering the intricate genetic underpinnings of the disease, clinicians are empowered with a more comprehensive toolkit to guide treatment strategies and optimize patient outcomes.

ROLE OF MRI AND MRI-TARGETED BIOPSY IN DETECTING LOW- AND INTERMEDIATE-RISK PCA

The PRECISION trial14 and the 4M study15 have shed light on the enhanced detection of clinically significant PCa through the use of mpMRI. Based on these findings, the EAU now advocates for the use of mpMRI before conducting a prostate biopsy, even in cases where previous biopsies have not been performed.16 However, it is important to acknowledge the continuing relevance of systematic biopsies alongside targeted ones due to their added diagnostic value.17

The application of mpMRI in PCa diagnosis also holds significant implications for identifying patients with intermediate-risk PCa who are candidates for active surveillance.18 A meta-analysis involving over 4000 patients revealed varying detection rates for clinically significant PCa based on Prostate Imaging Reporting and Data System (PI-RADS) scores, ranging from low rates in PI-RADS 1–2 to high rates in PI-RADS 5 lesions. The PRECISION trial found that patients without radiological progression during active surveillance are unlikely to experience clinical progression. In contrast, the Canary Prostate Active Surveillance Study (PASS) reported notable findings of Gleason GG ≥2 PCa in both targeted and nontargeted lesions during mpMRI-targeted biopsy.19 Additionally, the findings from the PRECISE trial indicated that patients without radiological progression during active surveillance have a minimal likelihood of experiencing clinical progression.20 However, in the PASS, where a substantial cohort of men on active surveillance underwent subsequent mpMRI-targeted biopsy, it was found that 11% had Gleason GG ≥2 PCa within the targeted lesion, and 13% had GG ≥2 PCa outside of it.21 Notably, mpMRI exhibited higher sensitivity in detecting ISUP Grade ≥2 PCa compared to ISUP Grade 1 PCa, particularly for small-sized PCa, those smaller than 0.5 cm.22 Interestingly, the Active Surveillance Magnetic Resonance Imaging Study (ASIST)23 found that incorporating MRI with targeted biopsies, in addition to systematic biopsies, resulted in an equivalent upgrading rate compared to relying solely on systematic biopsy. Moreover, the upgrading rate observed with 2-core targeted biopsies alone was comparable to that seen with a 12-core systematic biopsy. For these discordant findings of the use of MRI in this setting of patients, several studies are focusing on improving mpMRI findings in the context of active surveillance, such as by integrating imaging results into risk assessment tools. For example, Gandaglia et al.24 developed a risk calculator aimed at refining the selection of intermediate-risk PCa patients suitable for active surveillance by incorporating mpMRI findings. In summary, the use of this risk score led to a 10% absolute increase in the number of patients eligible for active surveillance, and its validity has been recently confirmed.25 A systematic review examined studies involving men who underwent RP, despite being initially considered suitable for active surveillance based on transrectal ultrasound (TRUS)-guided biopsy results (specifically, those with Gleason 3+3 alone). Among 677 men with a positive preoperative mpMRI, 291 (43%) were subsequently upgraded to Gleason 3+4 or higher. In contrast, men with a negative mpMRI had a significantly lower rate of upgrades, with 78 out of 293 (27%) experiencing such changes.21 Targeted biopsy of suspicious lesions identified through mpMRI has proven effective in reducing the risk of overdiagnosis of low-risk PCa.26 However, there is currently a debate surrounding whether MRI-targeted biopsy could potentially lead to an incorrect grade assignment, potentially causing overtreatment of PCa that could otherwise be managed through active surveillance.27 Depending on the number and direction of MRI-targeted biopsies, the pathologist’s report may vary from Gleason 3 + 3 to 4 + 4 lesion, raising the risk of subsequent overtreatment. The primary concern here is the potential for overtreatment, which means treating a patient who might have been suitable for initial management through active surveillance. In a study of 173 patients conducted by Yu et al.,28 it was observed that when MRI-targeted biopsies were added to systematic biopsies, there was a significant increase in the rate of downgrading upon final pathological analysis after RP (16.8% vs 8.7%). However, it is important to note that only two cases were downgraded to GG 1 disease. In another study by Martini et al.,29 involving GG 2 PCa patients who underwent MRI-targeted biopsy, the downgrading rate (from GG 2 on targeted biopsy to GG 1 on RP specimens) was 2.6%, which is in line with the number of patients who might have been overtreated. In another study,28 the risk of downgrading to a lower GG on surgical pathology was 8.7% for systematic biopsy, 13.3% for targeted biopsy, and 16.8% for combination biopsy. Notably, combination biopsy exhibited a significant overestimation of the final GG on RP compared to systematic biopsy and targeted biopsy alone. The integration of image-guided biopsies into routine practice has led to questions about the best approach to report PCa grade for this specific set of biopsies.14 In a clinician survey conducted by the Genitourinary Pathology Society, 69% of the panelists considered the highest GG, rather than the overall GG, in systematic prostate biopsies to be the preferred clinical grade for determining treatment and management decisions.29 However, a similar approach for targeted biopsies is yet to be validated. It is important to note that, with a median number of three to five targeted cores, perilesional biopsies (those taken in a circumferential area of 5 mm to 10 mm around the MRI-identified index lesion) often contain the most clinically significant PCa cores that are not present within the lesion itself.30 Nonetheless, it remains to be determined whether perilesional sampling could further reduce the risk of overgrading and subsequent overtreatment. While it is widely acknowledged that the transperineal biopsy route is associated with lower rates of infectious complications, the question of its efficacy in cancer detection and accurate grading compared to other biopsy routes remains open for investigation.31,32

ROLE OF ⁶⁸Ga-PSMA PET/CT IN MEN WITH NEWLY DIAGNOSED LOW- OR FAVORABLE INTERMEDIATE-RISK PCA

A previous study has assessed the utility of ⁶⁸Ga-PSMA PET/CT in a first-line diagnostic setting, particularly in patients with high-risk and biochemically recurrent PCa.33 The hypothesized impact of ⁶⁸Ga-PSMA PET/CT on decision-making and disease management has been confirmed, highlighting its substantial influence on clinical decision-making, especially within high-risk PCa patients.34

PSMA-PET demonstrates significantly higher sensitivity and specificity compared to CT, mpMRI, and BS for staging nodal and bone metastases. Additionally, it shows greater sensitivity than mpMRI for local tumor staging when combined with PSMA PET/MRI. However, these conclusions are applicable exclusively to patients with intermediate- to high-risk PCa, as those with low-risk PCa constituted less than 2.2% of the available studies in the current literature.35

A previous study has explored the limitations of ⁶⁸Ga-PSMA PET in detecting cases of low- and intermediate-risk PCa.36 This limitation arises from the infrequent occurrence of extraprostatic disease, particularly in the presence of low levels of PSA.36 Thus, the use of PSMA PET/CT in the setting of low- and intermediate-risk PCa still appears to be investigational and likely excessive, possibly representing a misapplication of molecular imaging.

TREATMENT OPTIONS

Monitoring

The Prostate Testing for Cancer and Treatment (ProtecT) trial, which examined survival outcomes among PCa patients randomized to active treatment (surgery or radiation therapy) or active monitoring, included 66% of patients with ISUP Grade <2 cancer and 90% of patients with PSA levels ≤10 ng ml⁻¹.37 Nevertheless, modern approaches to risk stratification reveal that as many as 34% of individuals in the ProtecT cohort had either intermediate- or high-risk PCa at the time of diagnosis. Following a median 15-year follow-up,38 the trial outcomes indicated no statistically significant variances in disease-specific or overall mortality among the treatment cohorts for patients with intermediate-risk cancer. Furthermore, no distinct impacts on cancer-specific mortality were observed concerning baseline PSA level, tumor stage or grade, or risk-stratification score. Nonetheless, early radical treatments, such as surgery or radiotherapy, demonstrated a significant 50% reduction in rates of disease progression and metastasis compared to active monitoring.

Patients in the ProtecT trial underwent active monitoring, involving PSA measurements every 3 months in the initial year of the study, followed by testing every 6–12 months thereafter. This monitoring protocol differs from standard AS protocols. Additionally, in the ProtecT study, individuals with a PSA increase of ≥50% in the previous 12 months underwent a review to consider management options, including active treatment.39 Based on the trial’s findings, recommendations endorsed by the American Society of Clinical Oncology (ASCO) society support active monitoring for patients with a PSA level of <10 ng ml⁻¹ and low core positivity.40 Additionally, Consensus Statements for Deferred Treatment with Curative Intent for Localised Prostate Cancer from an International Collaborative Study (DETECTIVE Study) determined that PSA density (PSAD) is an inclusion criterion, while intraductal and cribriform histology serves as an exclusion criterion for active surveillance.41 Importantly, patients should be informed that ISUP Grade 2 is associated with a threefold increased risk of metastases compared to ISUP Grade 1.42

Surgery

The Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4)43 and the Prostate Cancer Intervention Versus Observation Trial (PIVOT) trials44 both investigated the efficacy of RP versus watchful waiting in intermediate-risk PCa. The SPCG-4 study revealed a noteworthy decrease in overall mortality, PCa-specific mortality, and distant metastases among intermediate-risk PCa patients treated with RP. In contrast, the PIVOT trial showed a noteworthy reduction in overall mortality through RP, but it did not exhibit a decrease in PCa-related deaths over an average follow-up period of 19 years.43,45 Nevertheless, findings from a 22-year follow-up indicated that RP led to better survival outcomes.44

Table 2 provides a summary of the advantages and disadvantages of various treatment modalities for intermediate-risk PCa.

Table 2.

Pros and cons of different treatment modalities for intermediate-risk prostate cancer

Treatment	Pros	Cons
Watchful waiting	Avoids immediate treatment and potential side effects	Potential for disease progression during observation
	Can spare patients unnecessary treatment and its impact	Limited immediate control over cancer growth
	Suitable for older patients with limited life expectancy	May require further treatment if cancer progresses
Active surveillance	Monitors tumor closely with active interventions if needed	Potential for disease progression and treatment delay
	Minimizes overtreatment, preserving quality of life	Frequent testing and surveillance can be stressful
	Avoids immediate side effects and complications	Psychological burden of living with untreated cancer
	Appropriate for low-risk and some intermediate-risk patients	Potential for needing treatment at a later stage
Focal therapies	Targeted treatment minimizes damage to healthy tissue	Limited long-term data on treatment effectiveness
	Potential to preserve urinary and sexual function	May not be suitable for larger or aggressive tumors
	Outpatient procedure with shorter recovery period	Treatment availability and expertise may be limited
	Minimal impact on quality of life compared to more aggressive treatments	Potential need for repeat treatments
Radiation therapy	Nonsurgical treatment option, avoiding surgical risks	Potential for urinary and bowel side effects
	Precise targeting of tumor tissue, minimizing damage to surrounding organs	Potential for erectile dysfunction
	Outpatient procedure, shorter recovery time compared to surgery	Potential for long-term radiation effects
	Effective in controlling cancer growth	May require multiple sessions or extended treatment
Radical prostatectomy	Provides definitive treatment, removing the tumor	Surgical risks and potential complications
	Immediate removal of cancer tissue and potential cure	Potential for urinary incontinence and erectile dysfunction
	Clear pathology assessment and staging information	Postoperative recovery period
	Potential for long-term cancer control	Irreversible impact on urinary and sexual function

Surgical robotic innovations for low- and intermediate-risk PCa

To minimize the risk of posttreatment incontinence and impotence, several surgical techniques for prostatic dissection are available to reduce long-term complications. Examples are omission of endopelvic fascia dissection, bladder neck preservation, incremental nerve sparing, preservation of the puboprostatic ligaments, and preservation of the dorsal venous complex.46,47

Retzius-sparing surgery has Level I evidence showing an earlier return to continence with the Retzius-sparing approach.47 With Retzius-sparing surgery, intrafascial anterograde nerve sparing can be performed when oncologically safe, especially for well-confined low-risk disease. Conversely, in the case of more advanced disease, an interfascial or extrafascial antegrade dissection can be preferred. However, clear data regarding the incidence of positive surgical margins and the implications for follow-up and further treatment are still missing.47

For individuals eligible for active surveillance who also suffer from considerable prostate enlargement causing lower urinary tract symptom not relieved by drug treatments, robotic total prostatectomy (RTP) offers a promising solution. The procedure involves carefully separating the back of the prostate from the surrounding pseudocapsule, facilitating the complete extraction of the prostate’s central, transitional, and peripheral zones. The approach of not extending the dissection beneath the pseudocapsule ensures the intact preservation of the seminal vesicles, the ampulla of the vasa deferentia, and the neurovascular bundles.48 Postsurgical outcomes have demonstrated effective relief from urinary symptoms and reliable cancer management, with negligible impact on sexual health. Full urinary control was attained within 3 months by all patients. This strategy offers a potential reduction in the negative consequences associated with more aggressive treatments in this particular group of patients.49 In the initial report covering 17 patients who underwent robotic anterior partial prostatectomy (APP) for isolated anterior low- and intermediate-risk cancers, we observed that the technique was safe and feasible, delivering positive functional and oncological outcomes.49,50 The long-term functional and oncological outcomes for 28 men treated with APP have been presented.51 Almost all the patients were low- and intermediate-risk PCa. Continence remained unaffected in 92% of the patients, while 69% retained erectile function without the need for medication. The median nadir PSA after APP was 0.36 ng ml⁻¹. However, cancer recurrence was observed in eight patients at the margins of the primary cancer resected area, leading to salvage completion of robotic RP at a median time of 3.25 years after the initial APP. The 7-year freedom from post-APP cancer recurrence was 62.7%. After the completion of RP, the 7-year freedom from biochemical recurrence was 94.7%. Importantly, all 28 patients in the study remained alive, with no reports of systemic treatment or metastases. These findings reiterate the positive outcomes associated with APP but underscore the significance of patient selection, especially considering criteria such as tumor volume (<3 ml) assessed by MRI. Equally important is the need for thorough discussions with patients regarding the potential for additional surgery following the initial APP.

The Menon Precision Prostatectomy (MPP) approach is a careful technique where surgeons delicately remove the prostate when leaving a tiny margin of 1–2 mm of tissue near the neurovascular bundles (NVB). Inclusion criteria for MPP are PSA with a confined disease, lower GG (≤3), and a PSA level of 15 ng ml⁻¹ or less at diagnosis. In a study shared by Sood et al.,52 they looked into 90 cases where MPP was used. They managed to successfully preserve a slender layer of tissue next to the NVB, opposite the main cancer site, demonstrating that this precise operation can be done both safely and effectively.

Furthermore, there is an innovative approach that has been explored for partially removing the prostate via a route through the bladder using the da Vinci SP surgical system.53

However, when it comes to the specific ways, we cut away the prostate during these surgeries, and we are still in the early days of understanding the best methods. Right now, these more conservative surgeries of partial prostatectomies are still investigational, so they are only recommended within the context of clinical research.

RT

RT is a standard treatment for localized PCa, offering outcomes comparable to surgery. Advancements in technology and radiobiology, including CT/MRI imaging and PET fusion, allow for precise dose adjustment and daily target monitoring with Imaging-Guided Radiotherapy (IGRT). These advances enable more accurate delivery of higher radiation doses to the prostate, improving treatment efficacy. Fractionation has evolved from 180–200 centigray (cGy) to 240–340 cGy and ≥500 cGy, reducing sessions and enhancing oncological results without added toxicity. The dramatic technical innovations in recent years have led to exploring the feasibility of stereotactic body ablative radiotherapy (SBRT) schedules in PCa. SBRT has the advantage of delivering high-precision and high-dose RT in a short period (generally 1 to 8–10 fractions). The results of Phase I, II, and III clinical trials and a recent meta-analysis54 showed promising results in terms of local control, biochemical relapse-free survival (bRFS), relapse-free survival (RFS) with an acceptable risk of genitourinary (GU) toxicity for a 7-fraction schedule, and a fair GU toxicity risk profile for the 5-fraction schedule. The intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B) noninferiority randomized Phase III trial55 comparing the 5-fraction schedule with moderately hypofractionated RT in low- and intermediate-risk patients in terms of freedom from biochemical recurrence and disease-free survival (DFS) is also ongoing. First results of the HYPO-RT-PC Phase III randomized trial have been published,54 with intermediate- and high-risk PCa patients in the SBRT arm presenting noninferior outcomes in comparison to normofractionated. In none of the two trials, androgen deprivation therapy (ADT) was permitted neither in the standard arm nor in the experimental one. In low- and intermediate-risk patients, the long-term results obtained with RT are comparable to those obtainable with radical surgery.

A recent systematic review covering studies from 2000 to 2022 evaluated the benefits and risks of external beam radiotherapy combined with brachytherapy (EBRT-BT) for localized/locally advanced prostate cancer, incorporating 73 studies, including 2 randomized controlled trials (RCTs) and 7 prospective studies. The findings revealed that EBRT-BT improved bPFS compared to EBRT, although outcomes such as metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS) were similar. Notably, there was an elevated risk of severe late genitourinary toxicity, particularly with low-dose-rate EBRT-BT. The recommendation to consider EBRT-BT for patients with good urinary function is weak, predominantly relying on biochemical control improvements, highlighting the necessity for new clinical trials to reassess its role in the context of evolving treatment modalities. The available evidence primarily pertains to participants with intermediate- and/or high-risk PCa, aligning with international guidelines suggesting EBRT-BT for unfavorable intermediate/high-risk cases. For low/favorable intermediate-risk PCa in suitable patients, brachytherapy (BT) monotherapy shows excellent outcomes, but for those with unfavorable intermediate/high risk, EBRT-BT may offer advantages by enabling dose escalation to the prostate and targeting regions of potential microscopic disease.56

In recent times, proton beam therapy has surfaced as a novel approach to radiation treatment. Unlike IMRT, this innovative technology has experienced a slower rate of adoption.

According to certain authors, proton beam therapy might prove cost-effective when applied to specific patient groups, particularly those with an elevated risk of cancer-related mortality.57

Nevertheless, there is a consensus that proton beam therapy comes with a higher cost compared to IMRT. The question of whether this added expense is warranted remains uncertain, as comprehensive data on critical outcomes such as cancer control and quality of life are still inadequately represented in the existing literature.58

Focal therapy

The success of FT hinges on precise patient selection. It is crucial to identify individuals who possess certain ideal qualifications, such as adequate prostate gland anatomy, PCa that is not suitable for active surveillance but falls within the localized low-intermediate risk category. Furthermore, it is essential to be able to effectively deliver FT to the targeted area and subsequently assess the treatment’s efficacy. Achieving these objectives requires a combination of advanced imaging techniques and biopsies conducted on appropriately chosen patients who are eligible for FT, using suitable energy sources. At present, focal therapies such as high-intensity focused ultrasound therapy (HIFU), cryotherapy, focal laser ablation (FLA), photodynamic therapy (PDT), electroporation (IRE), radiofrequency ablation (RFA), prostatic artery embolization (PAE), and cyber knife robotic radiosurgery technology are not widely recommended outside of clinical trials. This caution is due to the lack of comprehensive prospective evaluations, particularly for intermediate-risk PCa cases. Furthermore, the majority of studies were in early research stages, predominantly IDEAL stages 2a and 2b, with only a few in stages 3 and 4.

A systematic review59 encompassing 72 studies with 5827 patients with localized PCa (mainly low- and intermediate-risk PCa), treated with eight energy sources. Oncological effectiveness was assessed through control biopsies, revealing clinically significant cancer in the treated area with a median of 14.7% (HIFU), 8.5% (IRE), 10% (PDT), 15% (cryoablation), 17% (FLA), 20% (RFA), 60% (PAE), and 0 (focal brachytherapy) of treated patients. Functional outcomes were generally favorable for all FT modalities. No significant changes in urinary continence were observed. However, the review notes the challenge in assessing oncological effectiveness due to relatively short follow-up durations and the absence of a direct comparison between technologies. Overall, focal therapy aims to gather robust evidence, allowing for the formulation of more informed clinical recommendations.60

CONCLUSIONS

The evolving landscape of PCa diagnosis and management, particularly within the intermediate-risk category, underscores the importance of tailored approaches and advanced diagnostic tools. Genomic insights, advanced imaging techniques, and innovative treatment techniques have redefined risk stratification and personalized treatment decisions, which is promising in improving outcomes for patients. This review informs clinicians and researchers about the evolving field of low- and intermediate-risk PCa. By addressing diagnosis, treatment strategies, and surgical techniques, it aids informed decision-making for improved patient care. As the field continues to advance, ongoing research and clinical trials will further refine our understanding and expand the armamentarium of options available for addressing intermediate-risk PCa.

AUTHOR CONTRIBUTIONS

FZ was responsible for the preparation of the manuscript. GG was involved in designing the study and also contributed to the preparation of the manuscript. FM and RB provided supervision and made corrections to the manuscript. All authors read and approved the final manuscript.

COMPETING INTERESTS

All authors declare no competing interests.