Focal therapy for prostate cancer: what is really needed to move from investigational to valid therapeutic alternative?—a narrative review

Introduction

The introduction of prostate-specific antigen (PSA) screening marked a trend towards the early diagnosis of more localised and less aggressive prostate cancer (PCa) (1). Treatment of localised PCa has historically been with whole-gland techniques such as radical prostatectomy (RP) and radiotherapy (RT) which even though offer treatment with a curative intent, can leave patients with important functional sequelae as a consequence of neurovascular bundle and external sphincter damage, such as erectile dysfunction and urinary incontinence in RP and rectal toxicity in RT (2,3).

The choice to undergo radical treatment and risk the emergence of functional complications is more difficult to accept when considering available evidence suggesting that there is a marginal difference in 10-year overall and cancer-specific survival in selected patients with low to intermediate-risk PCa treated with either active monitoring, or RP or RT (4), making complications associated with active treatment difficult to accept. To this end, strategies such as active surveillance (AS) have increased for low-risk PCa to prevent overtreatment in the past 20 years. However, approximately 50% will ultimately require whole-gland treatment due to disease progression at 10 years and only 40% of patients eligible for AS will actually opt for this treatment strategy with the rest choosing directly radical therapy to avoid the added burden of repeat hospital visits, PSA tests and biopsies without any evidence of clinical progression (4).

For these reasons, there appears to be a need for a gland-sparing focal therapy (FT) to bridge the gap between AS and radical therapy and to provide patients with more tailored approaches that aim to reduce the harms carried by radical therapies. There are various forms of FT in use, including cryotherapy, high-intensity focused ultrasound and photodynamic therapy (PDT). However, as of today, adoption of FT in clinical practice has been scarce. Indeed, the vast majority of evidence supporting the role of FT as a valid therapeutic alternative comes from retrospective series with medium term follow-up and lack of standardized treatment protocols and follow-up strategies (5). As a consequence, agreement among urologists concerning FT as a treatment strategy is scarce.

Surveys recently performed on European urologists exploring the community’s view on FT revealed that, while most agreed FT will become a standard option for localised PCa in the near future, the same cohort converged on the suggestion that some areas of debate must first be resolved before it be considered as a valid alternative to radical treatment for some patients (6). Among the most critical issues undermining the introduction of FT as a therapeutic alternative to RP there seem to be a few crucial aspects that need to be assessed. Firstly, optimizing patient selection seems pivotal in order to achieve the right balance between oncological and functional outcomes. Secondly, given the presence of several FT techniques, a standardization of treatment and follow-up protocols is mandatory. Finally, to provide strong and reliable evidence supporting the efficacy of FT, valid clinical endpoints, surrogate of treatment response, and valid salvage therapies in case of failure need to be identified, as there is currently no reliable comparable data comparing FT to RP. In this study we aimed at exploring and identifying the key factors that might push FT forward among the set of PCa therapeutic alternatives. We present the following article in accordance with the Narrative Review reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-22-50/rc).

Methods

In this study we aimed to explore and evaluate what is really needed to push forward FT from the “investigational” status to that of a valid alternative that needs to be considered and to be proposed to selected patients. To do this, we reviewed relevant literature on FT, and described and compared available studies, in order to generate a comprehensive overview of the recommendations regarding FT.

No specific time-period was used to determine relevant studies, as FT is a nascent technique, and as such, characterised by numerous biases and differing methodologies. That said, most evidence provided in this review comes from studies published after 2016, as larger studies were emerging. The search strategy is shown in Table 1.

Patient selection

Although partial-gland therapies have been adopted in most other organ systems in oncologic surgery, the prostate has been particularly challenging for three aspects: cancer multifocality (7), accurate imaging mapping tumor foci (8), and a significant heterogeneity among PCa patients in terms of PCa aggressiveness (9).

When first introduced, FT was proposed to patients with low-risk disease, therefore as an alternative to AS, raising criticisms that FT was itself a form of overtreatment. On the other hand, the few studies that have performed FT on patients with high-risk PCa however have shown an increased risk for biochemical failure, recurrent cancer and treatment failure (10). The best potential candidates for FT are those patients with a well-defined, low-volume intermediate-risk PCa, with Gleason Group 2 to 3 (11). A correct selection of the disease to treat represents the first important step to provide acceptable outcomes and to avoid misleading results that undermine the reliability of FT as a therapeutic alternative.

As FT is based on selective ablation of a region of the prostate containing cancerous tissue, regardless of the type of FT used, treatment success is largely dependent on patient selection and precise index lesion characterization. An index lesion is defined as the largest and highest grade lesion within the prostate, which some studies have shown to be the main driver of PCa progression (12).

That said, in the past, eligibility for enrolment in AS was through systematic sextant random biopsies, meaning that approximately 25% of patients enrolled in AS were likely harbouring a more aggressive disease with a higher Gleason score and/or tumor volume than reported (13,14). Introduction of prostate mpMRI and standardized reporting systems (e.g., PI-RADS) with both targeted and systematic biopsies to patient selection has allowed a superior patient definition and correct identification of the candidate index lesion in more than 80% of cases (8). This enabled a growing confidence of correctly identifying ideal FT candidates and consequently the treatment was safely extended to include intermediate-risk patients (15).

A study by Nassiri et al. assessed this topic. The aim of the study was to refine the impact of patient selection criteria on FT eligibility (16). Applying FT eligibility criteria based on the NCCN (National Comprehensive Cancer Network) intermediate risk definition (17), the authors retrospectively studied 454 men who underwent MRI/US fusion biopsy. They examined whole organ concordance of eligibility assessment in a subset of patients who underwent radical prostatectomy to confirm biopsy findings and derive the accuracy of fusion biopsy for FT eligibility. Eligibility determined by fusion biopsy was concordant with whole mount histology in 75% of cases. In addition, the study showed that using intermediate risk eligibility criteria, more than a third of men with a targeted biopsy proven lesion identified on mpMRI imaging would have been eligible for focal therapy (16).

As of today, mpMRI allows a reliable visualization of the prostate and PCa index lesions, enabling safe adoption of FT. However, there is room for improvement. When compared to whole-mount pathology, mpMRI has been shown to underestimate tumor boundaries by as much as 10 mm (8,18). In fact, to overcome this, it is common practice for urologists to add a 10 mm treatment margin surrounding the index lesion when planning needle positioning to ensure complete ablation (19). A list of the main studies improving patient selection is shown in Table 2.

In the future, further technical advances in prostate mpMRI such as the introduction of ultra-high field mpMRI, with a higher signal-to-noise ratio should lead to greater spatial and temporal resolutions, resulting in improved lesion details and higher diagnostic confidence (20). Moreover, advances in machine learning could provide better consistency in identifying prostate lesions and more accurately distinguish between clinically significant and indolent cancers (21).

A recent addition to PCa imaging assessment on top of mpMRI is the use of prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) to identify intra- and extra-prostatic disease localization. While currently used mostly in the setting of PCa recurrence, recent evidence suggests a potential role in the primary setting, in particular for evaluating lymph node invasion (22,23) and improving the detection of clinically significant prostate cancer (csPCa) when paired with mpMRI (22). In fact, recent studies are assessing the role of adding PSMA-PET to previously developed nomograms. Therefore, addition of PSMA PET/CT in the pre-operative assessment alongside mpMRI for FT may help to precociously identify those patients with extra-prostatic disease extension where a local, gland-sparing surgery may not be sufficient for disease eradication. The use of accurate imaging modalities represents a cornerstone of the patient selection that could help in selecting men with less probability to harbour multifocal significant disease, overcoming one of the most important obstacles to FT use.

On top of adding superior imaging methods to improve patient selection for FT, genetic testing for aberrations associated with more aggressive forms of cancer may aid in improving patient selection in the near future. Genetic testing, according to the European Association of Urology guidelines, is currently offered to patients with metastatic disease or young newly diagnosed patients with a strong family history (24). As of today, germline and somatic testing still have prohibitive costs and are not deemed cost-effective in the assessment of localised PCa, since they currently have little impact on management (25). That said, genetic testing may have its role in enrolling patients to FT and determining whether it is considered an overtreatment and best suited for AS or conversely the disease may be more aggressive than perceived, therefore it best be treated using whole-gland radical therapy.

Taken together, patients which would benefit the most from FT are intermediate-risk PCa patients and assessed using mpMRI with both systematic and index lesions’ targeted biopsies. That said, patient selection process needs to be better calibrated through improved imaging modalities and patient risk assessment, further strengthening the choice to perform FT compared to whole-gland therapy, ultimately decreasing patient morbidity in the correct sub-population of patients. Lastly, a better comprehension of biological behaviour of multifocal disease as compared to unifocal disease and insights on index lesion and satellite foci subcellular differences are needed to implement the selection of best potential candidate to FT for PCa.

Standardization and definition of FT

As with most newly introduced treatment modalities, there is a high level of heterogeneity regarding FT (26). FT can be defined by the type of technology modality used and by the treatment strategy used.

High-intensity focused ultrasound (HIFU) uses thermal energy generated from high-intensity ultrasound to cause tissue ablation via coagulative necrosis and tissue cavitation. Cryotherapy is another form of thermal energy, which however relies on very low temperatures to cause tissue ablation via osmotic injury, apoptosis and vascular injury. Laser interstitial thermal therapy (LITT) uses thermal energy as well, however unlike HIFU, LITT delivers heat generated from a laser device directly to the target area. PDT ablation relies on the activation of a vascular photosensitizer resulting in the generation of reactive oxygen species within the target area causing apoptosis, vessel damage and necrosis. Irreversible electroporation (IRE) ablation relies on trans-perineal electrodes which deliver high voltage, low energy electric current within the target tissue. Each technique described has a different indication depending on both prostate and lesion characteristics (26).

Besides the several energy modalities, among the aspects considered mandatory to affirm FT as a valid therapeutic alternative, standardization and widely used definitions represent pivotal points that need to be addressed (27). In particular, starting from definition and moving through treatment modalities, different energies and follow-up protocols are the main fields that need discussion. A list of the main studies improving standardization in FT is shown in Table 3.

Treatment definition

Prior consensus statements have made a distinction between PGA (Partial Gland Ablation) therapies (based on regional tumor localization as defined by biopsy or by imaging), and the image targeted FT (27,28). There are various minimally invasive tissue ablation strategies generically labeled as FT of the prostate (33). A recent consensus by Lebastchi et al. considers that the specific term “Focal Therapy” must be meant to describe guided ablation of an image-defined, biopsy confirmed, cancerous lesion(s) with a safety margin surrounding the target lesion (28). The Consensus panel also reached agreement that the current standard of care regarding the imaging modality is mpMRI (28).

Uniforming the administration of PGA and FT is possible. Treatment templates for PGA do not depend on imaging identification of the tumor but instead on their biopsy location only. PGA makes use of the anatomic boundaries of the prostate in order to preserve its functionality while achieving tumor treatment and it is for this reason standardizable. The Multidisciplinary Consensus lists four types of PGA. (I) Quadrant Ablation: destruction of all prostate tissue within a quadrant of the prostate; (II) Hemiablation (lateral or anterior): destruction of all the prostatic tissue within a lateralized hemisphere or the anterior half of the prostate; (III) Hockey stick Ablation: destruction of all the prostatic tissue within a lateralized hemisphere plus anterior contralateral region; (IV) Subtotal Ablation: destruction of all the prostatic tissue with the preservation of a posterior lateral region (28). On the other hand, FT, as stated by its own definition, is an image-targeted, biopsy-confirmed treatment modality. In this context attention should not be so much placed on a treatment template to be respected, rather on the correct localization of the neoplastic burden and the ablation of the previously described safety margin (34). As aforementioned, the implementation of preoperative diagnostic modalities is needed in order to deliver a disease tailored approach. Indeed, with the goal of achieving the lowest rate of side effect while obtaining cancer control, a true FT approach (with proper safety margins) should be considered as standard of care.

Energy type

Regarding the type of energy, to date, there is no evidence in support of the use of a specific FT modality over another and there are very few studies in literature that try to provide evidence.

Linares Espinós et al. considered the PCa location within the prostate as pivotal to define the best modality to be used (29). The proposed “à la carte” approach considers not only the lesion’s location, but also the technical characteristics of each type of energy, the patient profile and the possible side effects. This model essentially guides the choice of the type of treatment by focusing on the site of the lesion: Cryotherapy is recommended for anterior lesions, while HIFU is particularly beneficial for posterior lesions (29).

In a more recent study, Stabile et al. tried to validate the “à la carte” approach using a propensity-score match analysis according to disease location in a population of men receiving FT with HIFU or cryotherapy (30). Results showed that both HIFU and cryotherapy likely achieve similar medium-term oncologic results regardless of PCa location even though cryotherapy seemed to be preferable for patients with apical disease (30).

What is certain about this aspect of the FT is that not all energies are the same and that each of them might have its own best case scenario of application. However, since no prospective comparative trial has been carried out yet, HIFU represents the most widely and supported energy modality used to date (35). Therefore the use of HIFU may be considered the “gold standard” of FT strategy, until other modalities wait for further and more reliable data to be provided.

Follow-up protocols

To include focal therapy as a valid therapeutic alternative, standardized follow-up is necessary, but literature is still scarce on patient follow-up after focal therapy and there is currently no validated method for monitoring treatment success.

A consensus conducted according to the Delphi method by Muller et al. recommends a minimum follow-up duration of 5 years and suggests the tools that should be included in assessing post-treatment outcomes: multiparametric MRI (mpMRI), biopsies, assessment of erectile function, quality of life (QoL), urinary symptoms and incontinence (31). Although it is clear what the tools are, unfortunately there is no agreement on how to use them.

In a study from 2016, Dickinson et al. assessed the diagnostic performance of prostate-specific antigen (PSA) parameters (post-HIFU PSA nadir, 6-month PSA, PSA density) vs. mpMRI (performed early: <3 weeks from the treatment, and late: 6 months from the treatment) compared to histological outcomes following focal therapy. The mpMRI strongly predicted a negative biopsy after focal therapy and their results showed that early and late mpMRI performed better than PSA measurements in the detection of residual tumor after focal therapy (32).

There is a lack of consensus regarding the optimal frequency and thresholds for prostate-specific antigen (PSA) monitoring after FT. PSA nadir had been proposed as a post-FT tool (36,37), but its value is highly influenced by several factors. There is a need for new PSA based follow-up tools after FT.

In a recent study, Stabile et al. tried to determine the relationship of the percentage of PSA reduction (%PSA reduction) after FT using HIFU in predicting the risk of any additional and radical treatment. Their findings endorse the use of %PSA reduction as a practical follow-up clinical tool (38). They showed how a %PSA reduction of >80% should be considered a proxy for excellent treatment quality and efficacy, while patients with a %PSA reduction of <40% have a high risk of receiving additional treatment within 5 years from treatment, suggesting that this subgroup of patients might be served by a stricter follow-up with mandatory biopsy at 12 months after FT (38).

Even though a few data exist on clinical tools to predict PCa recurrence after FT, almost all data come from retrospective series. So far, the use of serial PSA, mpMRI seem to be mandatory after FT for PCa. Furthermore, given the lack of evidence supporting the accuracy of neither PSA nor mpMRI in predicting PCa recurrence after FT, protocol follow-up biopsies seem to be so far mandatory. The prompt identification of PCa recurrence is mandatory at this stage of FT evaluation, in order to deliver salvage therapies [i.e., salvage radical prostatectomy, salvage (RT)] at an early stage to avoid unfavorable outcomes after salvage therapies for recurrence after FT. Providing reliable data on the validity of salvage therapies is of utmost importance for both patients’ counseling and to support the presence of a feasible safety net in case of PCa recurrence.

Further studies are needed to improve evidence in order to identify subset of patients potentially cured after FT without the need of performing further biopsies.

Proving oncological effectiveness

The initial studies assessing the primary outcomes of FT were mostly proof-of-concept, single-arm, retrospective studies geared towards the feasibility of delivering FT safely and with few functional repercussions (5). Such trials therefore recruited mostly men with low-risk disease, which today would be offered AS (5).

One of the most debated topic in the field of FT effectiveness is represented by the possibility and the need to perform follow-up biopsies. As in other types of focal treatments for other organs, there is a risk (in some series not negligible) of treatment failure after FT for PCa (39). The preferred biopsy in the post-FT setting is mpMRI-Targeted, always combined with systematic sampling to also evaluate the area of the untreated prostate parenchyma. Indeed, follow-up biopsy assessment needs to be investigated with a discrimination of in-field and out-of-field site of disease recurrence (28).

The in-field failure is defined as residual tumor identified within the treated area of the prostate, while the out-of-field failure is represented by the presence of disease within untreated areas. The out-of-field recurrence might be represented by wither disease that already existed prior to the initial treatment but missed by the initial assessment or de-novo PCa foci become clinically apparent (28). Most of the studies available in the literature refer to an overall biopsy failure when talking about of FT failure (35). This method of reporting disease recurrence is both inaccurate and potentially underestimating FT effectiveness. In order to being able to assess more accurately and correctly the FT oncological outcomes, both for retrospective and prospective studies it should be considered mandatory to separately report in-field and out-of-field PCa recurrence.

In studies performed in the past decade, FT has always shown acceptable functional outcomes. For instance, studies assessing HIFU reported a pad-free rate of 95% and emergence of erectile dysfunction in up to 20% patients after treatment (26).

Nonetheless, it is the lack of comparable oncological outcomes that hinders the most FT acceptance in the urological community when considered an alternative therapeutic strategy against radical therapies. Unlike functional outcomes, oncological outcomes should be assessed with randomised controlled trials (RCTs) with a comparator arm offering standard of care (SOC). As FT is a possible treatment modality in patients with clinically significant PCa, (RT)or RP should be used to compare outcomes and efficacy of treatment. However, the clinical endpoints commonly used to show whole-gland treatments efficacy (i.e., post-operative PSA, biochemical recurrence, etc.) cannot be applied to FT, as it is a treatment that spares part of the prostatic tissue. To this end, a recent systematic review (26) identified six studies (35,40-44) which were considered IDEAL stage 3 or greater (45). Of these, five studies (40-44) compared FT to SOC, where RP was used as the comparator only in 3 studies, of which two were propensity score matched studies (40,43) and one was a feasibility randomised controlled trial (44). None of the studies were prospective comparative studies of RP versus FT. A weakness common to all studies previously mentioned was that the longest follow-up present was 36 months, too short a time to determine any oncological benefit of receiving FT compared to RP for PCa. Furthermore, a few attempts in comparing FT with radical therapies were performed by carrying out matched analysis comparing the need for local salvage or systemic therapy or emergence of metastases after FT and RP (46). The study showed that FT had a similar cancer control to RP, albeit with a follow-up of less than 10 years. Unfortunately, no evidence was provided regarding the proportion of men in the FT arm receiving a follow-up biopsy and reporting the proportion of men that had a persistence/recurrence of PCa. Moreover, no standardized protocol was used to decide on whether to deliver additional treatments.

In addition to the lack of comparable oncological outcomes, as aforementioned, reliable follow-up clinical tools are needed to identify men at risk of PCa recurrence. To this end, the percentage PSA reduction 6 months post-treatment was recently proposed as an ideal candidate for follow-up, as it correlated with favourable oncological outcomes and a reduced risk of requiring any additional treatment (38). Indeed, a PSA reduction of greater than 80% correlated with less than 20% requiring a radical treatment at 5 years. Conversely, a reduction of less than 25% increased the risk of additional treatment. Granted the limitation of a short follow-up, this regimen allows physicians to tailor follow-up in patients undergoing FT, increasing patient and physician confidence, improving technique adoption.

In addition, an interesting finding comes from a very recent study by Huber et al. investigating the role of the PSA nadir following therapy of non-metastatic Prostate Cancer using HIFU (47). The aim of the study was to test whether prostate specific antigen criteria could diagnose treatment failure. After a retrospective analysis conducted on 598 patients (from a prospectively maintained national database) the authors concluded that after focal HIFU, PSA nadir + 1.0 ng/mL at 12 months and PSA nadir + 1.5 ng/mL at 24 to 36 months might be used to triage men requiring further tests (mpMRI and biopsy). As also recalled by the authors, in light of the retrospective nature of the study, these results need further prospective validation (47).

A list of the main studies improving providing tools for oncological effectiveness is shown in Table 4.

Robust oncological outcomes coming from investigations are still lacking. This could be due to the inherent long natural history and high event-free rate of localised PCa mean resulting in outcomes such as time-to-metastasis and cancer-specific mortality requiring a very large sample size and a 10–15-year follow-up period in order to demonstrate any significance. Secondly, there have been numerous failures of setting up RCTs in localised PCa, due to low accrual rates and low compliance (49).

Hence, due to the numerous failures of ‘traditional’ RCTs in localised PCa, the Imperial Prostate (IP4) Comparative Health Research Outcomes of Novel Surgery in prostate cancer (IP4-CHRONOS) was established to deliver FT oncological outcomes by using an innovative RCT framework (48). It does so by running two separate parallel RCTs where on one side a ‘traditional’ head-to-head RCT comparing FT to radical treatment is assessed, and on the other, for those who express a strong preference for focal therapy, a surgical multi-arm, multi-stage (MAMS) RCT. A MAMS trial offers multiple different treatment options, all under the same regulatory framework. In this case, the MAMS RCT compares focal therapy alone to focal therapy combined with different neoadjuvant agents, which allows to determine whether failure can be improved with these additional treatments. The choice of enrolment in the parallel RCT is determined by participant and physician preference and discussion. This framework allows better recruitment, acceptance of randomisation and compliance to the allocated arm, overcoming the difficulties encountered in the past.

There are currently four RCTs comparing FT to whole gland treatment [NCT04278261, NCT03668652, ISRCTN17249875 (44), NCT04049747 (50)]. In detail, these are: two large RCTs from the United Kingdom (ISRCTN17249875, n=800; and NCT04049747, n=2,450) comparing FT with radical treatment (RP or EBRT or brachytherapy), a RCT in China (NCT04278261, n=438) comparing focal IRE to RP and a RCT in Sweden (NCT03668652, n=250) is comparing HIFU to RP. Therefore, it seems high quality data will be generated from these studies. Unfortunately, the study with the earliest estimated completion date is the British PART study, which should be concluded in 2024 (44). All studies aforementioned should be completed by 2027. This means that before these dates, we must accept that there will be a lack of comparable data between whole-gland treatment and FT. A list of the on-going RCTs comparing FT to whole gland treatment and their most relevant characteristics is offered in Table 5.

A way to overcome the long natural history of localised PCa, and facilitate the early introduction of FT in clinical practice is to identify intermediate clinical endpoints (ICEs) predicting long-term overall survival (OS) may also be useful (51). These surrogate markers might include the need for local re-intervention or systemic therapy [as previously mentioned (46)], changes in PSA dynamics or changes in PSMA/PET imaging.

To conclude, available evidence demonstrates encouraging results. In recent years, there has been an increase in investigations regarding FT. Such studies are nowadays rightly focused on intermediate-risk PCa, as an alternative to RP. However, standardization of definitions and interventions in the field of FT is important to lower the sample size required to demonstrate oncological efficacy. Moreover, notwithstanding the consensus meetings performed in the past, trials are still relatively heterogeneous, hindering evidence acquisition. There are ongoing trials investigating FT in its correct therapeutical window, i.e., as an alternative to RP and not AS, albeit it will take until the second half of the decade before results will be available. Finally, with improvements in imaging, identifying patients most suitable for gland-sparing interventions should improve.

Salvage therapies for FT failure

Notwithstanding important advances in patient selection, up to a third of patients may require further local salvage treatment after ablative therapy failure (52). Options for patients experiencing recurrence after FT include salvage robotic-assisted radical prostatectomy (sRARP), salvage radiotherapy (sRT) and repeat FT. Literature regarding salvage therapies for FT failure is limited, mostly descriptive in nature and with small cohorts.

In the past, sRARP was avoided as it was considered complex and unsafe, as prior FT generated peri-prostatic fibrosis, adhesions and loss of anatomical planes (53). However, a study by Pierrard et al. (54), showed that sRARP post vascular-targeted PDT was feasible and safe without difficulty for most of the surgeons involved. In most cases the reported difficulty was due to lateral fibrosis during dissection of the nerve bundles on the PDT treated lobe. A second difficulty encountered was linked to posterior fibrosis with consequent adherence to the rectum (54). Accordingly, in another study comparing sRARP and RARP, it was found that while operating times are longer in sRARP compared to primary RARP, and general surgical perception agrees that sRARP are more complex procedures, a matched analysis demonstrated no significant differences in post-operative Clavien-Dindo scores (55). The same study also showed that while sRARP had a 25% increased risk of positive surgical margins and a three-fold greater incidence of PSA persistence, there was no substantial difference in BCR incidence, albeit with a short 36 month follow-up (55). On the other hand, functional outcomes diverged significantly between sRARP and primary radical treatment. Indeed, only 55% of patients treated with sRARP recovered continence at three years, as opposed to 83% in the second group (55). Similarly, recovery of potency was achieved only in 13% patients undergoing sRARP, half compared to primary RARP. Part of the divergence in functional outcomes may be attributed to the feasibility in performing a full or partial nerve-sparing procedure. Indeed, nerve sparing was performed less in patients undergoing sRARP, due to peri-prostatic fibrosis (55). However, in a separate propensity score-matched analysis between sRARP after FT and primary RARP, a sub-analysis on patients who underwent a full nerve-sparing procedure showed that potency rates remained inferior in the cohort with prior FT, possibly owing to a lower quality of nerve-sparing and prior direct nerve damage from FT (56).

Salvage radiotherapy (sRT) is another possibility. Indeed, a recent single-institution study compared sRARP and sRT with concomitant hormone therapy in patients previously treated with FT (57). The study confirmed that like sRARP, oncological and functional outcomes of sRT are inferior compared with primary radical outcomes. When compared in the salvage setting, it appears that sRT may provide better medium-term oncological control compared to sRARP, as overall BCR-free survival at 3 years was 89% and 69%, respectively (57). A potential explanation for this outcome in this particular study was the higher prevalence of high-risk disease in the sRARP cohort (indeed, no significant oncological difference was present in patients with intermediate-risk disease) and concomitant hormone therapy in sRT, resulting in a biochemical suppression. Cumulative sRT-related bowel and urinary toxicity was 25% and 61%, respectively. When comparing functional outcomes, sRT provides a similar urinary continence rate, but a superior erectile function (EF) profile, as potency at 2 years was 21% and 73% for sRARP and sRT, respectively (57).

If FT failure is due to a low volume intermediate-risk disease, repeat FT is a viable option. Indeed, in a previously cited study looking at oncological outcomes in men treated with HIFU, patients were followed for 3 years. Twenty-six per cent required salvage treatment, of which 193 (71%) opted for a repeat focal HIFU, with 74% of these patients not requiring further treatment (35).

In conclusion, sRARP performed by experienced surgeons is a feasible treatment option in patients experiencing FT failure. Both sRARP and sRT appear to provide acceptable oncological control, albeit at the cost of worse functional outcomes when compared to a primary radical treatment. Definitive evidence of oncological control using ‘hard’endpoints such as overall survival are still needed in this setting. Potency was significantly more preserved in patients which had undergone sRT, therefore careful counselling and patient preference should be performed when deciding on the ideal salvage treatment option.

However, it is worth mentioning that current data in the salvage setting are afflicted by the poor disease features of current patients candidate for salvage therapies. For instance, in the previously cited study by Bhat et al. (55), 50% of patients had at least ISUP Grade Group 3 or more disease. Furthermore, at the final pathology assessment, 66% and 9% of men had locally advanced disease and nodal metastasis, respectively. Again, this is most probably due to poor patient selection and lack of a standardized post-FT follow-up. This leads to poor outcomes in the salvage setting and consequent hesitation towards welcoming FT as a valid therapeutic alternative (58). A list of the main studies improving patient selection is shown in Table 6.

Conclusions and future directions

In conclusion, it appears that FT for PCa is in a transition phase, exiting from being an experimental treatment, albeit too premature to be considered an established treatment.

The shift from treating low-risk to intermediate-risk PCa patients is the correct direction, considering the effectiveness of current management in the former cohort. Moreover, the continuous improvement in imaging modalities should allow a better characterization of the index lesion, improving patient selection and further justifying treating solely the index lesion, ensuring optimal functional outcomes. Equally important, standardising and harmonising the different FT approaches will be important to allow comparability and promote widespread adoption of FT. Finally, the ultimate step in consolidating the transition and establishing FT as valid alternative is the generation of robust long-term oncological outcomes.

However, the need to wait several years for RCT data to be published might be overcome by providing solid data based on well-selected comparative series with standardized follow-up, in order to understand as soon as possible whether or not FT could be considered among the set of therapeutic alternatives and providing patients with a further option that is awaited in the field of treatment of clinically localized PCa.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-22-50/rc

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