The prostate cancer focal therapy
Prostate cancer (PCa) is the most common non-cutaneous cancer in western countries (1) with more than one million cases currently diagnosed annually (2). Over the past 25 years, the improvement of treatments, together with the early diagnosis, allowed an increasing from 69% to almost 99% of the 5-year overall survival (OS) for PCa, but these therapies are also associated with considerable morbidity, particularly in genito-urinary dysfunction (1-5).
Therefore, clinicians and patients need to assess together the balance of risks and benefits of therapies using a shared decision-making approach: the aim is to treat the PCa with the lowest risk of recurrence and, at the same time, with minimal morbidity from side effects or complications (6).
The conventional approach includes definitive treatment as the radical prostatectomy (RP) for organ-confined tumor and radiation therapy (RT) for extraprostatic tumor (7). The most important step of patient’s management is to differentiate between intra-capsular PCa (stage T1 or T2, according to the TNM staging system) and locally extraglandular PCa (stage T3) (8). Indeed, it was demonstrated that curative treatment is most likely when the TNM stage is ≤ T2c, namely when extracapsular extension (stage T3a), seminal vesicle invasion (stage T3b) or metastatic disease (N+ and/or M+) are not present (8-10).
Advanced PCa is decreasing because of stage migration with prostate-specific antigen (PSA) testing (11). On the other hand, the introduction of PSA-screening, although it has been associated with a significant reduction in PCa mortality, resulted in overdiagnosis and overtreatment of indolent PCa, exposing many men to non-negligible risks and complications without real and concrete benefits (12). For these reasons, conservative treatment option, specifically active surveillance (AS), became increasingly used, demonstrating as a legitimate choice for patients with low risk PCa without any additional morbidity (13). As a result, men with localized PCa face a difficult choice: AS versus RP. The available evidence from contemporary literature demonstrates that there is no relevant difference between AS and RP in 10 years OS (14,15). The patient’s dilemma is based on the significant rates of genito-urinary (erectile dysfunction and urinary toxicity, either as obstructive symptoms or incontinence) and rectal side effects of the RP and RT due to their side effects on the adjacent structures (neurovascular bundles, sphincter, bladder neck and rectal wall) (16-19). On the other hand, AS can be associated with psychosocial and financial burdens for participating patients (20). In order to overcome these obstacles and to maintain the oncological benefit of active treatment, while avoiding genito-urinary dysfunction and rectal complications, in the last decade the focal therapy (FT) has been evaluated as a novel strategy in selected patient with localized PCa, representing the middle ground between AS and more aggressive options like RP and RT (21).
FT is a well-established treatment of many other solid-organ malignancies, including those in the breast (22,23), kidney (24,25), thyroid (26), liver (27,28), pancreas (29) and brain (30). The fundamental aspect of FT is the targeted destruction of neoplastic tissue with the preservation of surrounding healthy parenchyma (31). In the case of PCa, this approach allows a more favorable morbidity profile, with the potential for improved urinary and fecal continence and sexual potency outcomes (32,33). Several energy modalities are available and have been used for the purposes of FT: irreversible electroporation (IRE), high-intensity focused ultrasound (HIFU), cryotherapy, focal laser ablation (FLA), photodynamic therapy (PDT), brachytherapy (BT) and radiofrequency ablation (RFA) (34,35).
The approach for PCa FT requires, as the first step, to define a cohort of patients whose PCa features are of higher risk than those indicated for AS and of lower risk than those for RP. These patients should undergo multiparametric magnetic resonance imaging (mpMRI) with the aim to select the target lesion within the prostate, namely the index lesion. The final step is to select types of energy suitable to treat and accomplish an oncological safe organ-sparing ablation with minimal toxicity, based on tumor characteristics and location (21,36-38).
Using the terms “prostate cancer” or “prostatic neoplasms” and “focal” or “partial” or “targeted” and “ablation” contained in title and/or abstract and/or keywords, a comprehensive literature review was conducted through Medline, Scopus and Google Scholar (from January 1990 to May 2017) databases.
Rationale of PCa FT
PCa has a very long evolution and this involves that patients who receive the diagnosis do not necessarily require therapy: most of PCa patients with low risk of clinically significant disease, neither die prematurely nor have a reduced quality of life (31,39,40). However, although overtreatment of patients with low risk PCa with RP is declining, it still occurs (6).
The use of PSA-screening has led to an impressive increase in the number of clinically insignificant PCa that are being detected and most of them undergo RP: between 2004 and 2007, 58% of men were treated with RP in comparison to less than 10% by AS (6,41). RP can cause loss of erectile function (the most common complication), incontinence and rectal toxic effects such as diarrhea, bleeding, and proctitis (21,34,42). Some physicians argued that for man who need treatment RP is effective and the patient has to accept the side effects (6). However, this same argument formerly used for other cancers (e.g., breast, kidney, liver, pancreas) is now obsolete (22-25,27-29,31,33). Additionally, patients are able to evaluate the benefits of their treatment (6) and nowadays men are not willing to accept any side effect unless they gain years of life expectancy in return (6,43).
Several recent studies have shown that screening for PCa, at worst, are of no benefit in reducing mortality (44) and, at best, prevent the death of 1 man for every 48 men who are treated over a 10-year period (45). On the other hand, there is not yet a definitive way to intercept men who will die from the PCa. Efforts have thus been focused on reducing the considerable burden imposed by complications related to treatment (46) and developing less radical and invasive therapy to treat men with low or moderate risk for clinically significant PCa. The aim of FT is to treat exclusively tumoral zones and to preserve the remnant gland resulting in lower incidence of side effects and complications compared with radical therapies.
A common criticism of the FT argues that PCa is tipically multifocal with only 15% of men having truly unifocal PCa (47). However, there is now evidence that it is the highest size and grade index lesion that drives the progression to extraglandular extension and metastases (6,48). Moreover, using genomic analysis among 30 men who had died of disseminated PCa, Liu et al. found that most metastatic PCa arise from a single precursor cancer cell (49) reinforcing the hypothesis that the natural history of the disease is driven by the index lesion (35,46,50). Risk stratification of the index lesion predicts the outcomes, irrespective of the presence of unilateral or bilateral PCa (51). Thus, FT of the index lesion alone might provide acceptable oncological outcomes because residual PCa in the untreated area does not compromise long-term disease control (31,46).
Selection criteria for FT
FT developed as an alternative way between AS, given the inherent risk of reclassification at subsequent repeat biopsy and due to the cancer-related anxiety, and RP, especially considering the urogenital side effects and complications of treatment (35,42,52). Prospective studies comparing RP to AS demonstrated that patients with low risk PCa are less likely to benefit from treatment than those with high and intermediate risk PCa (35,52). Therefore, FT should be considered as a less aggressive alternative compared with RP in men with significant disease, excluding patients with very low risk PCa eligible for AS (35). The International Task Force of Prostate Cancer outlined the use of FT in selected patients with low risk PCa in 2007 (52). However, further publications highlight the increasing use of FT in men with intermediate risk PCa (39,40). The 2015 international multidisciplinary consensus on inclusion criteria for FT candidates selection for trials included patients with PSA <15 ng/mL, clinical stage ≤ T2a, GS =3+3 or GS= 3+4 (35,37). No tumor volume has been established as a limit for FT (21).
At the best of our knowledge, at least 20 clinical trials on FT in PCa are actively recruiting; 3 of them were recruiting patients with low risk PCa and 17 were recruiting men with low risk or intermediate risk (GS <8) PCa (31). Accordingly, current opinion suggests that suitable candidates for FT can have low or intermediate-risk, with GS >6 PCa localized to one lobe (42) and life expectancy ≥10 years (21). Patients with a single focus of GS =3+4 PCa with limited surrounding tissue of GS =3+3 and patients who are particularly motivated to receive a low-morbidity treatment could be suitable candidates (37), but they should be informed about the lack of long-term follow-up data on the oncological outcome of FT (21).
Detection of the index lesion to be treated
The essential for succesfull FT is the definite identification and localization of the PCa’s index lesion (46,48) and mpMRI is actually considered the most accurate imaging technique for clinically significant PCa detection and localization (7,53-55). In order to improve accuracy in detecting PCa, an advanced mpMRI paradigm has been developed in the last decade to obtain both anatomical and functional images (53,56). In 2015, the second version of Prostate Imaging Reporting and Data System (PI-RADSv2) helped to improve the reproducibility in the reading of mpMRI between different centers and radiologists (57), reaching very high sensitivity rate of diagnosis and localization of clinically significant PCa (54,58,59). Both T1-weighted imaging (WI) and T2-WI should be obtained for all prostate mpMRI. T1-WI determines the presence of hemorrhage within the gland (57) and the “T1 hemorrhage exclusion sign” represents an additional aid for localization of larger foci of PCa on mpMRI performed after biopsy (60). On T2W images, PCa appears as hypointense focal lesions; however, this appearance is not specific and can be seen in various conditions such as prostatitis, benign hyperplasia, biopsy-related scars, and after FT (57). Therefore, the diffusion-weighted imaging (DWI) and the apparent diffusion coefficient (ADC) map are the real added-value to this imaging technique since they allow assessment of tissue cellularity: in PCa, the cellularity in the lesion is very high (61), then the lesion appears hypointense on ADC maps and normal tissue appears bright (57). Dynamic contrast-enhanced MRI (DCE-MRI) is a valuable tool in providing a map of blood flow of the prostate, which is increased with more vascular permeability in PCa (62) and it is useful not only for the detection of PCa (63,64), but also when there is suspicion of residual or recurrent disease after RT or FT (65). After FT, mpMRI is used to assess the extent and distribution of the expected necrosis in the target region: on contrast-enhanced T1-WIs, non-enhancing low-signal-intensity regions are expected at sites of treated PCa (representing necrosis), while focal areas of enhancement (representing viable tissue) are suspicious for recurrence (65). In the last decades, a resurgent interest for functional imaging based on a special theory named intravoxel incoherent motion (IVIM) developed (66) and there are studies demonstrating that extract IVIM parameters in mpMRI is clinically relevant for PCa detection (67-69). One appealing feature of these data is that applying IVIM protocol, the perfusion information could be obtained without the need for intravenous contrast media (68,70,71), which is especially relevant considering nephrogenic systemic fibrosis due to the gadolinium-based contrast (72,73) and the rising concern of gadolinium deposition in neural tissues (74).
Lastly, new imaging fusion platforms allow utilizing functional properties to target candidate lesions for biopsy and FT (75). MRI-guided biopsies of suspicious lesions were shown with increased accuracy compared to conventional blind and random biopsies (13,76). However, some recent studies showed an mpMRI underestimation of the true histological tumor volume and boundaries, which have key implications in planning and performing FT procedures (77). In 2015, Le Nobin et al. evaluated the correlation between mpMRI and histopathology for PCa volume and contours estimation using an automatic deformable 3D co-registration platform. They found that histological tumor boundaries tended to be underestimated by mpMRI especially for GS ≥7: for this reason a 9 mm-safety margins around the visible tumor on mpMRI should be applied during FT procedures for effective ablation of the entire PCa (78).
IRE corresponds to a non-thermal ablation modality that uses short electric pulses to create irreversible pores in the cell membrane, thus, causing cell death to the inability to maintain homeostasis (79). IRE uses needle electrodes placed in or around index lesion to deliver a series of brief direct-current electrical pulses with the intention of inducing a permanently porous cell membrane, which result in cell apoptosis (80). Pathology specimens have clarified that IRE lesions cause a complete destruction of tissue extended directly up to the vessel wall, avoiding completely the heat sink effect, a common problem in the thermal ablation techniques. At the same time, IRE lesions show a sharp demarcation between ablated and non-ablated tissue and, if the correct ablation protocols are respected, that can lead to the saving of all the neuro-vascular structures next to the treated area: this characteristic has major implications, particularly in the prostate, where preservation of blood flow is a key component of maintaining erectile function (81).
IRE requires a transperineal approach for electrodes placement and patients need general anesthesia with deep muscle paralysis (82). The number of electrodes used depends on the size and the shape of the index lesion (35). In the design of the IRE protocol the voltages on the electrodes and the distances between the electrodes are chosen in such a way as to produce a range of IRE fields that encompasses the entire undesirable area of tissue. The effects of the electrical pulses are a function of several parameters, including the electrical field, pulse length, pulse shape, interval between pulses and number of pulses. In addition, electrical pulses produce heat, which increases tissue temperature. Damage due to thermal effects is completely different from damage due to IRE. While IRE affects only the cell membrane and does not affect connective tissue, if the temperature during the application of IRE is sufficiently increased to induce thermal damage, it can cause the necrosis of connective tissue, blood vessels or urethra. Therefore, it is desirable when designing an IRE protocol to choose such parameters that, while inducing IRE damage, do not produce thermal modes of damage (83).
The first experience with IRE for Prostate Ablation was of Onik et al. in 2007 (81) reaching encouraging results and confirming that IRE lesions in the prostate had unique characteristics compared to thermal lesions. In particular the margins of the IRE lesions were very distinct with a narrow zone of transition from normal to complete necrosis and there was complete destruction within the index nodule and rapid resolution of the post-treatment lesions with marked shrinkage within 2 weeks. After this paper, the attention for this procedure grew and two human in vivo pilot studies have been building up with the purpose to determine the safety and the efficacy of IRE in the PCa treatment (84,85). A recent large cohort study by Van den Bos et al. (86) confirmed the safety and feasibility of IRE and farther it shows a promising oncological outcome.
However, IRE has also some limitations, as it requires general anesthesia and it is still much more expensive compared to other FT techniques. Given these bounds, it is expected that IRE will be especially useful in treating tumors otherwise non-treatable by other thermal ablation methods, or when tumors are particularly closed to vital structures as large blood vessels, bowel, nerves and ducts.
HIFU was initially used in urology to treat benign prostatic hyperplasia (87). A spherical transducer produces ultrasound waves generated by that deposit energy as they travel through tissues (35). HIFU allows the deposition of a large amount of energy into tissue, resulting in its destruction through cellular disruption and coagulative necrosis in the targeted area while preserving adjacent tissues (88). Efficiency of HIFU depends on acoustic characteristics of targeted tissue and a mathematic model has been developed to be optimized for PCa treatment (89).
Both US-guided probes and MRI-guided systems have been developed in HIFU treatment for PCa. US probes are inserted per rectum and incorporate both imaging and therapeutic transducers in one unit, whereas a prostate-dedicated MRI-HIFU system makes use of either the transrectal or transurethral approach (87). In addition, neoadjuvant transurethral resection of the prostate can be combined with HIFU to reduce the gland size, facilitate tissue destruction and to minimize side effects (90). For some authors, MRI monitoring can be considered superior to US as a guidance tool because it has better anatomical and contrast resolution. Additionally, MRI offers great real-time thermometry, allowing for measurement of temperature changes and cumulative thermal dose, enabling predictions of the tissue damage extension (91).
Cryotherapy consists in cellular destruction by freezing: the cellular damages caused vary including direct (membranes disruption) and indirect lesions (ischemia and coagulative necrosis) (92). Cryotherapy was the first ablation technique evaluated as a possible treatment for PCa (93). Cryotherapy is feasible by insertion of dedicated interstitial needles using a transperineal approach under guidance of imaging, usually performed under general anesthesia (35). A nadir temperature of –40 to –50 °C is necessary to achieve systematic cell death (35). A rapid freezing followed by a more progressive reheating period provides the best results to induce a “cryolesion” (central necrosis and peripheral edema reaction) with maximal cellular damage (94) whom size may vary according to the type and number of needles, the distance between them, the duration of procedure and the number of freeze-thaw cycles (35). Two freezing cycles are required in the procedure firstly described by Onik et al. (95). Needles placement and cryotherapy procedure monitoring are performed under transrectal-US (TRUS) or MRI-real time monitoring (96). Cryotherapy has been extensively used both for whole and partial gland ablation (97), preserving genito-urinary structures and function from injury and suggesting acceptable disease control for both procedures (98).
FLA’s action results from the absorption of radiant energy by tissue receptive chromophores inducing rapid heat production with irreversible damages, resulting in cell death (32). The thermal damage depends on two factors: the amount of heat energy delivered and the depth of light distribution. The first one is determined by both temperature and the heating duration. Studies involving theoretical models have demonstrated that the ideal temperature for prostate FT is generally assumed of 50 °C (78,99). Indeed, it has been assessed that, despite immediate protein denaturation could be obtained only for temperatures ≥ 60 °C, the use of temperature range of 40–60 °C could also induce irreversible damages if applied for a longer duration (100). Moreover, the extension of thermal lesions grows with the heating duration. Concerning the depth of light distribution, this depends on the wavelength of the laser. It was reported that wavelengths in the range of 590 to 1,064 nm are the most adequate to induce a maximal photothermic effect in human tissue (101). After FLA, coagulative necrosis develops in 24–72 hours and treated areas appear as well-demarcated foci of necrosis surrounded by a thin rim of hemorrhage with no viable glandular tissue after vital staining (32,102).
FLA is currently considered a minimal invasive treatment, able to reduce the risk of healthy adjacent structures damage (102-104). Since 1993, when Amin et al. reported the first case of a clinical application of FLA for local recurrence of PCa (105), a number of studies in the following years have established the feasibility of FLA in PCa treatment (102,106-109). The largest series of patients was evaluated in 2009 by Lindner et al. (103) who performed a phase I trial treating 12 patients with biopsy proven low risk PCa with US-guided FLA. The authors concluded that FLA of low risk PCa is feasible and that the targeted region can be ablated with minimal adverse effects, representing an alternative treatment approach to AS and RP in selected patients (103).
However, some cautions are needed in order to avoid complications. Preoperative thermal damage prediction is required and dedicated software have been developed for the dosimetric planning, allowing the calculation of the light distribution, the temperature rise, and the extent of thermal damage (110). Furthermore, a correct FLA treatment requires the laser-diffusing fiber to be placed within the index lesion (110,111). Some authors assessed that a robot can be successfully used to provide adequate dose coverage of low-volume tumors with difficult location (32). Eventually, FLA requires a perioperative control of the ablated zone. One of the advantages of laser technology is that the control of temperature during the procedure can be performed with MRI: real-time 3D temperature maps could be obtained during FLA procedure and analyzing the acquired images with dedicated software to estimate the thermal changes. This possibility was largely explored in literature both in pre-clinical (112,113) and clinical studies (107-109). In 2017, Natarajan et al. (114) proposed to use as an alternative option, the employ of MRI-ultrasound fusion for guidance during FLA. The authors enrolled 11 men with intermediate risk PCa in a prospective pilot study and they used MRI-US fusion to guide laser fibers transrectally into index lesion and thermal probes for real-time monitoring of intraprostatic temperatures during laser activation, demonstrating that this technique appears safe and feasible (114).
PDT implies the activation of a photosensitive agent (PS) using a source of light with a specific wavelength in the targeted tissue (35). The presence of oxygen is essential since the PDT action is based on the induction of chain reactions leading to the generation of radical intermediates and of the highly cytotoxic singlet oxygen by energy transfer from the photo-excited sensitizer. The latter can induce tissue necrosis either directly with a cytotoxic effect or indirectly causing an acute inflammatory response (35,115,116). Traditional PDT consists in the intravenous injection of a PS which is distributed throughout the body. Then under imaging guidance, standard BT stabilizing frames are placed to allow the positioning in the prostate of small energy-delivering probes that deliver PDT either to a portion of or to the entire gland (117). However, this kind of approach lacks of selectivity and it is linked with some post-treatment inconveniences such as collateral tissue necrosis to adjacent structures or general photosensitivity with consequent need to avoid sunlight exposure for some days after PDT (117). A possible solution is the employ of a variant of PDT called vascular-targeted PDT (VTP) that consists in the use of vascular-activated agents that are currently synthesized from native bacteriochlorophyll, a molecule produced in dark-growing bacteria under aerobic conditions (118). This strategy has some major advantages. Firstly, the radical oxygen species generated by these PS are strictly limited to the vascular bed, determining tissue necrosis only indirectly through vascular occlusion or vascular oxidative stress (119). Secondly, these PS are rapidly cleared first from the circulation and then from the liver. Hence, avoidance of sunlight and other forms of photonic radiation shortly after VTP is not strictly necessary (120). Furthermore, some authors (117,120) suggest that prostate connective tissue is less sensitive to VTP effect and reflects back into the gland a significant amount of the incident light produced during the intervention. The corollary of this theory is that VTP would allow a better preservation of extracapsular structures such as the neurovascular bundle or the adjacent organs. The conclusions of two consecutive clinical trials performed by the Trachtenberg group and other recent studies seem to confirm this fact, although further investigations are needed (121,122). Eventually, the lighting activation is achieved employing near infra-red wavelengths using multichannel diode lasers that deliver illumination from cylindrical laser fibers placed in the prostate under US guidance (123). Also this fact can be considered an advantage, since the use of these wavelengths is associated to a deeper penetration into tissues, as it is convenient for large tissue volume ablations. Because optical characteristics of the prostate are variable, affecting the light absorption and physical effect of PDT and VTP (101), investigators developed dedicated software for the optimization of the parameters of treatment according to tumor and prostate characteristics on preoperative mpMRI (35).
BT is a kind of radiotherapy in which radiation is delivered to the cancer-affected organ by the insertion of seeds containing radioactive material. The biological effect is achieved thanks to the multiple ionizations induced via the Compton Effect that cause DNA damages, cell cycle arrest and ultimately cell death (35). For PCa, whole-gland BT has become one of the most used options for low and intermediate risk PCa (124). The most utilized radioisotopes are Iodine-125 and Paladium-103.
Two different BT modalities are employed to treat PCa, both performed via a transperineal approach: low-dose rate (LDR), in which radioactive seeds are permanently implanted into the prostate, and high-dose rate (HDR), in which the radiation is delivered by a source temporarily introduced into the prostate tissue, being administered in single or multiple fractions. While LDR-BT is an option for patients with low risk PCa (125), HDR-BT is often used in intermediate or high risk PCa in order to achieve dose escalation (7).
BT, although usually performed on the entire gland tissue, can be easily customized to treat a specific partial prostate volume at a specific dose level, and thus appears to be particularly suitable for FT (126). Considering the higher prevalence of PCa in the peripheral zone, an attractive concept has been to direct BT only to this part of the gland, sparing the anterior base (127). Before this subtotal approach, several groups had performed whole gland treatments with a boosted dose to the index lesion (128). Another technique focuses on the ablation of the half prostate affected by the cancer, with hemi-gland LDR technique (129,130). In 2013, Cosset et al. (126) reported on a pilot study in which only index lesions were treated in 21 patients with LDR technique. Although the limited follow-up of that series precluded any definitive data about relapse-free survival, the authors concluded that their approach was feasible and that focal BT, thanks to its ability to treat a well-defined partial prostatic volume with a precise dose, could stand as one of the best FT modalities to be proposed to carefully selected patients.
Traditional whole gland BT uses TRUS to visualize the entire prostate, to calculate its volume for treatment planning and to guide the implantation of radiation sources. In order to treat the specific gland volume affected by the disease, MRI is also widely used for the identification of the suspected area with good results (126,127). MRI-US fusion provides real time guidance to the procedure (124). An invasive localization method is the transperineal mapping biopsy performed via a template grid that is subsequently used for seed implantation (131). Lastly, SPECT images registered with CT has been employed to define intraprostatic biological target volume (132).
RFA treats tumors by delivering an alternating current, producing ionic agitation, which generates heat (with temperatures of around 100 °C) thanks to the Joule effect, and eventually cause coagulative necrosis of the target tissue (133). Operatively, the procedure is performed inserting in the body a needle electrode connected to a generator that produces electromagnetic waves with a frequency in the order of 500 kHz (134).
There is limited literature regarding the use of RFA in PCa; however, RFA has proved to be safe and effective in the treatment of primary and secondary hepatic tumors (135) and promising results have been reported in various other neoplasms (136). Prostate RFA is performed with a transperineal approach, using TRUS for needle insertion guidance. A disadvantage of RFA, however, is the inability to precisely assess the extent of the thermal lesion using US, because there are no specific findings correlating with the post-treatment evolution of the index lesion. Therefore, TRUS is not reliable and cannot be used for monitoring the extent of necrosis, which has to be verified by MRI (134). Some technical difficulties need to be considered (137). Monopolar electrodes are susceptible to a cooling effect by adjacent blood vessels that limits the extent of tissue destruction. In addition, using standard monopolar RFA devices, it is difficult to obtain areas of consistent and complete cell-kill with precise margins. Another major obstacle comes from the technical difficulties in using MRI to guide the FT: the RF generator, indeed, may interfere with the radiofrequency pulses of the MR system and the needle electrode produces large image artifacts. Subtotal RFA has been described in cases of recurrent PCa after prior RT showing good results in term of tissue ablation and low complication rate (138). Given the paucity of data, the use of RFA for PCa remains experimental (139) and it is not still mentioned among the “Alternative Local Treatment Options” in the most recent guidelines produced by the competent European societies (7).
Currently, insufficient data are available to evaluate the long-term oncological FT effectiveness in PCa. The studies on FT are small with a large heterogeneity in study design, target population, risk stratification, type of focal ablation, follow-up schedule and outcome measures of morbidity. Also, the encouraging short-to-midterm outcomes comes from high volume expert centers and reproducibility still has to be confirmed by larger, standardized and controlled studies.
Successful FT consists in effective ablation of the index lesion, improving oncological outcomes and preservation of surrounding structures as assessed by the very low incidence of urinary and sexual disfunctions. Published trials of FT have determined ablation success by using a predetermined protocol of mpMRI of the treatment zone with targeted biopsy as necessary (37).
Oncological success has not been clearly defined, but its evaluation can be derived from the agreed definitions of treatment failure as assessed by PSA monitoring, post-treatment biopsy sampling and rates of retreatment (31). Current literature uses the American Society Radiation oncology (ASTRO) criteria and the Phoenix criteria for the PSA monitoring (127). However, these criteria have not been validated for use with FT, in which considerable amount of functional prostate parenchyma is preserved which continues to produce physiological PSA. Mandatory prostate biopsy one year after treatment is a widely used outcome measure in the available literature and provides a useful tool in assessing the efficacy of FT (40). Other typical triggers for biopsy include rising serum PSA or detection of a suspicious lesion on postoperative mpMRI (37,140). The 2015 expert consensus panel agreed that a residual disease GS ≥3+4 in the treated area represents treatment failure (37). The expert consensus is that retreatment rates of ≤20% after FT are clinically acceptable (37).
As recently described by Valerio et al. (39,40), 3,230 patients who underwent FT has been analyzed in 37 clinical studies using different sources of energy; most studies are on focal HIFU (13) and focal cryotherapy (11) whereas focal PDT (3), FLA (4), BT (2), IRE (3) and RFA (1) are less extensively studied. To date, cryotherapy is the most extensively investigated FT strategy (11 series evaluating focal cryotherapy in 1,950 patients): OS and disease-specific survival were 100% and 100% respectively, the biochemical recurrence-free survival was 71–93%, significant residual PCa in the treated area ranged from 0% to 6.5% and the probability of secondary treatment was 3.3–18.6% after 9–70 months of follow-up monitoring. Significant adverse events, in most parts cases of recto-urethral fistula occurred in only 2.5% patients; pad-free continence and erectile function preservation were achieved in 100% and 81.5% respectively (31,40,141). In HIFU strategies, Valerio et al. have taken into account 13 series evaluating focal HIFU in 346 men (40). Despite the heterogeneity of the materials, the methods and the population of the studies, the primary results were encouraging, showing a low overall probability of transition to secondary local treatment of 7.8%, an excellent OS and disease-specific survival of 100% and an achievement of 100% in pad-free continence and in erectile function preservation. Significant adverse events occurred in only 1.5% of cases (40).
Clinical data assessing use of PDT in PCa remains limited. In a large series and a pooled analysis of trials, post-treatment recurrent PCa rates were around 25% at biopsy sampling after 6 months and salve RP for locally recurrent PCa has been reported safe and effective (123,142,143). Significant adverse events occurred in 10.6% (40). Early studies have demonstrated the safety and feasibility of FLA but studies are small and outcome data are premature with the presence of significant cancer in the treated area between 2.4–4.8% and secondary treatment in none (40). Only 2 series in 339 patients have reported oncological outcomes of focal BT with a biochemical recurrence-free survival rate at the 5-year follow-up of 92% was reported (127). In another smaller series a 5% residual PCa rate at the treatment site was reported (126,144). IRE has been studied in 141 patients, with significant residual PCa in the treated area between 2.9% and 19% and transition to secondary treatment in 12% (39,80). RFA has been studied in only 1 study in 15 men (134).
FT for PCa enables the neurovascular bundles to be spared, thereby reducing the risk of sexual dysfunction or incontinence. To date, considerable heterogeneity exists in the outcome measures used to define post-treatment sexual function with either the International Index Of Erectile Function (IIEF) or Sexual Healthy Inventory for Men (SHIM) questionnaires being used (31,97,122,126,142). Rates of erectile range from 0% to 42% for cryotherapy (31,145-147), and from 11% to 45% for HIFU (31,148,149). Insufficient data are available to determine rates for the other FT modalities. Barret et al. compared three groups of patients undergoing cryotherapy, HIFU, PDT and identified no difference in postoperative IIEF scores between treatment groups (4).
Similar to erectile function, preserved continence after FT for PCa has not been reported universally but seems to do better than in RP: rates of pad-free status are reported to be between 85–100% in cryotherapy (4,31,40,145,148,149), but there is only limited data for the remaining FT modalities. Objective measures including the International Prostate Symptom Score (IPSS) have been introduced to quantify lower urinary tract symptoms and limited reductions in mean IPSS of 3–8 have been reported after cryotherapy, HIFU and PDT up to 6 months after FT (4,31,102,142,148,149).
No formal data are currently available for assessing cost-effectiveness but as FT progress, cost reductions in equipment and facilities will occur and will correspond with a reduction in cost per patient. Minimally invasive approaches lead to reductions in length of hospital stay and associated inpatient procedures, but patients require more stringent follow-up monitoring with costly imaging modalities and potential retreatments.
FT consists in ablation of the index lesion (31,37,40) in men with low or moderate risk of clinically significant PCa. Although definitive data about long-term cancer control are still lacking, FT represents a valid alternative to the AS, entailing cancer-related anxiety, and RP, whose adverse effects may reduce the patient’s quality of life.
With accurate localization of the index lesion, FT can provide uncompromised oncologic outcome with significantly less comorbidity and with genito-urinary functional preservation.
Conflicts of Interest: The authors have no conflicts of interest to declare
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