Ablative Procedures for Prostate Cancer

Number: 0843

Table Of Contents

Applicable CPT / HCPCS / ICD-10 Codes


Scope of Policy

This Clinical Policy Bulletin addresses ablative procedures for prostate cancer.

  1. Experimental and Investigational

    Aetna considers the following ablative procedures experimental and investigational for the treatment (primary or salvage therapy) of prostate cancer because their effectiveness has not been established (not an all-inclusive list):

    1. Dual-fiber laser ablation
    2. Focal thermo-ablative therapy for the treatment of oligometastatic prostate cancer (OMPC)
    3. Irreversible electroporation therapy (see CPB 0828 - Irreversible Electroporation (NanoKnife))
    4. Local therapy/metastasis-directed therapy for the treatment of oligo-metastatic/oligo-progressive prostate cancer
    5. Magnetic field induction ablation
    6. Magnetic resonance imaging (MRI)-guided focal laser ablation (e.g., the Visualase Laser Ablation System)
    7. MRI-guided transurethral ultrasound ablation
    8. Photothermal ablation with copper sulfide nanoplates
    9. Vascular targeted photodynamic therapy (also known as soluble focal therapy)
    10. Water vapor thermotherapy.
  2. Related Policies


CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

CPT codes not covered for indications listed in the CPB:

MRI-guided focal laser ablation of prostate (e.g., the Visualase Laser Ablation System), Irreversible electroporation therapy, dual-fiber laser ablation, photothermal ablation with copper sulfide nanoplates, focal thermo-ablative therapy, local therapy/metastasis-directed therapy - no specific code
0582T Transurethral ablation of malignant prostate tissue by high-energy water vapor thermotherapy, including intraoperative imaging and needle guidance
0738T Treatment planning for magnetic field induction ablation of malignant prostate tissue, using data from previously performed magnetic resonance imaging (MRI) examination
0739T Ablation of malignant prostate tissue by magnetic field induction, including all intraprocedural, transperineal needle/catheter placement for nanoparticle installation and intraprocedural temperature monitoring, thermal dosimetry, bladder irrigation, and magnetic field nanoparticle activation
53854 Transurethral destruction of prostate tissue; by radiofrequency generated water vapor thermotherapy
96570 Photodynamic therapy by endoscopic application of light to ablate abnormal tissue via activation of photosensitive drug(s); first 30 minutes (List separately in addition to code for endoscopy or bronchoscopy procedures of lung and gastrointestinal tract) [vascular targeted and/orsoluble focal therapy]
96571 Photodynamic therapy by endoscopic application of light to ablate abnormal tissue via activation of photosensitive drug(s); each additional 15 minutes (List separately in addition to code for endoscopy or bronchoscopy procedures of lung and gastrointestinal tract) [vascular targeted and/or soluble focal therapy]

HCPCS codes not covered for indications listed in the CPB:

C9734 Focused ultrasound ablation/therapeutic intervention, other than uterine leiomyomata, with magnetic resonance (MR) guidance [transurethral]

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C61 Malignant neoplasm of prostate [primary or salvage therapy]
Z19.2 Hormone resistant malignancy status [Castrate resistant malignancy status]


Magnetic Resonance Imaging-Guided Focal Laser Ablation

Prostate cancer (PCa), accounting for 33 % of all male cancers, is the second leading cause of cancer death in men, exceeded only by lung cancer.  The disease is histologically evident in as many as 34 % of men during their fifth decade of life and in up to 70 % of men aged 80 years and older.  The American Urological Association (AUA)'s Prostate Cancer Clinical Guideline Update Panel (Thompson et al, 2007) stated that standard options for the management of clinically localized PCa include watchful waiting and active surveillance, interstitial prostate brachytherapy, external beam radio-therapy (EBRT), radical prostatectomy, as well as primary hormonal therapy (including androgen deprivation therapy, e.g., bicalutamide).  Other treatment modalities entailed cryotherapy, high-intensity focused ultrasound (HIFU), and combinations of treatments (e.g., EBRT and interstitial prostate bracytherapy).  While watchful waiting and active surveillance, radiation therapy, and radical prostatectomy remain the current standard for the treatment of PCa, laser-induced thermal therapy (LITT) has recently been explored as a means of treatment of PCa.

Stafford et al (2010) stated that image-guided ablation of tumors is assuming an increasingly important role in many oncology services as a minimally invasive alternative to conventional surgical interventions for patients who are not good candidates for surgery.  Laser-induced thermal therapy is a percutaneous tumor-ablation technique that utilizes high-power lasers placed interstitially in the tumor to deliver therapy.  Multiple laser fibers can be placed into the treatment volume and, unlike other interstitial heating techniques, can be fired simultaneously to rapidly treat large volumes of tissue.  Modern systems utilize small, compact, high-power laser diode systems with actively cooled applicators to help keep tissue from charring during procedures.  Additionally, because this approach to thermal therapy is easily made magnetic resonance compatible, the incorporation of magnetic resonance imaging (MRI) for treatment planning, targeting, monitoring, and verification has helped to expand the number of applications in which LITT can be applied safely and effectively.  These investigators provided an overview of the clinically used technology and algorithms that provide the foundations for current state-of-the-art MR-guided LITT (MRgLITT), including procedures in the bone, brain, liver, and prostate as examples.  In addition to advances in imaging and delivery, such as the incorporation of nanotechnology, next-generation MRgLITT systems are anticipated to incorporate an increasing presence of in silico-based modeling of MRgLITT procedures to provide human-assisted computational tools for planning, MR model-assisted temperature monitoring, thermal-dose assessment, and optimal control.

The Visualase Laser Ablation System (Visualase Inc., Houston, TX) is a minimally invasive laser ablation system for the treatment of epilepsy as well as the destruction of tumors (e.g., bone including spinal metastases, brain, kidney, liver and prostate).  It consists of a fiber optic laser; its placement is guided by a surgical navigation system, and confirmed by MRI before treatment.  It is designed to destroy tumor and limit injury to surrounding structures.  For PCa, the Visualase Laser Ablation System is being studied for the treatment of organ-confined disease (Gleason score of 6 or 7 or below).

In a phase I clinical study, Lindner et al (2009) examined the feasibility and safety of image-guided targeted photothermal focal therapy for localized PCa.  A total of 12 patients with biopsy proven low-risk PCa underwent interstitial photothermal ablation of the cancer.  The area of interest was confirmed and targeted using MRI.  Three-dimensional ultrasound was used to guide a laser to the magnetic resonance to ultrasound fused area of interest.  Follow-up was performed with a combination of MRI and prostate biopsy.  Validated quality-of-life (QOL) questionnaires were used to assess the effect on voiding symptoms and erectile function, and adverse events were recorded.  Interstitial photothermal focal therapy was technically feasible to perform.  Of the patients studied, 75 % were discharged home free from catheter the same day with the remainder discharged home the following day.  The treatment created an identifiable hypo-vascular defect that coincided with the targeted prostatic lesion.  There were no peri-operative complications and minimal morbidity.  All patients who were potent before the procedure maintained potency after the procedure.  Continence levels were not compromised.  Based on multi-core total prostate biopsy at 6 months, 67 % of patients were free of tumor in the targeted area and 50 % were free of disease.  The authors concluded that image-guided focal photothermal ablation of low-risk and low-volume PCa is feasible.  Early clinical, histological and MRI responses suggested that the targeted region can be ablated with minimal adverse effects.  It may represent an alternate treatment approach to observation or delayed standard therapy in carefully selected patients.  Moreover, they stated that further trials are needed to demonstrate the effectiveness of this treatment concept.

Raz et al (2010) reported the findings of 2 patients with low-risk PCa who were treated with outpatient in-bore MRI-guided focal laser ablation (FLA).  The tumor was identified on MRI.  A laser fiber was delivered via a catheter inserted through a perineal template and guided to the target with MRI.  The tissue temperature was monitored during laser ablation by MRI thermometry.  Accumulated thermal damage was calculated in real time.  Immediate post-treatment contrast-enhanced MRI confirmed de-vascularization of the target.  No adverse events were noted.  The authors stated that MRI-guided FLA of low-risk PCa is feasible and may offer a good balance between cancer control and side effects; refinement of this outpatient procedure may result in an inexpensive, minimally invasive alternative to current active therapies.  Moreover, they noted that further trials will be necessary to define the safety and oncologic efficacy of this therapy, but these early findings are promising.

Eggener et al (2010) reviewed the rationale, patient selection criteria, diagnostic imaging, biopsy schemes, and treatment modalities available for the focal therapy of localized PCa.  A National Center for Biotechnology Information PubMed search was performed from 1995 to 2009 using medical subject headings "focal therapy" or "ablative" and "prostate cancer".  Additional articles were extracted based on recommendations from an expert panel of authors.  Focal therapy of the prostate in patients with low-risk cancer characteristics is a proposed treatment approach in development that aims to eradicate all known foci of cancer while minimizing damage to adjacent structures necessary for the preservation of urinary, sexual, and bowel function.  Conceptually, focal therapy has the potential to minimize treatment-related toxicity without compromising cancer-specific outcome.  Limitations include the inability to stage or grade the cancer(s) accurately, suboptimal imaging capabilities, uncertainty regarding the natural history of untreated cancer foci, challenges with post-treatment monitoring, and the lack of QOL data compared with alternative treatment strategies.  Early clinical experiences with modest follow-up evaluating a variety of modalities are encouraging but hampered by study design limitations and small sample sizes.  The authors concluded that prostate focal therapy is a promising and emerging treatment strategy for men with a low-risk of cancer progression or metastasis.  They stated that evaluation in formal prospective clinical trials is essential before this new strategy is accepted in clinical practice.  Adequate trials must include appropriate end points, whether absence of cancer on biopsy or reduction in progression of cancer, along with assessments of safety and longitudinal alterations in QOL.

Nguyen and Jones (2011) evaluated the rationale, effectiveness, and morbidity of various methods of achieving focal prostatic ablation.  These investigators performed a literature review of focal therapy in prostate cancer with an emphasis on more established methods (e.g., cryotherapy and HIFU).  The authors concluded that focal ablative methods allow targeted destruction of prostatic tissue while limiting the morbidity associated with whole-gland therapy.  Local cancer control after focal therapy appears promising but does not approach that of established whole-gland therapies.  Until it is feasible to identify patients reliably with truly focal disease and predict their natural history, focal therapy cannot be considered to be the definitive therapy for localized PCa.

Colin et al (2012) noted that current challenges and innovations in PCa management concern the development of focal therapies that allow the treatment of only the cancer areas sparing the rest of the gland to minimize the potential morbidity.  Among these techniques, FLA appears as a potential candidate to reach the goal of focusing energy delivery on the identified targets.  These investigators performed an up-to-date review of this new therapeutic modality.  Relevant literature was identified using Medline database with no language restrictions (entries: focal therapy, laser interstitial thermotherapy, prostate cancer, FLA) and by cross-referencing from previously identified studies.  Precision, real-time monitoring, MRI compatibility, and low-cost of integrated system were principal advantages of FLA.  Feasibility and safety of this technique have been reported in phase I studies.  Focal laser ablation might eventually prove to be a middle ground between active surveillance and radical treatment.  The authors concluded that FLA may have found a role in the management of PCa.  However, they stated that further trials are needed to demonstrate the oncologic effectiveness in the long-term.

Bozzini et al (2013) reviewed the literature to concentrate on the practical aspects of focal therapy for PCa with the following key words: photodynamic therapy (PDT), high-intensity focused ultrasound, cryotherapy, focal laser ablation, electroporation, radiofrequency, external beam radiation, organ-sparing approach, focal therapy, prostate cancer, and then by cross-referencing from previously identified studies.  Prostatic tumor ablation can be achieved with different energies: freezing effect for cryotherapy, thermal effect using focalized ultrasound for HIFU, and using thermal effect of light for FLA and activation of a photo-sensitizer by light for PDT, among others.  Radiofrequency and microwave therapy have been tested in this field and demonstrated their usefulness.  Electroporation is currently being developed on pre-clinical models.  External beam radiation with microboost on neoplastic foci is under evaluation.  High-intensity focused ultrasound and cryotherapy require the use of sophisticated and expensive machines and, consequently, the procedure is expensive.  Laser techniques seem to be less onerous, with the added advantage of size.  The authors concluded that several energy modalities are being developed to achieve the trifecta of continence, potency, and oncologic efficiency.  Those techniques come with low-morbidity but clinical experience is limited regarding to oncologic outcome.  Comparison of the different focal approaches is complex owing to important heterogeneity of the trials.  In the future, it seems likely that each technique will have its own selective indications.

In a review on “Focal therapy in the management of prostate cancer”, Nomura and Mimata (2012) noted that a widespread screening with prostate-specific antigen has led increased diagnosis of localized PCa along with a reduction in the proportion of advanced-stage disease at diagnosis.  Over the past decade, interest in focal therapy as a less morbid option for the treatment of localized low-risk PCa has recently been renewed due to downward stage migration.  Focal therapy stands midway between active surveillance and radical treatments, combining minimal morbidity with cancer control.  Several techniques of focal therapy have potential for isolated ablation of a tumor focus with sparing of uninvolved surround tissue demonstrating excellent short-term cancer control and a favorable patient's QOL.  However, to date, tissue ablation has mostly used for near-whole prostate gland ablation without taking advantage of accompanying the technological capabilities.  The available ablative technologies include cryotherapy, HIFU, and vascular-targeted photodynamic therapy.  Despite the interest in focal therapy, this technology has not yet been a well-established procedure nor provided sufficient data, because of the lack of randomized trial comparing the efficacy and morbidity of the standard treatment options.  Interestingly, FLA is not mentioned as an emerging approach for the treatment of localized PCa.

An UpToDate review on “Initial approach to low-risk clinically localized prostate cancer” (Klein, 2012) states that “The role of ablation with cryotherapy or HIFU as an alternative to radical prostatectomy or RT [radiation therapy] remains uncertain.  Potential advantages in men with localized disease include the ability to destroy cancer cells using a relatively noninvasive procedure.  As such, these procedures are associated with minimal blood loss and pain.  There is also a more rapid post-treatment convalescence.  Whether the long-term outcomes are equivalent to those with definitive surgery or RT is uncertain however.  Additional experience and longer follow-up are required to compare the rate of disease control and side effects profiles with other treatment modalities”.  This review and another UpToDate review entitled “Cryotherapy and other ablative techniques for the initial treatment of prostate cancer” (Pisters and Spiess, 2012) do not mention the use of FLA. 

The National Comprehensive Cancer Network's clinical practice guideline on "Prostate cancer" (Version 1.2013) does not mention the use of focal laser ablation as a therapeutic option.  Furthermore, there is a National Cancer Institute-sponsored phase II clinical trial on “MR Image Guided Therapy in Prostate Cancer” that is ongoing, but not recruiting participants (last verified: July 28, 2017).  Its objective is to examine the safety and effectiveness of treating PCa with laser therapy guided by MRI.

Wenger et al (2014) stated that focal laser ablation (FLA) is an emerging treatment paradigm for prostate cancer that aims to successfully eradicate disease while also reducing the risk of side-effects compared with whole-gland therapies.  Pre-clinical and phase I clinical trials for low-risk prostate cancer have shown that FLA produces accurate, predictable, and reproducible ablation zones with negligible injury to the surrounding tissues.  Because FLA is magnetic resonance compatible, the procedure can be monitored with real-time feedback to optimize targeted treatment of cancerous foci and minimize quality-of-life side-effects.  The authors concluded that FLA is a well-tolerated and feasible therapy for low-risk prostate cancer, and the oncologic effectiveness of this treatment modality is currently under investigation in phase II clinical trials at several institutions.

A review by Sankineni et al (2014) summarized the evidence for MRI-guided focused laser ablation for prostate cancer.  The article indicated that the feasibility has been demonstrated in a canine model and a cadaveric model (citing Stafford et al, 2010; Woodrum et al, 2010), followed by case reports (citing Raz et al, 2010) and 2 phase I studies, citing a study by Oto et al, 2013 and an abstract by Lindner et al, 2013.  The author stated that the most concerning finding of the latter phase I study by Linder et al (2013) was that 26 % of the MRI-guided FLA treated patients showed a positive biopsy at the 4-month follow-up in a site other than the ablated region.  Sankineni et al (2014) concluded that “While these results are pointing in the right direction, it is important that larger, long term trials validate these findings”.

There is currently a clinical trial studying laser interstitial thermal therapy (LITT) for the treatment of PCa. The laser system that will be used is called the Visualase Thermal Therapy System. This system has been used for the treatment of brain, bone (spine), thyroid, and liver cancers. However, this is the first time this system is being studied for use in the treatment of PCa with a trans-rectal approach. This study is currently recruiting participants (last verified September 2016).

Furthermore, there is also a phase II clinical trial to study LITT (using Visualase) in the focal treatment of localized PCa. This study is ongoing, but not recruiting participants (last verified September 2016).

Lepor et al (2015) reported that from April 2013 to July 2014, a total of 25 consecutive men participated in a longitudinal outcomes study following in-bore MRgFLA of PCa. Eligibility criteria were clinical stage T1c and T2a disease; prostate-specific antigen (PSA) less than 10 ng/ml; Gleason score less than 8; and cancer-suspicious regions (CSRs) on multi-parametric MRI harboring PCa. CSRs harboring PCa were ablated using a Visualase cooled laser applicator system. Tissue temperature was monitored throughout the ablation cycle by proton resonance frequency shift magnetic resonance thermometry from phase-sensitive images. There were no significant differences between baseline and 3-month mean American Urological Association Symptom Score or Sexual Health Inventory in Men scores. No man required pads at any time. Overall, the mean reduction in PSA between baseline and 3 months was 2.3 ng/ml (44.2 %). Of 28 sites subjected to target biopsy after FLA, 26 (96 %) showed no evidence of PCa. The authors stated that the findings of this study provided encouraging evidence that excellent early oncologic control of significant PCa can be achieved following FLA, with virtually no complications or adverse impact on quality of life. Moreover, they stated that longer follow-up is needed to show that oncologic control is durable. These researchers stated that early results for focal laser ablation of PCa are very encouraging; however, until long-term oncologic control is confirmed, focal laser ablation must be considered an investigational treatment option.

In a phase I clinical trial, Natarajan and colleagues (2016) examined the safety of trans-rectal MRI-guided (in-bore) FLA in men with intermediate risk PCa. An exploratory end-point is cancer control after 6 months.  These researchers studied FLA in 8 men with intermediate risk PCa diagnosed using magnetic resonance-ultrasound fusion.  Focal laser ablation was performed by inserting a cylindrically diffusing, water cooled laser fiber into magnetic resonance visible regions of interest, followed by interstitial heating at 10 to 15 W for up to 3 minutes.  Secondary safety monitors (thermal probes) were inserted to assess the accuracy of magnetic resonance thermometry.  Comprehensive magnetic resonance-ultrasound fusion biopsy was performed after 6 months.  Adverse events and health related QOL questionnaires were recorded.  Focal laser ablation was successfully performed in all 8 subjects.  No grade 3 or greater adverse events occurred and no changes in International Prostate Symptom Score (IPSS) or 5-item version of the International Index of Erectile Function (IIEF-5) were observed.  Ablation zones, as measured by post-treatment MRI, had a median volume of 3 cc or 7.7 % of prostate volume; PSA decreased in 7 men (p < 0.01).  At follow-up magnetic resonance-ultrasound fusion biopsy cancer was not detected in the ablation zone in 5 men; but was present outside the treatment margin in 6 men.  The authors concluded that FLA of the prostate is feasible and safe in men with intermediate risk PCa without serious adverse events or changes in urinary or sexual function at 6 months.  They stated that comprehensive biopsy follow-up indicated that larger treatment margins than previously thought necessary may be needed for complete tumor ablation.

In a phase I study, Bomers and associates (2016) correlated treatment effects of MRI-guided FLA in patients with PCa with imaging using prostatectomy as standard of reference. Three weeks before prostatectomy, 5 patients with histopathologically proven, low/intermediate grade PCa underwent trans-rectal MRI-guided FLA. Per patient, only 1 ablation was performed to investigate the effect of ablation on the tissue rather than the effectiveness of ablation.  Ablation was continuously monitored with real-time MR temperature mapping, and damage-estimation maps were computed.  A post-ablation high-resolution T1-weighted contrast-enhanced sequence was acquired.  Ablation volumes were contoured and measured on histopathology specimens (with a shrinkage factor of 1.15), T1-weighted contrast-enhanced images, and damage-estimation maps, and were compared.  A significant volume correlation was seen between the ablation zone on T1-weighted contrast-enhanced images and the whole-mount histopathology section (r = 0.94, p = 0.018).  The damage-estimation maps and histopathology specimen showed a correlation of r = 0.33 (p = 0.583).  On histopathology, the homogeneous necrotic area was surrounded by a reactive transition zone (1 to 5 mm) zone, showing neo-vascularization, and an increased mitotic index, indicating increased tumor activity.  The authors concluded that the actual ablation zone was better indicated by T1-weighted contrast-enhanced than by damage-estimation maps.  Histopathology results highlighted the importance of complete tumor ablation with a safety margin.

Eggener and co-workers (2016) stated that MRI-guided FLA is an investigational strategy for treatment of PCa. These researchers carried out a phase II evaluation of FLA that included men with stage T1c to T2a, PSA less than 15 ng/ml or PSA density less than 0.15 ng/ml3, Gleason less than or equal to 7 in less than or equal to 25 % of biopsies, and MRI with 1 to 2 lesions concordant with biopsy-detected cancer.  At 3 months, all had MRI with biopsy of ablation zone(s).  At 12 months, all underwent MRI and systematic biopsy.  International Prostate Symptom Score (IPSS) and Sexual Health Inventory for Men (SHIM) scores were collected before FLA and at 1, 3 and 12 months.  Primary end-point was no cancer on 3-month biopsy of ablation zone; secondary end-points were safety, 12-month biopsy, and urinary/sexual function.  Among 27 men, median age was 62 and mean PSA was 4.4 ng/ml.  Biopsy Gleason was 6 in 23 (85 %) and Gleason 7 in 4 (15 %); 7 (26 %) had low-volume Gleason 6 outside the intended ablation zone(s).  At 3 months, 26 (96 %) had no evidence of cancer on MRI-guided biopsy of the ablation zone.  No significant IPSS changes were observed (all p > 0.05); SHIM was lower at 1 month (p = 0.03), marginally lower at 3 months (p = 0.05), and without significant difference at 12 months (p = 0.38).  At 12-month biopsy, 10 (37 %) had cancer identified, 3 (11 %) within the ablation zone(s) and 8 (30 %) outside the ablation zone(s) (1 had cancer within and outside the ablation zone).  The authors concluded that for select men with localized PCa and visible MR lesions, FLA has an acceptable morbidity profile and is associated with encouraging short-term oncologic outcomes.  They stated that significantly longer follow-up is mandatory to fully evaluate this novel treatment.

Mathew and Oto (2017) noted that with the advent of focal therapy as a recognized treatment option for men with PCa, there are a host of emerging interventions that take advantage of MRI for image guidance.  Focal therapy affords a middle-ground option for patients with low- to intermediate-grade PCa by providing a means of keeping their cancer at bay while avoiding the negative consequences of radical therapies.  However, the practice of focal treatment is far from straight-forward, with some believing focal treatment errs on the side of over-treatment among patients with low-grade cancer; others worry it is under-treatment in potentially significant multi-focal disease.  The authors concluded that further research is needed, both relating to focal therapy in general and to the utility of each MRI-guided focal treatment discussed.

Ouzzane and colleagues (2017) stated that focal therapy may offer a promising therapeutic option in the field of low-to-intermediate risk localized PCa.  The aim of this concept is to combine minimal morbidity with cancer control as well as maintain the possibility of re-treatment.  Recent advances in MRI and targeted biopsy has improved the diagnostic pathway of PCa and increased the interest in focal therapy.  However, before implementation of focal therapy in routine clinical practice, several challenges still needed to be overcome including patient selection, treatment planning, post-therapy monitoring and definition of oncologic outcome surrogates.

Tay and associates (2017a) stated that prostate focal therapy offers men the opportunity to achieve oncological control while preserving sexual and urinary function.  The prerequisites for successful focal therapy are to accurately identify, localize and completely ablate the clinically significant cancer(s) within the prostate.  These investigators evaluated the evidence for current and upcoming technologies that could shape the future of PCa focal therapy in the next 5 years.  They summarized current literature on advances in patient selection using imaging, biopsy and biomarkers, ablation techniques and adjuvant treatments for focal therapy.  A literature search of major databases was performed using the search terms “focal therapy”, “focal ablation”, “partial ablation”, “targeted ablation”, “image guided therapy” and “prostate cancer”.  Advanced radiological tools such as multi-parametric MRI (mpMRI), multi-parametric ultrasound (mpUS), prostate-specific-membrane-antigen positron emission tomography (PSMA-PET) represent a revolution in the ability to understand cancer function and biology.  The authors concluded that advances in ablative technologies now provide a menu of modalities that can be rationalized based on lesion location, size and perhaps in the near future, pre-determined resistance to therapy; however, these need to be carefully studied to establish their safety and effectiveness parameters; adjuvant strategies to enhance focal ablation are under development.

In summary, there is currently insufficient evidence to support the use of focal laser ablation for the treatment of prostate cancer.  The oncologic efficacy of MRI-guided FLA is currently being evaluated in ongoing phase II clinical trials (Wenger et al, 2014).

van Luijtelaar and colleagues (2019) examined the role of FLA as clinical treatment of PCa using the Delphi consensus method.  A panel of international experts in the field of FT in PCa conducted a collaborative consensus project using the Delphi method.  Experts were invited to online questionnaires focusing on patient selection and treatment of PCa with FLA during 4 subsequent rounds.  After each round, outcomes were displayed, and questionnaires were modified based on the comments provided by panelists.  Results were finalized and discussed during face-to-face meetings.  A total of 37 experts agreed to participate, and consensus was achieved on 39/43 topics.  Clinically significant PCa (csPCa) was defined as any volume Grade Group 2 [Gleason score (GS) 3+4].  Focal therapy was specified as treatment of all csPCa and could be considered primary treatment as an alternative to radical treatment in carefully selected patients.  In patients with intermediate-risk PCa (GS 3+4) as well as patients with MRI-visible and biopsy-confirmed local recurrence, FLA is optimal for targeted ablation of a specific MRI-visible focus.  However, FLA should not be applied to candidates for active surveillance and close follow-up is needed.  Suitability for FLA is based on tumor volume, location to vital structures, GS, MRI-visibility, and biopsy confirmation.  The authors concluded that FLA is a promising technique for treatment of clinically localized PCa and should ideally be performed within approved clinical trials.  So far, only few studies have reported on FLA and further validation with longer follow-up is needed before widespread clinical implementation is justified.

Magnetic Resonance Imaging-Guided Transurethral Ultrasound Ablation

Ghai and associates (2015) reported the 6-month follow-up oncologic and functional data of the initial phase 1 clinical trial of patients treated with focal trans-rectal MRI-guided focused ultrasound. A total of 4 patients with a PSA level of 10 ng/ml or less, tumor classification cT2a or less, and a Gleason score of 6 (3 + 3) were prospectively enrolled in the study and underwent multi-parametric MRI and trans-rectal ultrasound (US)-guided prostate systematic biopsy.  Under MRI guidance and real-time monitoring with MR thermography, focused high-frequency US energy was delivered to ablate the target tissue.  The incidence and severity of treatment-related adverse events were recorded along with responses to serial QOL questionnaires for 6 months after treatment.  Oncologic outcomes were evaluated with multi-parametric MRI and repeat trans-rectal US (TRUS)-guided biopsy 6 months after treatment.  Four patients with a total of 6 target lesions were treated and had complications graded Clavien-Dindo I or less; QOL parameters were similar between baseline and 6-months.  All 4 patients had normal MRI findings in the treated regions (100 %), biopsy showed that 3 patients (75 %) were clear of disease in the treated regions, representing complete ablation of 5 target lesions (83 %).  All patients had at least 1 Gleason 6-positive core outside of the treated zone.  The authors concluded that MRI-guided focused US is a feasible method of non-invasively ablating low-risk PCa with low morbidity.  They stated that further investigation and follow-up are needed in a larger patient series with appropriate statistical analysis of oncologic and functional outcome measures.

In a prospective, single-arm, phase I clinical trial, Chin and colleagues (2016) determined the clinical safety and feasibility of magnetic resonance imaging-guided transurethral ultrasound ablation (MRI-TULSA) for whole-gland prostate ablation in a primary treatment setting of localized PCa. A total of 30 patients (median age of 69 years; interquartile range [IQR]: 67 to 71 years) with biopsy-proven low-risk (80 %) and intermediate-risk (20 %) PCa were treated and followed for 12 months.  Magnetic resonance imaging-TULSA treatment was delivered with the therapeutic intent of conservative whole-gland ablation including 3-mm safety margins and 10 % residual viable prostate expected around the capsule.  Primary end-points were safety (adverse events) and feasibility (technical accuracy and precision of conformal thermal ablation).  Exploratory outcomes included QOL, PSA, and biopsy at 12 months.  Median treatment time was 36 minutes (IQR: 26 to 44) and prostate volume was 44 ml (IQR: 38 to 48).  Spatial control of thermal ablation was ±1.3 mm on MRI thermometry.  Common Terminology Criteria for Adverse Events included hematuria (43 % grade [G] 1; 6.7 % G2), urinary tract infections (33 % G2), acute urinary retention (10 % G1; 17 % G2), and epididymitis (3.3 % G3).  There were no rectal injuries.  Median pre-treatment IPSS 8 (IQR: 5 to 13) returned to 6 (IQR: 4 to 10) at 3 months (mean change: -2; 95 % confidence interval [CI]: -4 to 1).  Median pre-treatment IIEF 13 (IQR: 6 to28) recovered to 13 (IQR: 5 to 25) at 12 months (mean change: -1; 95 % CI: -5 to 3).  Median PSA decreased 87 % at 1 month and was stable at 0.8 ng/ml (IQR: 0.6 to 1.1) to 12 months.  Positive biopsies showed 61 % reduction in total cancer length, clinically significant disease in 9 of 29 patients (31 %; 95 % CI: 15 to 51), and any disease in 16 of 29 patients (55 %; 95 % CI: 36 to 74).  The authors concluded that MRI-TULSA was feasible, safe, and technically precise for whole-gland prostate ablation in patients with localized PCa.  They stated that these findings from a phase I study are sufficiently compelling to study MRI-TULSA further in a larger prospective trial with reduced safety margins.

In a pilot study, Ramsay and colleagues (2017) evaluated MRI-TULSA as a treatment for MRI-defined focal PCa using subsequent prostatectomy and histology as the reference standard.  A total of 5 men completed this study, which was approved by the institutional review board.  Prior to radical prostatectomy focal tumors identified by MRI were treated by coagulating targeted subtotal 3-D volumes of prostate tissue using MRI-TULSA.  Treatment was performed with a 3 Tesla clinical MRI unit combined with modified clinical planning software for high intensity focused ultrasound therapy.  After prostatectomy, whole mount histological sections parallel to the MRI treatment planes were used to compare MRI measurements with thermal damage at the cellular level and, thus, evaluating treatment and target accuracy; 3-D target volumes of 4 to 20 cc and with radii up to 35 mm from the urethra were treated successfully.  Mean ± SD temperature control accuracy at the target boundary was -1.6 ± 4.8 C and the mean spatial targeting accuracy achieved was -1.5 ± 2.8 mm.  Mean treatment accuracy with respect to histology was -0.4 ± 1.7 mm with all index tumors falling inside the histological outer limit of thermal injury.  The authors concluded that MRI-TULSA was capable of generating thermal coagulation and tumor destruction in targeted 3-D angular sectors out to the prostate capsule for prostate glands up to 70 cc in volume; US parameters needed to achieve ablation at the prostate capsule were determined, providing a foundation for future studies.

Tay and associates (2017b) reported the safety profile and 2-year functional outcomes of in-bore magnetic resonance (MR)-guided focused ultrasound on single cancer foci in men with PCa.  Ethics approval was obtained from the centralized institutional review board for this prospective single-arm study, and patients provided informed consent.  Patients with untreated low-volume low-grade PCa (clinical stage T2a or lower; Gleason score, 3+3; index tumor less than or equal to 10 mm3) underwent MR-guided focused ultrasound between July 2011 and February 2013.  All patients underwent robotic trans-perineal mapping biopsy and multi-parametric MR imaging.  Only those with a maximum of 2 lesions smaller than 10 mm at mapping biopsy were included.  Target areas were sonicated with real-time MR thermometry monitoring, excluding critical areas from the beam path.  Serum PSA and Expanded Prostate Index Composite (EPIC) scores were obtained at baseline and at 1, 3, 6, 12, 18, and 24 months and were plotted to observe their trend.  Mean EPIC sub-domain score changes at each serial time-point were compared with the baseline score by using paired t-tests (level of significance, p < 0.007).  Repeat trans-perineal biopsy was performed at 6 and 24 months.  A total of 14 men (mean age of 62.8 years; median PSA level, 8.3 ng/ml) underwent treatment, with 12 men completing 2-year follow-up.  A median reduction of PSA level by 2.9 ng/ml was observed at 6 months; 7 men had Clavien-Dindo grade 1 to 2 complications.  There was a slight insignificant deterioration of EPIC urinary symptom score (mean increase of 7.8 points compared with baseline, p = 0.012) noted at 1 month, but it returned to baseline by 3 months.  There was a trend to deterioration in sexual function score (mean decrease, 4.4 points; p = 0.04 [non-significant]) that normalized at 3 months.  There was no significant change in EPIC sub-domain scores from baseline over the 24 months.  At 6-month template biopsy, 1 man had cancer with a Gleason score greater than 6; at 24 months, 3 men had cancer with a Gleason score greater than 6.  The authors concluded that MR-guided focused ultrasound was technically feasible for focal prostate ablation and appeared to have a favorable early safety and functional profile.  Moreover, they stated that further clinical trials are needed to establish oncologic efficacy.

In a prospective, phase-I clinical trial, Ghai and co-workers (2018) evaluated the feasibility and safety of focal therapy for low-intermediate risk PCa with magnetic resonance-guided high frequency focused ultrasound (MRgFUS).  This trial enrolled 8 patients with PSA less than or equal to 10 ng/ml, less than or equal to cT2a and Gleason score less than or equal to 7 (4 + 3) disease following informed consent.  Under MRI guidance, focused high frequency (HF) US energy was delivered to ablate the target tissue.  Treatment-related adverse events (AEs) were recorded.  Oncologic outcomes were evaluated with multi-parametric MRI, PSA and TRUS biopsy at 6 months following treatment.  A total of 10 target lesions [6 Gleason 6 lesions, 2 Gleason 7 (3 + 4) and 2 Gleason 7 (4 + 3)] were treated in 8 men (prostate volume range of 25 to 50 cc; mean MRI time, 248 mins per patient; mean sonication duration, 65 mins).  Mean target volume was 2.7 cc and mean post-treatment non-perfused volume was 4.3 cc; QOL parameters were similar between baseline and 6 months in 6/8 patients.  All treated regions were negative on MRI; 4/8 patients and 6/10 target lesions (60 %) were clear of disease on biopsy; 1 patient with 2-mm Gleason 8 disease in 1 of 5 cores from treatment site (4 + 3 disease at baseline) subsequently underwent prostatectomy with negative surgical margins; 3 patients with low volume (5 to 15 %) Gleason 6 residual disease were offered active surveillance.  Mean PSA decreased from 5.06 at baseline to 3.4 ng/ml at 6 months.  The authors concluded that MRgFUS is a feasible and safe method of non-invasively ablating low-intermediate risk PCa with acceptable short-term oncologic outcomes.

Linares-Espinos and colleagues (2018) reviewed the oncological and functional outcomes of new and established primary focal treatments (FT) for localized PCa.  These investigators performed a systematic search of published studies on FT for localized PCa using electronic databases (Medline and Embase).  These studies included reports on hemi-ablation, focal ablation and target-ablation.  They excluded salvage focal therapy studies and limited the search to those with a minimum of 12 months of follow-up.  These researchers selected 20 studies with a total of 2,523 patients who were treated in the primary setting.  The energy sources used were cryotherapy (n = 8 studies), HIFU (n = 9), irreversible electroporation (n = 1), PDT (n = 1) and FLA (n = 1), with 65 % hemi-ablation, 25 % focal ablation and 10 % target-ablation.  The median follow-ups ranged from 6 to 44.4 months.  Mean age was 60.4-70 years and mean OSA was 4.4 to less than 10 ng/dL; 26 to 100 % had a Gleason Score of 6, and 0 to 65 % had a Gleason Score of 7.  Patient selection was carried out by TRUS biopsy in 9 studies, while trans-perineal template mapping biopsy and mpMRI were employed in 6 and 13 studies, respectively.  The overall post-treatment positive biopsy rate was 1.2 to 51 % with 1.6 to 32 % patients having a residual disease in the treated area.  The post-treatment continence rates were 90 to 100 %, and the rates of erectile dysfunction ranged from 0 to 53.2 %.  The authors concluded that reliable evidence for the partial-gland treatment of PCa is increasing, and encouraging mid-term oncologic outcomes with the preservation of sexual and urinary functions have been reported.  They stated that accurate patient selection at the outset of treatment and careful follow-up appeared to be key attributes to achieve excellent functional results and encouraging oncological outcomes.

Ashrafi and co-workers (2018) presented a perspective on the current status and future directions of focal therapy for PCa.  Focal therapy for localized PCa is a rapidly evolving field.  Various recent concepts -- the index lesion driving prognosis, the enhanced detection of clinically significant PCa using multi-parametric MRI and targeted biopsy, improved risk-stratification using novel blood/tissue biomarkers, the recognition that reducing radical treatment-related morbidity (along with reducing pathologic progression) is a clinically meaningful end-point -- have all led to a growing interest in focal therapy.  Novel focal therapy modalities are being investigated, mostly in phase-I and phase-II clinical trials.  Recently, level I prospective randomized data comparing partial gland ablation with standard-of-care treatment became available from 1 study.  Recent developments in imaging, including 7-T MRI, functional imaging, radiomics and contrast-enhanced US showed early promise.  The authors concluded that PCa focal therapy has evolved considerably in the recent few years.  Overall, these novel focal therapy treatments demonstrated safety and feasibility, low treatment-related toxicity and acceptable short-term and in some cases medium-term oncologic outcomes.  As imaging techniques evolve, patient selection, detection of clinically significant PCa and non-invasive assessment of therapeutic efficacy will be further optimized.  The aspirational goal of achieving oncologic control while reducing radical treatment-related morbidity will drive further innovation in the field.

Hatiboglu and colleagues (2020) examined the effect of intensified treatment parameters on safety, functional outcomes, and PSA after MR-Guided TULSA of prostatic tissue.  Baseline and 6-month follow-up data were collected for a single-center cohort of the multi-center Phase-I (n = 14/30 at 3 sites) and Pivotal (n = 15/115 at 13 sites) trials of TULSA in men with localized PCa.  The Pivotal trial used intensified treatment parameters (increased temperature and spatial extent of ablation coverage).  The reporting site recruited the most patients to both trials, minimizing the influence of physician experience on this comparison of AEs, urinary symptoms, continence, and erectile function between subgroups of both studies.  For Phase-I and TACT patients, median age was 71.0 and 67.0 years, prostate volume 41.0 and 44.5 ml, and PSA 6.7 and 6.7 ng/ml, respectively.  All 14 Phase-I patients had low-risk PCa, whereas 7 of 15 TACT patients had intermediate-risk disease.  Baseline IIEF, IPSS, QOL, and pad use were similar between groups.  Pad use at 1 month and QOL at 3 months favored Phase-I patients.  At 6 months, there were no significant differences in functional outcomes or AEs.  The authors concluded that TULSA demonstrated acceptable clinical safety in Phase-I trial.  Intensified treatment parameters in the TACT Pivotal trial increased ablation coverage from 90 to 98 % of the prostate without affecting 6-month AEs or functional outcomes.  These researchers stated that long-term follow-up and 12-month biopsies are needed to evaluate oncological safety.

Busch (2022) noted that PCa continues to have a negative impact on the duration and QOL for men and their families.  MRI is transforming the pathway of PCa detection, diagnosis, staging, and surveillance, backed by multiple Level 1 studies and robust reporting standards.  This evolving paradigm of MRI-directed care is now being expanded to include in-bore MRI-guided prostate tissue ablation techniques, which reduce the burden of genitourinary complications associated with standard-of-care (SOC) treatments, without sacrificing cancer control.  The workflow for MRI-guided transurethral US ablation relies on intra-procedural MRI guidance for treatment planning, automated and physician-monitored treatment delivery, and post-treatment assessment at both immediate and long-term time-points.  The author stated that their early experience has identified several procedural refinements; and aligns with early evidence from prospective clinical studies using transurethral US ablation for treatment of patients with either primary or recurrent disease.  The author concluded that their promising early experience with MRI-guided transurethral US ablation in treating primary or recurrent cancer and BPH with a range of customized ablation plans aligns with the growing body of evidence suggesting that MRI-guided ablation techniques deliver improved functional preservation over conventional treatments, without compromising cancer control.

Irreversible Electroporation Therapy

Scheltema and associates (2017) evaluated the feasibility, safety, early QOL and oncological outcomes of salvage focal irreversible electroporation (IRE) for radio-recurrent PCa.  Patients with localized, radio-recurrent PCa without evidence of metastatic or nodal disease were offered focal IRE according to the consensus guidelines.  Patients with a minimum follow-up of 6 months were eligible for analysis; AEs were monitored using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 4.0). Patient-reported QOL data were collected at baseline, 6 weeks, 3, 6 and 12 months using the EPIC, the AUA symptom score and the 12-item short-from health survey (SF-12) physical and mental component summary questionnaires.  Oncological control was evaluated according to serial PSA, 6-month mpMRI and 12-month prostate biopsy.  Wilcoxon's signed rank test was used to assess QOL differences over time in paired continuous variables.  A total of 18 patients were included in the analysis.  The median follow-up was 21 months.  No high-grade AEs (Common Terminology Criteria for Adverse Events (CTCAE) of greater than 2) or recto-urethral fistulae occurred.  No statistically significant declines were observed in QOL outcomes (n = 11) on the EPIC bowel domain (p = 0.29); AUA symptom score (p = 0.77), or the SF-12 physical (p = 0.17) or SF-12 mental component summary (p = 0.77) questionnaires.  At 6 months, patients who had undergone salvage therapy experienced a decline in EPIC sexual domain score (median of 38 to 24; p = 0.028) and urinary domain (median of 96 to 92; p = 0.074).  Pad-free continence and erections sufficient for intercourse were preserved in 8/11 patients and 2/6 patients at 6 months, respectively.  The mpMRI was clear in 11/13 patients, with 2 single out-field lesions (true-positive and false-positive, respectively).  The median (IQR) nadir PSA was 0.39 (0.04 to 0.43) μg/L; 3 and 4 patients experienced biochemical failure using the Phoenix and Stuttgart definitions of biochemical failure, respectively; 8 of 10 of the patients were clear of any PCa on follow-up biopsy, whereas 2 patients had significant PCa on follow-up biopsy (International Society of Urological Pathology [ISUP] grade 5).  The authors concluded that the short-term safety, QOL and oncological control data showed that focal IRE is a feasible salvage option for localized radio-recurrent PCa.  Moreover, they stated that a prospective, multi-center study (FIRE trial) has been initiated that will provide further insight into the ability of focal IRE to obtain oncological control of radio-recurrent PCa with acceptable patient morbidity.

van den Bos and co-workers (2018) examined the safety, QOL and short-term oncological outcomes of primary focal IRE for the treatment of localized PCa, and identified potential risk factors for oncological failure.  Patients who met the consensus guidelines on patient criteria and selection methods for primary focal therapy were eligible for analysis.  Focal IRE was performed for organ-confined clinically significant PCa, defined as high-volume disease with Gleason sum score 6 (ISUP grade 1) or any Gleason sum score of 7 (ISUP grades 2 to 3).  Oncological, AE and QOL outcome data, with a minimum of 6 months' follow-up, were analyzed.  Patient characteristics and peri-operative treatment variables were compared between patients with and without oncological failure on follow-up biopsy.  Wilcoxon's signed rank test, Wilcoxon's rank sum test and the Chi-squared test were used to assess statistically significant differences in paired continuous, unpaired continuous and categorical variables respectively.  A total of 63 patients met all eligibility criteria and were included in the final analysis.  No high-grade AEs occurred; QOL questionnaire analysis demonstrated no significant change from baseline in physical (p = 0.81), mental (p = 0.48), bowel (p = 0.25) or urinary QOL domains (p = 0.41 and p = 0.25), but there was a mild decrease in the sexual QOL domain (median score 66 at baseline versus 54 at 6 months; p < 0.001).  Compared with baseline, a decline of 70 % in PSA level (1.8 ng/ml, IQR 0.96 to 4.8 ng/ml) was seen at 6 to 12 months.  A narrow safety margin (p = 0.047) and system errors (p = 0.010) were identified as potential early risk factors for in-field oncological failure.  In-field and whole-gland oncological control on follow-up biopsies was 84 % (38/45 patients) and 76 % (34/45 patients); this increased to 97 % (38/39 patients) and 87 % (34/39 patients) when patients treated with a narrow safety margin and system errors were excluded.  The authors concluded that these data supported the safety and feasibility of focal IRE as a primary treatment for localized PCa with effective short-term oncological control in carefully selected men. 

Dong and colleagues (2018) stated that IRE, as a non-thermal therapy of PCa, has been used in clinic for several years.  The mechanism of IRE ablation is thermal-independent; thus, the main structures (e.g., rectum, urethra, and neurovascular bundle) in prostate are spared during the treatment, which leads to the retention of prostate function.  However, various clinical trials have shown that muscle contractions occur during this therapy, which warrants deep muscle anesthesia.  Use of HF bipolar pulses has been proposed to reduce muscle contractions during treatment, which has already triggered a multitude of studies at the cellular and animal scale. In this study, these investigators examined the safety and efficacy of HF bipolar pulses in human PCa ablation.  There were 40 men with PCa aged between 51 and 85 years involved in this study.  All patients received 250 HF bipolar pulse bursts with the repeat frequency of 1-Hz.  Each burst comprised 20 individual pulses of 5 microseconds, so 1 burst total energized time was 100 microseconds.  The number of the electrodes ranged 2 to 6, depending on tumor size.  A small amount of muscle relaxant was still needed, so there were no visible muscle contractions during the pulse delivery process.  Four weeks after treatment, it was found that the ablation margins were distinct in MRI scans, and the prostate capsule and urethra were retained; 8 patients underwent radical prostatectomy for pathological analysis after treatment, and the results of hematoxylin and eosin staining revealed that the urethra and major vasculature in prostate have been preserved.  By overlaying the electric field contour on the ablation zone, the electric field lethality threshold was determined to be 522 ± 74 V/cm.  The authors concluded that this study was the first to validate the feasibility of tumor ablation by HF bipolar pulses and provided valuable experience of IRE in clinical applications.

Scheltema and co-workers (2018) examined the effect of robot-assisted radical prostatectomy (RARP) versus focal IRE on patient-reported QOL and early oncological control using propensity-scored matching.  Patients with T1c-cT2b significant PCa (high-volume ISUP 1 or any 2/3) who received uni-focal IRE were pair-matched to patients who received nerve-sparing RARP.  Patient-reported outcomes were prospectively assessed using the EPIC, AUA symptom score and SF-12 physical and mental components.  Oncological failure was defined as biochemical recurrence (RARP) or positive follow-up biopsies (IRE).  Generalized mixed-effect models were used to compare IRE and RARP.  A total of 50 IRE patients were matched to 50 RARP patients by propensity score; IRE was significantly superior to RARP in preserving pad-free continence (UC) and erections sufficient for intercourse (ESI).  The absolute differences were 44, 21, 13, 14 % for UC and 32, 46, 27, 22 % for ESI at 1.5, 3, 6, and 12 months, respectively.  The EPIC summary scores showed no statistically significant differences.  Urinary symptoms were reduced for IRE and RARP patients at 12 months, although IRE patient initially had more complaints; IRE patients experienced more early oncological failure than RARP patients.  The authors concluded that these data demonstrated the superior preservation of UC and ESI with IRE compared to RARP up to 12 months after treatment.  Moreover, they stated that long-term oncological data are needed to provide ultimate proof for or against focal therapy.

Werntz and Eggener (2018) discussed novel focal therapy therapeutic options for PCa.  With the widespread adoption of mpMRI-guided biopsies for PCa, use of image-guided treatment of prostate cancer has increased.  Focal therapies leading to partial gland ablation such as partial prostatectomy, focal laser ablation, IRE, vascular targeted PDT, and focal radiofrequency ablation have emerged and begun to be properly evaluated.  This review covered published phase-I and phase-II clinical trials of each treatment and discussed potential limitations of each modality.  The authors concluded that focal therapy of PCa is being actively investigated.  On the basis of limited published data, the treatments appeared to be well-tolerated and have an acceptable side effect profile.  Importantly, short-term oncologic control has been mixed and there are no long-term outcomes.  The acquisition of more data is essential to evaluate these novel technology platforms.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Prostate cancer” (Version 4.2018) does not mention irreversible electroporation as a therapeutic option.

Guenther and colleagues (2019) reported the retrospective assessment of 471 IRE treatments in 429 patients of all grades and stages of PCa with 6-year maximum follow-up time.  The patient cohort consisted of low (n = 25), intermediate (n = 88) and high-risk PCa (n = 312).  All had multi-parametric MRI, and 199 men had additional 3D-mapping biopsy for diagnostic work-up prior to IRE.  Patients were treated either focally (n = 123), sub-whole-gland (n = 154), whole-gland (n = 134) or for recurrent disease (n = 63) after previous radical prostatectomy, radiation therapy, etc.  Adverse effects were mild (19.7 %), moderate (3.7 %) and severe (1.4 %), never life-threatening.  Urinary continence was preserved in all cases; IRE-induced erectile dysfunction (ED) persisted in 3 % of the evaluated cases 12 months post-treatment.  Mean transient IIEF-5-Score reduction was 33 % within 12-month post-IRE follow-up and 15 % after 12 months.  Recurrences within the follow-up period occurred in 10 % of the treated men, 23 in or adjacent to the treatment field and 18 outside the treatment field (residuals).  Including residuals for worst case analysis, Kaplan Maier estimation on recurrence rate at 5 years resulted in 5.6 % (95 % CI: 1.8 to 16.93) for Gleason 6, 14.6 % (95 % CI: 8.8 to 23.7) for Gleason 7 and 39.5 % (95 % CI: 23.5 to 61.4) for Gleason 8-10.  The authors concluded that the findings of this study indicated comparable efficacy of IRE to standard radical prostatectomy in terms of 5-year recurrence rates and better preservation of urogenital function, proving the safety and suitability of IRE for PCa treatment.  The data also showed that IRE, besides focal therapy of early PCa, could also be used for whole-gland ablations, in patients with recurrent PCa, and as a problem-solver for local tumor control in T4-cancers not amenable to surgery and radiation therapy anymore.  Moreover, these researchers stated that before IRE has the potential to become a new standard of care for the treatment of PCa, these findings need to be confirmed by more systematic studies.  A more stringent evaluation is of course needed, of which the multi-center registry (NCT02255890) is a first step, as well as optimization and standardization of diagnostic work-up, patient selection, the technical procedure of IRE and follow-up regime.

The authors stated that this study had 2 main drawbacks.  First, being retrospective, the significance of these data was limited to heterogeneity, incompleteness and inconsistencies.  One of the main concerns was that more patients with recurrences would be lost to follow-up than patients without, presumably because they were disappointed with IRE and turned towards radical prostatectomy (RPE) or radiation therapy.  This might bias the data towards lower recurrence rates.  The opposite would also be conceivable: Patients without signs of a recurrence might avoid follow-up because of inconvenience and cost.  To test both hypothesis, these investigators generated Kaplan-Meier-curves only including patients who fulfilled the follow-up requirements (MRI + PSA) for longer than 1 year and in whom the last complete follow-up was not older than 1 year.  The curve suggested that within the CIs there was no significant difference in the mean “slope”, hence the drop-out-rates appeared to be evenly distributed between patients with and without recurrences.  Second, follow-up MRI and PSA scores had a median time till last follow-up data-point of 12 months, with accessible follow-up data of less than 1 year in approximately 50 % of all patients.  Fortunately, this fact did not result in a mean bias in the presented Kaplan-Meier-curves, as the drop-out group due to follow-up appeared randomly distributed.  However, with PCa being a slowly growing cancer, follow-up periods need to be extended to obtain a clearer understanding of oncological and functional outcomes.

Vascular Targeted Photodynamic Therapy

Azzouzi and colleagues (2015) evaluated the 6-month effects of the recommended drug and light dosage in focal vascular-targeted photodynamic therapy (VTP) using TOOKAD Soluble in patients with localized PCa (LPCa).  These investigators performed a pooled analysis of 117 men with LPCa, PSA less than 10 ng/ml, and Gleason score less than or equal to 7 (3 + 4), from 3 studies who received a 10-min intravenous infusion of a single dose of 4 mg/kg TOOKAD Soluble, activated by a 753-nm light at 200 J/cm delivered in the prostate by trans-perineal fibers under TRUS guidance.  Primary end-point was 6-month negative biopsies in the treated lobe(s); PSA was measured at month 1, 3, and 6; MRI was performed at day 7, month 3, and 6.; IPSS, IIEF-5 and AEs were reported at day 7, month 1, 3, and 6.  Month 6 negative biopsy rate was 68.4 % in the overall evaluable population (n = 114) and 80.6 % for patients treated by hemi-ablation with light density index (LDI) greater than or equal to 1 (n = 67).  Mean prostate necroses at week-1 were 76.5 % and 86.3 %, respectively.  In both groups, PSA levels at month 6 decreased by 2.0 ng/ml.  Small changes from baseline for IPSS and IIEF-5 indicated a slight improvement in urinary function and a slight deterioration in sexual function.  The authors concluded that focal VTP treatment with TOOKAD Soluble at 4 mg/kg and 200 J/cm resulted in a negative 6-month biopsy rate of 68.4 % for the whole population and 80.6 % for patients treated by hemi-ablation with LDI greater than or equal to 1.  The treatment was well-tolerated; 2 phase-III clinical trials would reach completion in early 2015.

Taneja and associates (2016) noted that VTP with WST11 (TOOKAD Soluble) is a form of tissue ablation that may be used therapeutically for LPCa.  To study dosing parameters and associated treatment effects, these researchers performed a prospective, multi-center, phase I/II clinical trial of WST11 VTP of PCa.  A total of 30 men with unilateral, low volume, Gleason 3 + 3 PCa were enrolled at 5 centers after local institutional review board approval.  Light energy, fiber number and WST11 dose were escalated to identify optimal dosing parameters for VTP hemi-ablation.  Men were treated with PDT and evaluated by post-treatment MRI and biopsy; PSA, light dose index (defined as fiber length/desired treatment volume), toxicity and QOL parameters were recorded.  After dose escalation 21 men received optimized dosing of 4 mg/kg WST11 at 200 J energy.  On post-treatment biopsy residual PCa was found in the treated lobe in 10 men, the untreated lobe in 4 and both lobes in 1.  At a light dose index of 1 or greater with optimal dosing in 15 men 73.3 % had a negative biopsy in the treated lobe; 6 men undergoing retreatment with the optimal dose and a light dose index of 1 or greater had a negative post-treatment biopsy.  Minimal effects were observed on urinary and sexual function, and overall QOL.  The authors concluded that hemi-ablation of the prostate with WST11 VTP was well-tolerated and resulted in a negative biopsy in the treated lobe in the majority of men.  Dosing parameters and the light dose index appeared related to tissue response as determined by MRI and biopsy.  They stated that these parameters may serve as the basis for further prospective studies.

In an open-label, phase III RCT, Azzouzi and colleagues (2017) compared VTP with the standard of care, active surveillance, in men with low-risk PCa.  This RCT was carried out in 47 European university centers and community hospitals.  Men with low-risk, LPCa (Gleason pattern 3) who had received no previous treatment were randomly assigned (1:1) to VTP (4 mg/kg padeliporfin intravenously over 10 mins and optical fibers inserted into the prostate to cover the desired treatment zone and subsequent activation by laser light 753 nm with a fixed power of 150 mW/cm for 22 mins 15 s) or active surveillance.  Randomization was done by a web-based allocation system stratified by center with balanced blocks of 2 or 4 patients.  Best practice for active surveillance at the time of study design was followed (i.e., biopsy at 12-month intervals and PSA measurement and digital rectal examination [DRE] at 3-month intervals).  The co-primary end-points were treatment failure (histological progression of cancer from low to moderate or high risk or death during 24 months' follow-up) and absence of definite cancer (absence of any histology result definitely positive for cancer at month 24).  Analysis was by intention-to-treat.  Treatment was open-label, but investigators assessing primary efficacy outcomes were masked to treatment allocation.  Between March 8, 2011, and April 30, 2013, these researchers randomly assigned 206 patients to VTP and 207 patients to active surveillance.  Median follow-up was 24 months (IQR 24 to 25).  The proportion of participants who had disease progression at month 24 was 58 (28 %) of 206 in the VTP group compared with 120 (58 %) of 207 in the active surveillance group (adjusted hazard ratio [HR] 0.34, 95 % CI: 0.24 to 0.46; p < 0.0001); 101 (49 %) men in the VTP group had a negative prostate biopsy result at 24 months post-treatment compared with 28 (14 %) men in the active surveillance group (adjusted risk ratio [RR] 3.67, 95 % CI: 2.53 to 5.33; p < 0.0001); VTP was well-tolerated.  The most common grade 3 to 4 AEs were prostatitis (3 [2 %] in the VTP group versus 1 [less than1 %] in the active surveillance group), acute urinary retention (3 [2 %] versus 1 [less than 1 %]) and erectile dysfunction (2 [1 %] versus 3 [1 %]).  The most common serious AE in the VTP group was retention of urine (15 patients; severe in 3); this event resolved within 2 months in all patients.  The most common serious AE in the active surveillance group was myocardial infarction (3 patients).  The authors concluded that padeliporfin VTP was a safe, effective treatment for low-risk, LPCa.  They stated that this treatment might allow more men to consider a tissue-preserving approach and defer or avoid radical therapy.

Lebdai and associates (2017) evaluated the mid-term oncologic outcomes of VTP with padeliporfin for low risk PCa treatment.  Patients were followed every 6 months.  All patients underwent prostate biopsies 6 months after treatment or when there was biological or clinical progression.  The primary end-point was progression-free survival (PFS).  Secondary end-points were absent clinically significant cancer in the treated lobes, radical therapy and the PSA rate.  Variables were compared with the Chi-square, Mann-Whitney or Wilcoxon test; PFS was reported with Kaplan-Meier curves.  A total of 82 men were treated with VTP; median follow-up was 68 months (range of 6 to 89).  Median PFS was 86 months (95 % CI: 82 to 90).  Median PSA decreased significantly by 41 % 6 months after treatment and it remained stable during follow-up (p < 0.001).  A total of 115 lobes were treated and absent clinically significant cancer was achieved in 94 (82 %).  Of the 82 patients 20 (24 %) underwent radical therapy, including radical prostatectomy in 18 and brachytherapy in 2, at a median of 22 months (range of 6 to 86).  The authors concluded that padeliporfin VTP for low risk PCa achieved an 82 % rate of absent clinically significant cancer in treated lobes and 76 % of patients avoided radical therapy at a median follow-up of 68 months.  Moreover, they stated that longer follow-up is needed to determine long-term outcomes.  The drawbacks of this study included a single-arm design, small population size (n = 82) and mid-term follow-up (68 months).

In a phase-II clinical trial, Noweski and co-workers (2019) evaluated the medium-term tumor control in patients with LPCa treated with VTP therapy with TOOKAD Soluble WST11 and assessed the medium-term tolerability of the treatment.  A total of 68 patients were treated with VTP under optimal treatment conditions (WST11 at 4 mg/kg, light energy at 200 J/cm, and a light density index greater than or equal to 1) and had been included in a 3.5-year follow-up.  Post-interventional visits were scheduled every 6 months and conducted as per local standard practice in each study center.  Cancer-free status was assessed by means of PSA kinetics, mpMRI and/or prostate biopsies.  At the end of the 3.5-year follow-up, overall successful focal ablation was achieved for 51 patients (75 %).  Cancer was identified in the untreated lobe in 17 patients (25 %).  In total, 34 patients (50 %) were cancer-free in both the prostate lobes.  In case of recurrent/persistent malignancy, the Gleason score remained consistent or changed at the maximum by 1 point (upgrading by 1 Gleason point to 3+4 for 8 patients and 4+3 for 2 patients).  There were 64 related AEs: 48 % were Clavien grade I, 47 % were grade II, and 5 % were grade III.  There were no Clavien grade IV and V AEs.  The authors concluded that VTP was a safe and efficient treatment and represented an alternative option for localized low-risk PCa management over the medium term.  The main drawbacks of this study included small sample size (n = 68) and heterogeneity in the follow-up for some centers.

Gill and associates (2018) noted that the prospective PCM301 trial randomized 413 men with low risk PCa to partial gland ablation with VTP in 207 and active surveillance in 206; 2-year outcomes were reported previously.  These investigators reported 4-year rates of intervention with radical therapy and further evaluated efficacy with biopsy results.  Prostate biopsies were mandated at 12 and 24 months.  Thereafter, patients were monitored for radical therapy with periodic biopsies performed according to the standard of care at each institution.  Ablation efficacy was assessed by biopsy results overall and in field in the treated lobe or the lobe with index cancer.  Conversion to radical therapy was less likely in the ablation cohort than in the surveillance cohort, including 7 % versus 32 % at 2 years, 15 % versus 44 % at 3 years and 24 % versus 53 % at 4 years (hazard ratio [HR] 0.31, 95 % CI: 0.21 to 0.46).  Radical therapy triggers were similar in the 2 arms.  Cancer progression rates overall and by grade were significantly lower in the ablation cohort (HR 0.42, 95 % CI: 0.29 to 0.59).  End of study biopsy results were negative throughout the prostate in 50 % of patients after ablation versus 14 % after surveillance (risk difference 36 %, 95 % CI: 28 to 44).  Gleason 7 or higher cancer was less likely for ablation than for surveillance (16 % versus 41 %).  Of the infield biopsies 10 % contained Gleason 7 cancer after ablation versus 34 % after surveillance.  The authors concluded that in this randomized trial of partial ablation of low risk PCa, photodynamic therapy significantly reduced the subsequent finding of higher grade cancer on biopsy.  Consequently fewer cases were converted to radical therapy, a clinically meaningful benefit that lowered treatment related morbidity.

Lodeizen and co-workers (2019) noted that in recent years, focal therapy has emerged as a therapeutic option for a selected group of men with LPCa.  Cryotherapy and HIFU are the most investigated types of focal treatment with other options currently under evaluation.  These investigators presented a comprehensive overview of 6 available focal therapeutic options for PCa with their rationale, delivery mechanism, and outcomes.  The Societe Internationale d’Urologie International Consultation on Urological Diseases (SIU ICUD) chapter on available Energies to Treat Prostate Cancer was used as a guide to describe the different technologies.  For outcomes, a literature search was conducted using PubMed key words including focal therapy, HIFU, cryotherapy, irreversible electroporation, vascular-targeted photodynamic therapy, laser interstitial therapy, radiofrequency ablation, microwave therapy, and their synonyms in MeSH terms.  The authors concluded that focal therapy appeared to have encouraging outcomes on QOL and urinary and erectile function.  For oncological outcomes, it is challenging to fully interpret the outcomes due to heterogeneity in patient selection and short-term follow-up.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Prostate cancer” (Version 4.2018) does not mention vascular targeted PDT as a therapeutic option.

Dual-Fiber Laser Ablation

Wu and colleagues (2018) noted that single-fiber laser treatment of the prostate has been widely accepted in the clinic due to its minimal invasiveness and high controllability.  However, for large tumors, multiple insertions of the laser probe would be needed to achieve full coverage of the tumor, increasing the complexity of the treatment and occasionally resulting in the incomplete killing of tumor cells due to a mismatch between the planned insertion location and the actual probe insertion location.  Treatment with a dual-fiber laser results in greater lesion coverage following a single insertion of the probe, with the lesion coverage being even greater than the sum of the coverage of 2 sequential insertion of a single-fiber laser probe, potentially reducing treatment time and clinical complications.  Both theoretical and experimental analyses have been performed to evaluate the proposed dual-fiber laser treatment.  A finite element model was established to simulate the treatment process.  The simulation results indicated that there is a clear difference between the ablation coverage created using dual-fiber laser ablation and that created using the superposition of sequential single-fiber laser ablation.  Furthermore, the coverage is dependent on the spacing distance between the 2 fibers.  Both ex-vivo and in-vivo canine prostate tissues were treated by dual-fiber laser ablation, with lesions analyzed by MRI, USimaging, and pathology.  The results demonstrated that dual-fiber laser ablation could markedly increase the range of the ablation zone when compared with single-fiber modes.  The authors concluded that the safety and feasibility of dual-fiber laser treatment has been confirmed, and a treatment plan using dual-fiber laser ablation has also been proposed.

Photothermal Ablation With Copper Sulfide Nanoplates

Chen and colleagues (2019) examined new therapies for castration-resistant PCa to improve patients' QOL and extend life.  The synthesis, morphology analysis, phase analysis, spectral analysis, and photothermal conversion test were referenced to the authors’ previous articles.  Then near-infrared light-driven copper sulfide (CuS) nanoplates to inhibit the growth of PCa cells in-vivo and in-vitro was performed.  Transmission electron microscope, mCherry-LC3 syncytial virus labeling, acridine orange staining, and autophagy protein were used to detect the autophagy caused by CuS nanoplates and chloroquine was used to inhibit the process of autophagy.  The CuS nanoplates prepared in this study featured low cytotoxicity, simple preparation, and high photothermal conversion efficiency.  Driven by 980-nm near-infrared light, CuS nanoplates could inhibit the growth of PCa cells in-vivo and in-vitro, while triggering the autophagy and cytoprotection of PCa cells.  The authors concluded that CuS nanoplates are a commendable photothermal therapy agent in castration-resistant PCa.  Autophagy inhibition enhanced the photothermal efficiency of CuS nanoplates, which indicated favorable application prospects in the treatment of advanced PCa.

Water Vapor Thermotherapy

Mollengarden and colleagues (2019) noted that convective radiofrequency (RF) water vapor thermotherapy with the Rezum system is a relatively new treatment for benign prostatic hyperplasia (BPH).  In a retrospective review (n = 129), these investigators presented findings from a single surgeon in an office setting.  The authors concluded that Rezum RF water vapor thermotherapy offered a minimally invasive option for BPH management with moderate improvement in symptoms and flow rate.  The results appeared to be independent of prostate size or presence of a median lobe, and have now been replicated in a single office setting.  However, there is a lack of evidence regarding the use of water vapor thermotherapy for the treatment of prostate cancer.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Prostate cancer” (Version 1.2020) does not mention water vapor thermotherapy as a therapeutic option.

Focal Thermo-Ablative Therapy for the Treatment of Oligometastatic Prostate Cancer

Giraud and colleagues (2021) noted that in-field PCa oligo-recurrence after pelvic radiotherapy (RT) is a challenging situation for which metastasis-directed treatments (MDTs)may be beneficial; however, options for focal therapies are scarce.  In a retrospective study, these researchers examined data for patients with 3 or less in-field oligo-recurrent nodal, bone and/or locally recurrent (prostate, seminal vesicles, or prostatic bed) PCa lesions following RT, identified with molecular imaging (PET and/or MRI) and treated by focal ablative therapy (cryotherapy or radiofrequency) at the authors’ institution between 2012 and 2020.  Chosen endpoints were the post-procedure PSA response (partially defined as a greater than 50 % reduction, complete as a PSA of less than 0.05 ng/ml), PFS defined as either a biochemical relapse (defined as a rise of greater than 25% of the Nadir and above 2 ng/ml), radiological relapse (on any imaging technique), decision of treatment modification (hormonotherapy initiation or line change) or death, and tolerance.  A total of 43 patients were included.  Diagnostic imaging was mostly 18F-choline PET/CT (75.0 %), PSMA PET/CT (9.1 %) or a combination of pelvic MRI, CT, and 99 mTc-bone scintigraphy (11.4 %).  PSA response was observed in 41.9 % patients (partial in 30.3 %, complete in 11.6 %).  In the hormone-sensitive exclusive focal ablation group (n = 31), partial and complete PSA responses were 32.3 % and 12.9 %, respectively.  Early local control (absence of visible residual active target) on the post-procedure imaging was achieved with 87.5 % success.  After a median follow-up of 30 months (IQR: 13.3 to 56.8), the median PFS was 9 months (95 % CI: 6 to 17), and 17 months (95 % CI: 11 to NA) for PSA responders.  Complications occurred in 11.4 % patients, with only 1 grade-IIIb Dindo-Clavien event (ureteral stenosis requiring endoscopic urethrotomy).  The authors concluded that in PCa patients showing in-field oligo-recurrence after pelvic radiotherapy, focal ablative treatment was a feasible option, possibly delaying a systemic treatment initiation or modification.  Moreover, these researchers stated that given the risk of morbidity and need of technical experience, these procedures should be discussed on a case-by-case basis in a multi-disciplinary setting and preferably performed in expert centers.

The authors stated that this study had several drawbacks mostly due to its retrospective nature and the limited size of the cohort (n = 43) emanating from a single center and containing heterogeneous patients in terms of initial tumor characteristics, natural history, and previous treatments.  In the final analysis, only ADT-free hormone-sensitive patients were described, as concomitant systemic treatment would have affected the outcomes.  Due to the extended period of study, there was also a discrepancy regarding imaging modalities, notably with the recent advent of choline and PSMA tracers, which could have impacted the therapeutic strategy.  These investigators noted that patient selection was crucial to select which patients could benefit the most from these aggressive strategies; ongoing trials should provide an answer whether focal therapy is beneficial when treating in-field oligo-recurrent patients and eventually translates to time-spared, or time-wasted.

Stereotactic Ablative Radiotherapy (Stereotactic Body Radiotherapy) for the Treatment of Oligometastatic Prostate Cancer

In a retrospective, cohort study, Ong and associates (2019) reported the outcomes of stereotactic ablative body radiotherapy (SABR) in men with oligometastatic prostate cancer (OMPC) diagnosed on PSMA-positron emission tomography/computed tomography (PET/CT), based on a single-institution experience and the published literature.  This trial included the first 20 consecutive men with OMPC, treated with SABR in a single institution, who had biochemical recurrence after previous curative treatment (surgery/radiotherapy), had no evidence of local recurrence, were not on palliative androgen deprivation therapy (ADT), and had PSMA-PET/CT-confirmed oligometastatic disease (less than or equal to 3 lesions).  These men were treated with SABR at a dose of 30 Gy in 3 fractions for bone metastases, and 35 to 40 Gy in 5 fractions for nodal metastases.  The outcomes of interest included PSA response; local PFS (LPFS); distant PFS (DPFS); and ADT-free survival (ADTFS).  They carried out a literature review to identify published studies reporting on outcomes of PSMA-PET/CT-guided SABR.  A total of 12 men (60 %) had a decline in PSA post-SABR; 1 man had local progression 9.6 months post-SABR, with 12-month LPFS of 93 %; 10 men had distant progression outside of their SABR treatment field, confirmed on PSMA-PET/CT, with 12-month DPFS of 62 %, of whom 4 were treated with palliative ADT, 2 received prostate bed radiotherapy for prostate bed progression (confirmed on MRI), and 4 received a further course of SABR (of whom 1 had further progression and was treated with palliative ADT).  At last follow-up, 6 men (1 with local progression and 5 with distant progression) had received palliative ADT.  The 12-month ADTFS was 70 %.  Men with longer intervals between local curative treatment and SABR had better DPFS (p = 0.03) and ADTFS (p = 0.005).  Four additional studies reporting on PSMA-PET/CT-guided SABR for OMPC were identified and included in the review, giving a total of 346 patients.  PSA decline was reported in 60 % to 70 % of men post-SABR.  The 2-year LPFS, DPFS and ADTFS rates were 76 % to 100 %, 27 % to 52 %, and 58 % to 62 %, respectively.  The authors concluded that the use of PSMA-PET/CT has allowed the better selection of men with OMPC.  It is also important to take into account the underlying natural history of PCa in each individual patient to select those who would benefit the most from metastatic-directed treatment.  Nonetheless, such an approach remains investigational at this stage, and eligible men should be encouraged to enroll in clinical trials.

Kalinauskaite et al (2020) stated that ADT remains the standard therapy for patients with OMPC; and PSMA-PET/CT-based stereotactic body radiotherapy (SBRT; sometimes known as SABR) is emerging as an alternative option to postpone starting ADT and its associated side effects including the development of drug resistance.  In a retrospective study, these researchers determined PFS and treatment failure free-survival (TFFS) following PSMA-PET/CT-based SBRT in OMPC patients.  The safety and efficacy of single-fraction radiosurgery (SFRS) and ADT delay were examined.  Patients with less than or equal to 5 metastases from OMPC, with/without ADT treated with PSMA-PET/CT-based SBRT were retrospectively analyzed; PFS and TFFS were primary endpoints.  Secondary endpoints were local control (LC), OS and ADTFS.  A total of 50 patients with a total of 75 metastases detected by PSMA-PET/CT were analyzed.  At the time of SBRT, 70 % of patients were castration-sensitive.  Overall, 80 % of metastases were treated with SFRS (median dose of 20 Gy, range of 16 to 25).  After median follow-up of 34 months (range of 5 to 70) median PFS and TFFS were 12 months (range of 2 to 63) and 14 months (range of 2 to 70), respectively.  A total of 32 (64 %) patients had repeat oligometastatic disease; 24 (48 %) patients with progression underwent a 2nd course of SBRT.  Two-year LC after SFRS was 96 %; grade-1 and grade-2 toxicities occurred in 3 (6 %) and 1 (2 %) patients, respectively.  ADTFS and OS rates at 2-years were 60.5 % and 100 %, respectively.  In multi-variate analysis, TFFS significantly improved in patients with time to 1st metastasis (TTM) greater than 36 months (p = 0.01) and PSA before SBRT of less than or equal to 1 ng/ml (p = 0.03).  The authors concluded that the findings of this study suggested that PSMA-PET/CT-based SFRS might be considered a valid therapeutic option for OMPC patients, including cases with repeat oligometastatic disease.  This way, the onset or escalation of palliative ADT and its potential side effects could be deferred/avoided.  Metastases treated with SFRS reached excellent LC rates with minimal toxicity.  Low PSA levels and longer TTM predicts elongated TFFS.  Moreover, these researchers stated that randomized studies are needed to validate these findings.

The authors stated that the retrospective study design, relatively small sample size (n = 50) including heterogeneous patients, inherent patient selection bias and lack of control group were the main drawbacks of this trial.  In addition, the comparison between SFRS and fractionated SBRT group needs to be interpreted with caution due to limited number of metastases treated with fractionated SBRT.  The majority of patients had a high risk PCa, so conclusions for patients with low and medium risk of PCa should be drawn carefully.

Connor and associates (2020) noted that MDT in the form of SABR, or in combination with surgical metastasectomy, may have a role in cancer control and disease progression.  These researchers carried out a systematic review of MDT (surgery or SABR) for oligometastatic (up to 10 metastases, recurrent or de-novo) hormone-sensitive PCa in addition to or following primary prostate gland treatment.  Medline, Embase, Cochrane Review database, and clinical trial databases were systematically searched for clinical trials reporting safety and oncological outcomes.  The risk of bias was evaluated with the Cochrane 2.0 or ROBINS-I tool.  A total of 1,025 articles identified; 4 clinical trials met the pre-specified criteria.  These included 2 randomized and 2 non-randomized clinical trials (n = 169).  Baseline PSA level, age, and metastasis ranged from 2.0 to 17.0 ng/ml, 43 to 75 years, and 1 to 7 lesions, respectively.  Nodal, bone, nodal and bone, and visceral metastases were present in 49.7 % (84/169), 33.7 % (57/169), 15.9 % (27/169), and 0.5 % (1/169) of patients, respectively.  Diagnostic conventional imaging was used in 43.7 % (74/169) and PET/CT in 56.2 % (95/169) of patients; SABR and surgical metastasectomy with SABR were used in 78.3 % (94/120) and 21.6 % (26/120) of patients, respectively.  Early PFS ranged from 19 % to 60 %; LC was reported as 93 % to 100 %; grade-II and grade-III SABR toxicities were reported in 8 % (8/100) and 1 % (1/100) of patients, respectively; grade-IIIa and grade-IIIb surgical complications were reported in 7.69 % (2/26) and 0 % (0/26) of patients, respectively.  The authors concluded that MDT is a promising investigational approach in men with hormone-sensitive OMPC; randomized comparative studies are needed to determine its role and optimal timing in oligometastatic recurrence and efficacy in de-novo synchronous disease.

These investigators stated that despite the inclusion of 4 clinical trials, most had small cohorts and lacked comparative primary endpoints preventing a meta-analysis.  Furthermore, there was significant heterogeneity in the dose/fractionation and surgical approaches (i.e., not all men who were enrolled into studies using combined MDT underwent treatment with both modalities), and a lack of standardized definitions of treatment failure.  More importantly, a selection of men with minimal disease burden was entered into studies using ADT-FS as an outcome, producing a potential selection bias.  Two trials (STOMP and ORIOLE) included patients who had treatment for nodal oligo-recurrent disease that was confined to the pelvis only, limiting the generalizability of the overall finding to the distant oligometastatic state.  Finally, MDT in de-novo synchronous disease is experimental and, findings presented were based on a single, non-randomized, pilot study.

Lehrer and colleagues (2021) noted that the oligometastatic paradigm postulates that patients with a limited number of metastases can be treated with ablative local therapy to each site of disease with curative intent; and SABR is a radiation technique that has become widely used in this setting.  However, prospective data are limited and are mainly from single-center studies.  In a systematic review and meta-analysis, these researchers examined the safety and clinical benefit of SABR in oligometastatic cancer.  They carried out a comprehensive search was conducted in PubMed / Medline, Embase, Cochrane Database of Systematic Reviews, and Cumulative Index to Nursing and Allied Health Literature on December 23, 2019, that included prospective clinical trials and review articles that were published within the past 15 years.  Inclusion criteria were single-arm or multi-arm prospective trials including patients with oligometastatic cancer (i.e., less than or equal to 5 sites of extra-cranial disease), and SABR was administered in less than or equal to 8 fractions with greater than or equal to 5 Gy/fraction.  The Population, Intervention, Control, Outcomes and Study Design; Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA); and Meta-analysis of Observational Studies in Epidemiology methods were used to identify eligible studies.  Study eligibility and data extraction were reviewed by 3 authors independently.  Random-effects meta-analyses using the Knapp-Hartung correction, arcsine transformation, and restricted maximum likelihood method were conducted.  Main outcomes and measures were safety (acute and late grade 3 to 5 toxic effects) and clinical benefit (1-year local control, 1-year overall survival [OS], and 1-year PFS).  A total of 21 studies comprising 943 patients and 1,290 oligometastases were included.  Median age was 63.8 years (IQR, 59.6 to 66.1 years) and median follow-up was 16.9 months (IQR, 13.7 to 24.5 months).  The most common primary sites were prostate (22.9 %), colorectal (16.6 %), breast (13.1 %), and lung (12.8 %).  The estimate for acute grade 3 to 5 toxic effect rates under the random-effects models was 1.2 % (95 % CI: 0 % to 3.8 %; I2 = 50 %; 95 % CI: 3 % to 74 %; and τ = 0.20 %; 95 % CI: 0.00 % to 1.43 %), and the estimate for late grade 3 to 5 toxic effects was 1.7 % (95 % CI: 0.2 % to 4.6 %; I2 = 54 %; 95 % CI: 11 % to 76 %; and τ = 0.25 %; 0.01 % to 1.00 %).  The random-effects estimate for 1-year local control was 94.7 % (95 % CI: 88.6 % to 98.6 %; I2 = 90 %; 95 % CI: 86 % to 94 %; and τ = 0.81 %; 95 % CI: 0.36 % to 2.38 %]).  The estimate for 1-year OS was 85.4 % (95 % CI: 77.1 % to 92.0 %; I2 = 82 %; 95 % CI: 71 % to 88 %; and τ = 0.72 %; 95 % CI: 0.30 % to 2.09 %) and 51.4 % (95 % CI: 42.7 % to 60.1 %; I2 = 58 %; 95 % CI: 17 % to 78 %; and τ = 0.20 %; 95 % CI: 0.02 % to 1.21 %) for 1-year PFS.  The authors concluded that SABR appeared to be relatively safe in patients with oligometastatic cancer with clinically acceptable rates of acute and late grade 3 to 5 toxic effects less than 13 % and with clinically acceptable rates of 1-year local control OS, and PFS.  Moreover, these researchers stated that these findings are hypothesis-generating and require validation by ongoing and planned prospective clinical trials.

Rogowski and co-workers (2021) noted that due to improved imaging sensitivity, the term "oligometastatic" PCa is diagnosed more often, leading to an increasing interest in MDT.  There are 2 types of radiation-based MDT used in the treatment of oligometastatic disease: SBRT (also known as SABR), generally used for bone metastases; or SBRT for isolated nodal oligometastases combined with prophylactic elective nodal radiotherapy.  In a systematic review, these researchers examined available evidence, which may shed light on the optimal management of this heterogeneous group of patients.  They carried out a systematic review of the Medline database through PubMed according to PRISMA guidelines.  All relevant studies published up to November 2020 were identified and screened; 56 studies were included.  Besides outcome parameters, different prognostic and predictive factors were evaluated, including site of metastases, time between primary treatment and MDT, use of systemic therapies, hormone sensitivity, as well as pattern of recurrence.  Evidence mainly consisted of retrospective case series and no consistent precise definition of oligometastasis exists; however, most investigators appeared to acknowledge the need to distinguish between patients presenting with what is frequently called "synchronous" versus "metachronous" oligometastatic disease.  Available data on RT as MDT demonstrated high local control rates and a small but relevant proportion of patients without progressive disease after 2 years.  This held true for both hormone-sensitive and castration-resistant PCa.  The use of 68Ga-PSMA PET/CT for staging increased dramatically.  Radiation doses and field sizes varied considerably among the studies.  The authors concluded that to their best knowledge this review on OMPC included the largest number of original articles.  It showed the therapeutic potential and challenges of MDT for OMPC.  Moreover, these researchers stated that prospective studies are under way and will provide further high-level evidence.

These researchers stated that although, the role of ADT in the OMPC patients treated with MDT remains an unsolved issue, it appeared most highly implausible that RT alone will ever be adequate.  While there is evidence from a phase-II clinical trial for a prolonged ADTFS with MDT in OMPC patients, concurrent ADT appeared to improve the effectivity of MDT in some other retrospective series.  Therefore, future studies should be designed to clarify the role of ADT in OMPC, especially in the context of the widespread usage of MDT.  It may be possible that different subgroup of OMPC patients benefit from different therapy approach, which also need to be addressed.  Several prospective studies on MDT in OMPC are ongoing.

In a retrospective, multi-institutional analysis, Ingrosso et al (2021) reported outcomes of SBRT in metastatic castration-resistant prostate cancer (mCRPC) patients with oligo-progression (less than or equal to 5 metastases) during 1st-line treatment with androgen receptor-targeted therapy (ARTT).  This study included mCRPC patients who were treated with SBRT for oligo-progressive lesions during ARTT.  Endpoints were time to next-line systemic treatment (NEST), radiological PFS (r-PFS) and OS.  Toxicity was registered according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0.  Survival analysis was performed using the Kaplan-Meier method, univariate and multivariate analysis (MVA) were carried out.  Data from 34 patients were analyzed.  Median NEST-free survival, r-PFS, and OS were 16.97, 13.47, and 38.3 months, respectively.  At MVA, factors associated with worse NEST-free survival and r-PFS were poly-metastatic burden at diagnosis of metastatic hormone-sensitive disease (HR 3.66, p = 0.009; HR 3.03, p = 0.034), PSA less than or equal to 7 ng/ml at mCRPC diagnosis (HR 0.23, p = 0.017; HR 0.19, p = 0.006) and PSA doubling time (PSADT) of less than or equal to 3 months at mCRPC diagnosis (HR 3.39, p = 0.026; HR 2.79, p = 0.037).  Poly-metastatic state at mHSPC diagnosis was associated with a decreased OS (HR 4.68, p = 0.029).  No patient developed acute or late grade greater than or equal to 2 toxicity.  The authors concluded that these findings suggested that SBRT in oligo-progressive mCPRC was safe, effective and appeared to prolong the efficacy of the ongoing systemic treatment positively affecting disease progression.  Moreover, these researchers stated that prospective trials are needed.

Magnetic Field Induction Ablation

Choi et al (2016) stated that newly designed biocompatible multi-functional magnetic submicron particles (CoFe₂O₄-HPs-FAs) of well-defined sizes (60, 133, 245, and 335 nm) were fabricated for use as a photo-sensitizer (PS) delivery agent for photodynamic therapy (PDT) in cancer cells.  To provide selective targeting of cancer cells and destruction of cancer cell functionality, basic cobalt ferrite (CoFe₂O₄) particles were covalently bonded with a PS, which comprises hematoporphyrin (HP), and folic acid (FA) molecules.  The magnetic properties of the CoFe₂O₄ particles were finely adjusted by controlling the size of the primary CoFe₂O₄ nanograins, and secondary super-structured composite particles were formed by aggregation of the nanograins.  The prepared CoFe₂O₄-HP-FA exhibited high water solubility, good MRI capacity, and biocompatibility without any in-vitro cytotoxicity.  In particular, the CoFe₂O₄-HP-FA exhibited remarkable photodynamic anti-cancer efficiency via induction of apoptotic death in PC-3 PCa cells in a particle size- and concentration-dependent manner.  This size-dependent effect was determined by the specific surface area of the particles because the number of HP molecules increased with decreasing size and increasing surface area.  The authors concluded that these findings indicated that their CoFe₂O₄-HP-FA may be applicable for PDT as a PS delivery material and a therapeutic agent for MRI-based PDT owing to their high saturation value for magnetization and super-para-magnetism.

Warrell et al (2017) noted that a practical means of delivering both therapeutic radiation and hyperthermia to a deep-seated target has been identified in the literature as highly desirable, provided it is capable of generating sufficient temperatures over the defined target volume.  These researchers presented continued development of a dual-modality thermos-brachytherapy (TB) seed, examining its capabilities in delivering prescribed hyperthermia to realistic deep-seated targets.  The TB seed was based on the ubiquitous low dose-rate (LDR) brachytherapy permanent implant.  Heat was generated by incorporating a ferro-magnetic core within the seed and placing the patient in an oscillating external magnetic field, producing eddy currents within the core and hence Joule heating.  A strategically selected Curie temperature resulted in thermal self-regulation.  The magnetic and thermal properties of the TB seed were studied experimentally by means of seed prototypes placed in a tissue-mimicking phantom and heated with an industrial induction heater, as well as computationally in the finite element analysis solver COMSOL Multiphysics.  Patient-specific seed distributions derived from LDR permanent prostate implants previously conducted at their institution were modeled in COMSOL to examine their ability to adequately cover a defined target volume and to overcome the loss of heat due to blood perfusion within tissue.  The calculated temperature distributions were analyzed by generating temperature-volume histograms, which were used to quantify coverage and temperature homogeneity for varied blood perfusion rates, seed Curie temperatures, and thermal power production rates.  Use of additional hyperthermia-only (HT-only) seeds in unused spots within the implantation needles was examined, as was an increase in these seeds' core size to increase their power.  The impact of the inter-seed attenuation and scatter (ISA) effect on radiation dose distributions of this seed was also quantified by Monte Carlo studies in the software package Monte Carlo N-Particle Version 5.  Increasing the power production of the seeds, as well as increasing their Curie point, would increase the maximum blood perfusion rate that a given seed distribution could overcome to obtain an acceptable temperature distribution.  However, this would also increase the maximum temperatures generated at the seed surfaces.  Auxiliary HT-only seeds served to improve the temperature uniformity within the target, as well as decrease the seed power generation requirements.  Both an increase in their core size and an increase in both seed types' Curie temperatures enhanced the resulting temperature coverage.  The inter-seed and scatter effect caused by both the TB and HT-only seeds was found to reduce the dose to 90 % of the target volume (D90) by a factor of 1.10 ± 0.02.  The authors described a systematic approach of combining LDR prostate brachytherapy with hyperthermia; and examined its ability to provide sufficient and uniform temperature distributions in realistic patient-specific implants.  A combination of TB and HT-only seeds may be used to produce a uniform temperature distribution in a defined target.  Various modeled changes to their design, such as optimization of their Curie temperature, improved their ability to overcome the thermal effects of blood perfusion.  The enhanced ISA of the TB and HT-only seeds must be taken into account for dose calculations; but is manageable.

Altanerova et al (2017) stated that magnetic hyperthermia, or the heating of tissues using magnetic materials, is a promising approach for treating cancer.  These investigators found that human mesenchymal stem cells (MSCs) isolated from various tissues and MSCs expressing the yeast cytosine deaminase:uracil phosphoribosyl transferase suicide fusion gene (yCD:UPRT) can be labeled with Venofer, an iron oxide carbohydrate nanoparticle.  Venofer labeling did not affect cell proliferation or the ability to home to tumors.  All Venofer-labeled MSCs released exosomes that contained iron oxide.  In addition, these exosomes were efficiently endocytosed by tumor cells.  Exosomes from Venofer-labeled MSCs expressing the yCD:UPRT gene in the presence of the prodrug 5-fluorocytosine inhibited tumor growth in a dose-dependent fashion.  The treated tumor cells were also effectively ablated following induction of hyperthermia using an external alternating magnetic field.  The authors found that magnetic nanoparticles packaged into MSC exosomes were efficiently endocytosed by tumor cells, facilitating targeted tumor cell ablation via magnetically induced hyperthermia.  These researchers stated that these findings have major implications for developing MSC-based therapies for cancer patients possessing tumors that are difficult to treat.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Prostate cancer” (Version 1.2023) does not mention magnetic field induction ablation as a management / therapeutic option.

Local Therapy/Metastasis-Directed Therapy for the Treatment of Oligo-Metastatic/Oligo-Progressive Prostate Cancer

Deek et al (2021) noted that available therapies for castration-resistant prostate cancer (CRPC) confer minimal survival advantage; therefore, there is interest in metastasis-directed therapy (MDT) for oligo-metastatic or oligo-progressive disease (OPD) to improve outcomes.  In a retrospective, cohort study, these researchers described outcomes of oligo-progressive CRPC treated with SABR.  Patients with oligo-progressive CRPC were retrospectively evaluated, and outcomes following MDT were reported.  Outcomes were additionally compared with oligo-progressive CRPC treated with change in systemic therapy alone.  Outcomes of interest were time to PSA failure, time to next intervention (TTNI), distant metastasis-free survival (DMFS), and OS.  Survival analysis was carried out using the Kaplan-Meier method, and uni-variable analysis and multi-variable analysis (MVA) were performed.  A total of 68 patients were included.  After MDT, median time to PSA recurrence, TTNI, and DMFS were 9.7, 15.6, and 10.8 months, respectively.  A total of 112 lesions were treated, and the cumulative incidences of local failure at 12 and 24 months were 2.1 % and 13.8 %, respectively.  Factors associated with the risk of local recurrence on univariable analysis were age (HR 1.07, p = 0.03) and Gleason grade group (HR 2.20, p = 0.07).  Compared with change in systemic therapy alone (n = 52), MDT (n = 31) was associated with improved median time to PSA failure (9.7 months versus 4.2 months, p = 0.066)), TTNI (14.9 months versus 8.8 months, p = 0.025), and DMFS (12.7 months versus 8.9 months, p = 0.045), and remained associated with improved outcomes on MVA.  The authors concluded that MDT was associated with favorable outcomes and improved cancer control as compared with change in systemic treatment alone.  Moreover, these researchers stated that future prospective trials are needed to confirm these findings.

The authors stated that this trial had several drawbacks.  First, as for any retrospective study, these findings were hypothesis-generating and must be viewed in the context of possible selection biases, such as referring healthier patients or those with fewer lesions for MDT.  Thus, prospective testing is needed before routine clinical use.  Second, the oncologic outcomes in the group with systemic therapy alone appeared to be worse than those documented in the currently available literature.  However, this was likely due to several differences in population including that this study cohort represented more advanced disease given the median of 3 previous systemic agents.  Third, the definition of progression differed between studies, with the authors’ being an increase of 2 ng/ml and 25 % above PSA nadir in comparison with the increase of 5 ng/ml and 50 % above nadir used for many reports in the published literature.

Kim et al (2022) successes of local therapy for oligo-metastatic cancers cannot be extrapolated to OPD because they are distinct clinical entities.  Given the limited prospective data on OPD to-date, summative analyses are urgently needed.  In a systematic review, these investigators examined the value of local therapy for the treatment of OPD.  Inclusion criteria for this PRISMA-guided systematic review were as follows.  First, only prospective data were included.  Second, progression had to have occurred on active/ongoing systemic therapy.  Third, the number of progressing areas of disease had to be explicitly listed and 5 or less in number.  Fourth, all progressing sites had to undergo local therapy (radiation therapy [RT] /surgery/non-radiation ablative procedures).  A total of 8 studies met criteria (totaling 290 patients), the vast majority of which used stereotactic RT as the local modality (most commonly, 19 to 20 Gy in 1 fraction, 27 to 33 Gy in 3 fractions, or 35 to 50 Gy in 5 fractions).  A study on non-small cell lung cancer (NSCLC) demonstrated that stereotactic RT improved PFS and OS compared with historical values with systemic therapy alone.  Two additional studies on epidermal growth factor receptor mutated (EGFRm) NSCLC also showed acceptable PFS with local therapy, especially in patients who oligo-progressed on osimertinib.  The only randomized trial analyzed showed that local therapy improved PFS for NSCLC but not breast cancer.  Two trials in CRPC reported a substantial proportion of patients did not require any changes in hormonal therapy or delayed the TTNI.  A total of 2 trials of renal cell carcinoma (RCC) showed high (90 % to 100 %) local control and median PFS of 9 months, and potentially a prolonged TTNI.  Finally, from all patients in all trials, local therapy was well-tolerated, with only 7 instances of grade 3+ toxicities.  The authors concluded that based on the limited data, local therapy for oligo-progression was safe and provided encouraging short-term preliminary outcomes; however, studies with larger sample sizes and longer follow-up are needed for more robust conclusions.

Chin and Lynn (2022) stated that cryotherapy is one of the recognized ablative modalities for both primary and salvage therapy for PCa.  It presents an alternative, less invasive treatment for an organ-confined disease, improved preservation of surrounding tissue and a more suitable option for patients who are unfit for radical prostatectomy.  Nevertheless, the currently available literature is relatively too scarce to provide definite conclusions regarding the treatment outcomes in cryotherapy.  These investigators examined the available oncological and survival outcomes in cryotherapy for primary and recurrent PCa.  In addition, this study aimed to establish the complications and functional outcomes of cryotherapy for PCa.  They carried out a literature search on the PubMed, Cochrane, and Google Scholar databases.  Current guidelines and recommendations from the European Association of Urology were also reviewed.  The search keywords used included “Cryotherapy, Prostate Cancer”, “Cryoablation, Prostate Cancer” and “Cryosurgery, Focal Prostate Cancer”.  Truncations and Boolean operators were used with the keywords.  All relevant studies from after 2015, including abstracts and non-English research assessing oncological and functional outcomes and complications, were included.  A total of 26 studies consisting of 11,228 patients were reviewed; 15 studies examined the outcomes of primary cryotherapy, whereas 11 studies reported the outcomes in salvage therapy.  The patient's age ranged from 55 to 85 years, and the pre-procedural PSA ranged from 0.01 to 49.33 ng/ml.  A total of 2,031 patients were classified to be at low-risk, 2,995 were at moderate-risk, and 253 were at high-risk on the D'Amico PCa risk classification system.  Follow-ups ranged from 9.0 to 297.6 months.  The disease-specific survival (DSS) rate was 65.5 % to 100.0 %, OS was 61.3 % to 99.1 %, the PSA nadir was 0.01 to 2.63 ng/ml, and the overall biochemical recurrence (BCR) rate was 15.4 % to 62.0 %.  The complications included ED (3.7 % to 88.0 %), urinary retention (2.13 % to 25.30 %) and bladder neck stricture/stenosis (3.0 % to 16.7 %).  The functional assessment showed a mixture of improved, unchanged, or worsened post-procedural outcomes in primary therapy.  The authors concluded that this systematic review did not find significant differences in the cancer-specific, overall, and biochemical-free survival rate between the primary and salvage cryotherapy cohorts.  The most common complications encountered in both cohorts were ED, UI, lower urinary tract/bladder neck stricture and infection.  These researchers stated that more prospective and double-arm studies are needed to provide guidance on the careful selection of patient cohorts for cryotherapy, whether for curative or salvage intent.

Khan et al (2023) noted that whole gland treatment of the prostate has known effectiveness in treating many grades of PCa; however, it is often associated with increased morbidity, including ED and urinary incontinence (UI).  Focal ablative therapies, including focal cryoablation (FC), are employed to minimize the risk of tumor progression and preserve erectile and urinary function.  There is little to no consensus on whether intermediate- or high-risk PCa should be treated with focal therapy.  However, there is a growing body of literature on the effectiveness of FC as an effective means of PCa control.  These researchers described their experience with 163 patients who underwent FC with a median follow-up of 39 months (IQR: 24 to 60).  A 163-patient retrospective cohort underwent FC of the prostate at a single clinic by a physician from November 2008 to December 2020.  Each of these T1c patients in this single-tail study was monitored for BCR and oncologic outcomes.  American Society for Radiation Oncology (ASTRO) definition of BCR is 3 consecutive PSA increases of more than 0.5 ng/ml or, along with the use of the Phoenix definition, a PSA greater than nadir by 2 ng/ml was used to define BCR.  This study's primary endpoint included BCR or biochemical disease-free survival (DFS) rates.  Secondary endpoints included patient side effects, such as measuring for UI and outcomes of salvage treatments.  Cox proportional hazard analyses defined univariate HRs and 95 % CIs for pre-operative PSA (POPSA), Decipher, and Gleason Grade Groups (GGGs) to determine the prognostic impact of pathologic factors.  Statistical analysis and BCR timeline analysis also included logistic regression and the Kaplan-Meier method, with significance considered at p < 0.05.  Select focal cryotherapy patients were monitored using genomic sequencing tests.  This cohort included 27 patients (16.5 %) with D'Amico low-risk, 115 patients (70.5 %) with intermediate-risk, and 23 patients (14.1 %) with high-risk PCa.  One month after FC, a 73 % reduction in PSA resulted in a median post-operative PSA of 1.39 ng/ml (IQR: 0.46 to 2.80 ng/ml).  At 5 years, this cohort yielded biochemical disease-free recurrence rates of 78 %, 74 %, and 55 % for low-, intermediate-, and high-grade cancers, respectively.  Genetic risk stratification results showed very similar BCR rates to patients whose tissues did not undergo genomic testing, at 27 %, 26 %, and 46 % for low-, intermediate-, and high-grade cancers, respectively.  Log-rank tests to map for BCR and HRs for pathologic factors did not yield any statistically significant predictive results.  UI and ED were reported in 1.8 % and 3.1 % of patients, respectively in the focal cohort.  The authors concluded that these findings added to the expanding body of literature around the effectiveness of focal ablative therapies in contrast to whole gland treatment.  Moreover, these investigators stated that the definitive extent of FC's effectiveness remains to be examined; however, their findings showed favorable PSA kinetics at 5-year follow-up.

Yoshida et al (2023) stated that the significance of MDT for oligo-metastatic PCa has been widely discussed, and targeted therapy for progressive sites is a feasible option as a multi-disciplinary treatment for CRPC.  When oligo-metastatic CRPC with only bone metastases progresses after targeted therapy, it tends to progress as multiple bone metastases.  The progression of oligo-metastatic CRPC after targeted therapy may be due in part to the presence of micro-metastatic lesions that, although undetected on imaging, were present before targeted therapy.  Therefore, the systemic treatment of micro-metastases in combination with targeted therapy for progressive sites is expected to enhance the therapeutic effect.  Radium-223 dichloride (radium-223) is a radiopharmaceutical that selectively binds to sites of increased bone turnover and inhibits the growth of adjacent tumor cells by emitting alpha rays.  Thus, for oligo-metastatic CRPC with only bone metastases, radium-223 may enhance the therapeutic effect of radiotherapy for active metastases.  In a randomized, phase-II clinical trial (the MEDAL Trial), these researchers will examine the use of radium-223 in combination with MDT in patients with oligo-metastatic CRPC confined to bone.  In this trial, patients with oligo-metastatic CRPC with 3 or fewer bone metastases on whole-body MRI with diffusion-weighted MRI (WB-DWI) will be randomized in a 1:1 ratio to receive radiotherapy for active metastases plus radium-223 or radiotherapy for active metastases alone.  The prior use of androgen receptor axis-targeted therapy and PSA doubling time will be used as allocation factors.  The primary endpoint will be radiological PFS against progression of bone metastases on WB-DWI.  The authors concluded that this will be the 1st randomized trial to examine the effect of radium-223 in combination with MDT in oligo-metastatic CRPC patients.  The combination of MDT for macroscopic metastases with radiopharmaceuticals targeting micro-metastasis is expected to be a promising new therapeutic strategy for patients with oligo-metastatic CRPC confined to bone.  Moreover, these investigators stated that it is hoped that the findings of this phase-II clinical trial will provide a sound basis for a prospective, randomized phase-III clinical trial.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Prostate Cancer” (Version 2.2023) states that “At this time, the panel recommends only cryosurgery and high-intensity focused ultrasound (HIFU; category 2B) as local therapy options for RT recurrence in the absence of metastatic disease”.


The above policy is based on the following references:

Magnetic Resonance Imaging-Guided Focal Laser Ablation

  1. Bomers JG, Cornel EB, Fütterer JJ, et al. MRI-guided focal laser ablation for prostate cancer followed by radical prostatectomy: Correlation of treatment effects with imaging. World J Urol. 2016;35(5):703-711.
  2. Bozzini G, Colin P, Nevoux P, et al. Focal therapy of prostate cancer: Energies and procedures. Urol Oncol. 2013;31(2):155-167. 
  3. Colin P, Mordon S, Nevoux P, et al. Focal laser ablation of prostate cancer: Definition, needs, and future. Adv Urol. 2012;2012:589160. 
  4. Eggener S, Salomon G, Scardino PT, et al. Focal therapy for prostate cancer: Possibilities and limitations. Eur Urol. 2010;58(1):57-64.
  5. Eggener SE, Yousuf A, Watson S, et al. Phase II evaluation of MRI-guided focal laser ablation of prostate cancer. J Urol. 2016;196(6):1670-1675.
  6. Klein EA. Initial approach to low-risk clinically localized prostate cancer. UpToDate [serial online]. Waltham, MA: UpToDate; reviewed November 2012.
  7. Lee T, Mendhiratta N, Sperling D, Lepor H. Focal laser ablation for localized prostate cancer: Principles, clinical trials, and our initial experience. Rev Urol. 2014;16(2):55-66.
  8. Lepor H, Llukani E, Sperling D, Fütterer JJ. Complications, recovery, and early functional outcomes and oncologic control following in-bore focal laser Ablation of prostate cancer. Eur Urol. 2015;68(6):924-926.
  9. Lindner U, Davidson S, Fleshner N, et al. Initial results of MR guided laser focal therapy for prostate cancer. J Urol. 2013; 189:e227–e8.
  10. Lindner U, Weersink RA, Haider MA, et al. Image guided photothermal focal therapy for localized prostate cancer: Phase I trial. J Urol. 2009;182(4):1371-1377.
  11. Mathew MS, Oto A. MRI-guided focal therapy of prostate cancer. Future Oncol. 2017;13(6):537-549.
  12. Natarajan S, Raman S, Priester AM, et al. Focal laser ablation of prostate cancer: Phase I clinical trial. J Urol. 2016;196(1):68-75.
  13. National Comprehensive Cancer Network (NCCN). Prostate cancer. NCCN Clinical Practice Guidelines in Oncology, Version 1.2013. Fort Washngton, PA: NCCN; 2013.
  14. National Comprehensive Cancer Network (NCCN). Prostate cancer. NCCN Clinical Practice Guidelines in Oncology, Version 4.2019. Fort Washngton, PA: NCCN; 2019.
  15. National Institutes of Health (NIH), National Library of Medicine (NLM). MR image guided therapy in prostate cancer. ClinicalTrials.gov. No. NCT01377753. Bethesda, MD: NIH; last verified: July 28, 2017. 
  16. National Institutes of Health (NIH), National Library of Medicine (NLM). Phase II laser focal therapy of prostate cancer (LITT or FLA). ClinicalTrials.gov. No. NCT02243033. Bethesda, MD: NIH; last verified: September, 2016. 
  17. National Institutes of Health (NIH), National Library of Medicine (NLM). Use of laser interstitial thermal therapy in the focal treatment of localized prostate cancer (LITT). ClinicalTrials.gov. No. NCT02224911. Bethesda, MD: NIH; last verified: September, 2016. 
  18. Nguyen CT, Jones JS. Focal therapy in the management of localized prostate cancer. BJU Int. 2011;107(9):1362-1368.
  19. Nomura T, Mimata H. Focal therapy in the management of prostate cancer: An emerging approach for localized prostate cancer. Adv Urol. 2012;2012:391437.
  20. Oto A, Sethi I, Karczmar G, et al. MR imaging-guided focal laser ablation for prostate cancer: Phase I trial. Radiology. 2013;267(3):932-940.
  21. Ouzzane A, Betrouni N, Valerio M, et al. Focal therapy as primary treatment for localized prostate cancer: Definition, needs and future. Future Oncol. 2017;13(8):727-741.
  22. Pisters LL, Spiess P. Cryotherapy and other ablative techniques for the initial treatment of prostate cancer. UpToDate [serial online]. Waltham, MA: UpToDate; reviewed November 2012. 
  23. Raz O, Haider MA, Davidson SR, et al. Real-time magnetic resonance imaging-guided focal laser therapy in patients with low-risk prostate cancer. Eur Urol. 2010;58(1):173-177.
  24. Sankineni S, Wood BJ, Rais-Bahrami S, et al. Image-guided focal therapy for prostate cancer. Diagn Interv Radiol. 2014;20(6):492-497.
  25. Stafford RJ, Fuentes D, Elliott AA, et al. Laser-induced thermal therapy for tumor ablation. Crit Rev Biomed Eng. 2010;38(1):79-100.
  26. Stafford RJ, Shetty A, Elliott AM, et al. Magnetic resonance guided, focal laser induced interstitial thermal therapy in a canine prostate model. J Urol. 2010;184(4):1514-1520.
  27. Tay KJ, Schulman AA, Sze C, et al. New advances in focal therapy for early stage prostate cancer. Expert Rev Anticancer Ther. 2017a;17(8):737-743. 
  28. Thompson I, Thrasher JB, Aus G, et al; AUA Prostate Cancer Clinical Guideline Update Panel. Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol. 2007;177(6):2106-2131.
  29. van Luijtelaar A, Greenwood BM, Ahmed HU, et al. Focal laser ablation as clinical treatment of prostate cancer: Report from a Delphi consensus project. World J Urol. 2019;37(10):2147-2153.
  30. Wenger H, Yousuf A, Oto A, Eggener S. Laser ablation as focal therapy for prostate cancer. Curr Opin Urol. 2014;24(3):236-240.
  31. Woodrum DA, Gorny KR, Mynderse LA, et al. Feasibility of 3.0T magnetic resonance imaging-guided laser ablation of a cadaveric prostate. Urology. 2010;75(6):1514.e1-e6.

Magnetic Resonance Imaging-Guided Transurethral Ultrasound Ablation

  1. Ashrafi AN, Tafuri A, Cacciamani GE, et al. Focal therapy for prostate cancer: Concepts and future directions. Curr Opin Urol. 2018;28(6):536-543.
  2. Busch JJ, Jr. The role for MRI-guided transurethral ultrasound ablation in the continuum of prostate cancer care. Br J Radiol. 2022;95(1131):20210959.
  3. Chin JL, Billia M, Relle J, et al. Magnetic resonance imaging-guided transurethral ultrasound ablation of prostate tissue in patients with localized prostate cancer: A prospective phase 1 clinical trial. Eur Urol. 2016;70(3):447-455.
  4. Ghai S, Louis AS, Van Vliet M, et al. Real-time MRI-guided focused ultrasound for focal therapy of locally confined low-risk prostate cancer: Feasibility and preliminary outcomes. AJR Am J Roentgenol. 2015;205(2):W177-W184.
  5. Ghai S, Perlis N, Lindner U, et al. Magnetic resonance guided focused high frequency ultrasound ablation for focal therapy in prostate cancer - phase 1 trial. Eur Radiol. 2018;28(10):4281-4287.
  6. Hatiboglu G, Popeneciu V, Bonekamp D, et al. Magnetic resonance imaging-guided transurethral ultrasound ablation of prostate tissue in patients with localized prostate cancer: single-center evaluation of 6-month treatment safety and functional outcomes of intensified treatment parameters. World J Urol. 2020;38(2):343-350.
  7. Linares-Espinos E, Carneiro A, Martínez-Salamanca JI, et al. New technologies and techniques for prostate cancer focal therapy. Minerva Urol Nefrol. 2018;70(3):252-263.
  8. Ramsay E, Mougenot C, Staruch R, et al. Evaluation of focal ablation of magnetic resonance imaging defined prostate cancer using magnetic resonance imaging controlled transurethral ultrasound therapy with prostatectomy as the reference standard. J Urol. 2017;197(1):255-261.
  9. Tay KJ, Cheng CWS, Lau WKO, et al. Focal therapy for prostate cancer with in-bore MR-guided focused ultrasound: Two-year follow-up of a phase I trial-complications and functional outcomes. Radiology. 2017b;285(2):620-628.

Irreversible Electroporation Therapy

  1. Collettini F, Enders J, Stephan C, et al. Image-guided irreversible electroporation of localized prostate cancer: Functional and oncologic outcomes. Radiology. 2019;292(1):250-257.
  2. Dong S, Wang H, Zhao Y, et al. First human trial of high-frequency irreversible electroporation therapy for prostate cancer. Technol Cancer Res Treat. 2018;17:1533033818789692.
  3. Guenther E, Klein N, Zapf S, et al. Prostate cancer treatment with irreversible electroporation (IRE): Safety, efficacy and clinical experience in 471 treatments. PLoS One. 2019;14(4):e0215093. 
  4. Marra G, Shah TT, D'Agate D, et al. The SAFE pilot trial -- SAlvage Focal Irreversible Electroporation -- for recurrent localized prostate cancer: Rationale and study protocol. Front Surg. 2022;9:900528.
  5. National Comprehensive Cancer Network (NCCN). Prostate cancer. NCCN Clinical Practice Guidelines in Oncology, Version 4.2018. Fort Washington, PA: NCCN; 2018.
  6. Scheltema MJ, Chang JI, Böhm M, et al. Pair-matched patient-reported quality of life and early oncological control following focal irreversible electroporation versus robot-assisted radical prostatectomy. World J Urol. 2018;36(9):1383-1389.
  7. Scheltema MJ, van den Bos W, Siriwardana AR, et al. Feasibility and safety of focal irreversible electroporation as salvage treatment for localized radio-recurrent prostate cancer. BJU Int. 2017;120 Suppl 3:51-58.
  8. van den Bos W, Scheltema MJ, Siriwardana AR, et al. Focal irreversible electroporation as primary treatment for localized prostate cancer. BJU Int. 2018;121(5):716-724.
  9. Werntz RP, Eggener SE. Novel focal therapy treatment options for prostate cancer. Curr Opin Urol. 2018;28(2):178-183.

Vascular Targeted Photodynamic Therapy

  1. Azzouzi AR, Barret E, Bennet J, et al. TOOKAD® Soluble focal therapy: Pooled analysis of three phase II studies assessing the minimally invasive ablation of localized prostate cancer. World J Urol. 2015;33(7):945-953.
  2. Azzouzi AR, Vincendeau S, Barret E, et al; PCM301 Study Group. Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk prostate cancer (CLIN1001 PCM301): An open-label, phase 3, randomised controlled trial. Lancet Oncol. 2017;18(2):181-191.
  3. Gill IS, Azzouzi AR, Emberton M, et al. Randomized trial of partial gland ablation with vascular targeted phototherapy versus active surveillance for low risk prostate cancer: Extended followup and analyses of effectiveness. J Urol. 2018;200(4):786-793.
  4. Lebdai S, Bigot P, Leroux PA, et al. Vascular targeted photodynamic therapy with padeliporfin for low risk prostate cancer treatment: Midterm oncologic outcomes. J Urol. 2017;198(2):335-344.
  5. Lodeizen O, de Bruin M, Eggener S, et al. Ablation energies for focal treatment of prostate cancer. World J Urol. 2019;37(3):409-418.
  6. Noweski A, Roosen A, Lebdai S, et al. Medium-term follow-up of vascular-targeted photodynamic therapy of localized prostate cancer using TOOKAD Soluble WST-11 (Phase II Trials). Eur Urol Focus. 2019;5(6):1022-1028.
  7. Taneja SS, Bennett J, Coleman J, et al. Final results of a phase I/II multicenter trial of WST11 vascular targeted photodynamic therapy for hemi-ablation of the prostate in men with unilateral low risk prostate cancer performed in the United States. J Urol. 2016;196(4):1096-1104.

Dual-Fiber Laser Ablation

  1. Wu X, Zhang K, Chen Y, et al. Theoretical and experimental study of dual-fiber laser ablation for prostate cancer. PLoS One. 2018;13(10):e0206065. 

Photothermal Ablation With Copper Sulfide Nanoplates

  1. Chen J, Wang ZJ, Zhang KL, et al. Selective castration-resistant prostate cancer photothermal ablation with copper sulfide nanoplates. Urology. 2019;125:248-255. 

Water Vapor Thermotherapy

  1. Mollengarden D, Goldberg K, Wong D, et al. Convective radiofrequency water vapor thermal therapy for benign prostatic hyperplasia: A single office experience. Prostate Cancer Prostatic Dis. 2018;21(3):379-385.
  2. National Comprehensive Cancer Network (NCCN). Prostate cancer. NCCN Clinical Practice Guidelines in Oncology, Version 1.2020. Fort Washington, PA: NCCN; 2020.

Other Investigational Procedures

  1. Altanerova U, Babincova M, Babinec P, et al. Human mesenchymal stem cell-derived iron oxide exosomes allow targeted ablation of tumor cells via magnetic hyperthermia. Int J Nanomedicine. 2017;12:7923-7936.
  2. Chin YF, Lynn N. Systematic review of focal and salvage cryotherapy for prostate cancer. Cureus. 2022;14(6):e26400.
  3. Choi K-H, Nam KC, Malkinski L, et al. Size-dependent photodynamic anticancer activity of biocompatible multifunctional magnetic submicron particles in prostate cancer cells. Molecules. 2016;21(9):1187.
  4. Connor MJ, Smith A, Miah S, et al. Targeting oligometastasis with stereotactic ablative radiation therapy or surgery in metastatic hormone-sensitive prostate cancer: A systematic review of prospective clinical trials. Eur Urol Oncol. 2020;3(5):582-593.
  5. Deek MP, Taparra K, Phillips R, et al. Metastasis-directed therapy prolongs efficacy of systemic therapy and improves clinical outcomes in oligoprogressive castration-resistant prostate cancer. Eur Urol Oncol. 2021;4(3):447-455.
  6. Giraud N, Buy X, Vuong N-S, et al. Single-center experience of focal thermo-ablative therapy after pelvic radiotherapy for in-field prostate cancer oligo-recurrence. Front Oncol. 2021;11:709779.
  7. Ingrosso G, Detti B, Fodor A, et al. Stereotactic ablative radiotherapy in castration-resistant prostate cancer patients with oligoprogression during androgen receptor-targeted therapy. Clin Transl Oncol. 2021;23(8):1577-1584.
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