Focal therapy of prostate cancer has been proposed as an alternative to whole-gland treatments.
To summarize the evidence regarding sources of energy employed in focal therapy.
Embase and Medline (PubMed) were searched from 1996 to October 31, 2015 following the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Ongoing trials were selected from electronic registries. The stage of assessment of each source of energy was determined using the Idea, Development, Exploration, Assessment, Long-term study recommendations.
Thirty-seven articles reporting on 3230 patients undergoing focal therapy were selected. Thirteen reported on high-intensity focused ultrasound, 11 on cryotherapy, three on photodynamic therapy, four on laser interstitial thermotherapy, two on brachytherapy, three on irreversible electroporation, and one on radiofrequency. High-intensity focused ultrasound, cryotherapy, photodynamic therapy, and brachytherapy have been assessed in up to Stage 2b studies. Laser interstitial thermotherapy and irreversible electroporation have been evaluated in up to Stage 2a studies. Radiofrequency has been evaluated in one Stage 1 study. Median follow-up varied between 4 mo and 61 mo, and the median rate of serious adverse events ranged between 0% and 10.6%. Pad-free leak-free continence and potency were obtained in 83.3–100% and 81.5–100%, respectively. In series with intention to treat, the median rate of significant and insignificant disease at control biopsy varied between 0% and 13.4% and 5.1% and 45.9%, respectively. The main limitations were the length of follow-up, the absence of a comparator arm, and study heterogeneity.
Focal therapy has been evaluated using seven sources of energy in single-arm retrospective and prospective development studies up to Stage 2b. Focal therapy seems to have a minor impact on quality of life and genito-urinary function. Oncological effectiveness is yet to be defined against standard of care.
Seven sources of energy have been employed to selectively ablate discrete areas of prostate cancer. There is high evidence that focal therapy is safe and has low detrimental impact on continence and potency. The oncological outcome has yet to be evaluated against standard of care.
Keywords: Focal therapy, Partial ablation, Prostate cancer.
In the last decade, focal therapy has been evaluated as a novel strategy in selected men harboring localized prostate cancer. The aim of this tissue-preserving strategy is to maintain the oncological benefit of active treatments, while optimizing genito-urinary function. Focal therapy has as its objective the eradication of clinically significant disease, thereby conferring to the individual a transition from a moderate or high-risk status to a lower one. This process aims to preserve as much tissue as is compatible with treating the target volume plus a margin. This approach seeks to protect key structures from injury whose integrity is essential for stable genito-urinary function (neurovascular bundles, urethral sphincter, and bladder neck) . Further, the bladder and the rectum, two structures that can be impaired by radiation therapy, are fully preserved. Although partial surgery and focal ablation in almost all solid cancers are accepted options in eligible patients, the legitimacy of focal therapy in prostate cancer is debated as this malignancy is multifocal in most cases  and .
While comparative effectiveness research against standard of care options is lacking, the rationale supporting this strategy relies on evidence-based elements. Firstly, the natural history of the disease seems to be linked to the index lesion in the majority of men, and secondary low-grade lesions seem to have an indolent behavior in most if not all cases , , and . Secondly, our ability to risk stratify men at a regional level within the prostate has significantly increased. There is growing evidence that the use of multiparametric magnetic resonance imaging (MRI) with targeted and mapping biopsy allows the detection of the index lesion with reliability over 90%, at least in expert centers . Thirdly, these diagnostic tools together are able to rule out clinically significant lesions within discrete areas of the prostate with again accuracy over 90% .
Focal therapy has been delivered employing a number of sources of energy: (1) high-intensity focused ultrasound (HIFU), (2) cryotherapy, (3) photodynamic therapy (PDT), (4) laser interstitial thermotherapy (LITT), (5) brachytherapy, (6) irreversible electroporation (IRE), and (7) radiofrequency ablation (RFA). The aim of this systematic review was to summarize the stage of assessment and the evidence available with respect to each of these sources of energy.
2. Evidence acquisition
2.1. Search strategy and selection criteria
This systematic review was performed in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement . Embase and Medline (through PubMed) were searched systematically using medical subject headings including “(<prostate cancer> OR <prostatic neoplasms>) AND (<focal> OR <subtotal> OR <hemiablation> OR <quadrant>).” The search was limited to studies reporting focal therapy outcomes between 1996 to October 31, 2015. Electronic links to related articles and references of selected articles were hand searched. Additional relevant articles were selected from authors’ bibliographies. In addition, ongoing and recruiting registered trials were retrieved from ClinicalTrial.gov and the International Standard Randomized Controlled Trial Number registry to assess the current status of evaluation of each source of energy.
Eligible articles included meta-analyses, randomized controlled trials (RCTs) or prospective case series including a control group, prospective development studies, and retrospective case series investigating ablative techniques to treat patients with biopsy-proven prostate cancer in a subtotal manner (focal, quadrant, hemi-ablation, dog-leg, etc.) in the primary setting. Case reports were excluded, as well as review articles and congress abstracts. Studies related to whole-gland treatment or performed in a salvage treatment setting were excluded while studies involving focal treatment followed by radical prostatectomy were included. The search was limited to human studies and English language. Eligibility was determined by two separate reporters (MV and YC) using the Covidence software (www.covidence.org). Covidence is a web-based software platform designed to ease and improve systematic reviews by facilitating duplicates exclusion and the independent process performed by the reviewers, from screening to data extraction. It also helps with resolution of discrepancies and agreement by consensus. In case of persistent discrepancies after discussion, the senior author (ME) arbitrated. Besides the source of energy used to ablate, at least one of the following main outcome measures had to be reported: (1) oncological outcomes, (2) morbidity, or (3) functional outcomes. All studies of interest were obtained as full text articles and scrutinized thoroughly. Relevant data were extracted and documented in a data extraction form developed a priori. In cases of potential duplicated datasets, the study was excluded. If overlapping was partial (< 50% sample size) and over a limited period of time, all studies were fully reported, although the risk of duplication was highlighted.
The primary objective of this study was to determine the stage of assessment of sources of energy currently used in focal therapy of the prostate. We employed the recommendation from the Idea, Development, Exploration, Assessment, Long-term study statement which defines the stage of assessment according to the design, the sample size, the outcome, and the outcome measures used to evaluate a novel surgical procedure . Briefly: (1) Stage 1 (Innovation) refers to the first description of a procedure, (2) Stage 2a (Development) refers to the development phase in which the procedure is carried out by early adopters in well selected patients, but the intervention needs to be refined, (3) Stage 2b (Exploration) refers to the exploration of indications, quality control measures, and reproducibility in larger groups of patients, (4) Stage 3 (Assessment) refers to comparative effectiveness research of the novel procedure against standard of care, (5) Stage 4 (Long-term) refers to the implementation and monitoring of established procedures. Secondary objectives included the definition of the target population, the type of focal therapy delivered, and the assessment of oncological, toxicity, and functional outcome.
2.3. Data extraction form
The following data were extracted from each study: (1) source of energy, (2) study design, (3) stage of assessment, (4) type of ablation, (5) patients’ characteristics (age, sample size, preoperative biopsy, preoperative imaging, spatial location of the tumor, prostate specific antigen [PSA], Gleason score, and risk stratification), (6) length of follow-up, percentage of patients lost to follow-up, length of hospital stay, disease control outcomes (reason and type of postfocal sampling, presence of residual significant and insignificant disease in the treated and untreated area, probability of transition to secondary and radical treatment, transition to metastatic disease, overall survival, and disease-specific survival), (7) morbidity (serious adverse events, stricture rate, urinary retention rate, urinary infection rate, and recto-urethral fistula rate), and (8) functional outcome (leak-free and pad-free continence, potency preservation, and new use of phosphodiesterase type-5 inhibitors). When available, the patient-reported outcomes measures (PROMs) used were recorded; their variation between beginning and last follow-up was also indicated for completeness (deterioration, stability, or improvement).
As we could not retrieve raw data, we accepted the definitions used by single studies to risk stratify the population (such as the threshold for clinically significant disease and risk stratification). When not available, we considered the presence of secondary pattern ≥4 in control biopsy as clinically significant disease.
2.4. Statistical analysis
Continuous variables are given using median, interquartile range (IQR), or overall range according to availability. The mean with standard deviation was used when the former was not available. Categorical variables are given using frequencies and percentages. To calculate oncological and functional outcomes, a decision had to be made with respect to the denominator considered. For determining overall oncological outcomes, only series with intention to treat were considered, although the results of each series were displayed for completeness. Men lost to follow-up were excluded from the denominator of all outcomes. In determining the rate of positive biopsy in studies with mandatory post-treatment biopsy, only those men actually undergoing biopsy were part of the denominator. Clinically significant threshold was accepted from each study; if not available, any Gleason pattern 4 was considered as clinically significant disease. Overall biopsy results considered only series with intention to treat, and excluded Stage I studies. Functional outcomes were determined as relative rates. For instance, to determine potency, only potent patients prior to focal therapy were part of the denominator. To summarize outcomes based on continuous values, we used median and IQR. All analyses were performed using SPSS version 20.0 (IBM Corporation, Armonk, NY, USA).
3. Evidence synthesis
Thirty-seven studies were included in the final analysis (Fig. 1) , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . Overall, 13 studies reported on focal HIFU, 11 on focal cryotherapy, three on focal PDT, four on focal LITT, two on focal brachytherapy, three on focal IRE, and one on focal RFA (Fig. 2). Across all series, 3230 patients were treated using any source of energy delivered in a focal manner.
Preferred Reporting Items for Systematic Review and Meta-analysis flowchart.
Schematic representation of the sources of energy used in actual series: (A) high-intensity focused ultrasound, (B) cryotherapy, (C) photodynamic therapy, (D) laser-induced interstitial thermotherapy, (E) brachytherapy, (F) irreversible electroporation, and (G) radiofrequency ablation.
Data extracted from each record are summarized in Table 1, Table 2, and Table 3 in order of the source of energy considered, and of the year of publication. In Table 1, the design of the study, the eligibility criteria, the ablation strategy, and the study population are displayed. In Table 2, the type and length of follow-up, the ablation and oncological outcomes are displayed. In Table 3, the morbidity, the functional outcomes including outcome measures are displayed. In Table 4, the design of ongoing registered trials investigating focal therapy is displayed.
Design, focal therapy strategy, and study population of the 37 series included
|Ref.||Source of energy||IDEAL stage||Design||Biopsy||Imaging||Location||Type of ablation||No.||Age (yr)||PSA (ng/ml)||Gleason score||Risk stratification|
|Madersbacher 1995||HIFU||1||Prospective development study||NR||NR||Unifocal or organ-confined||Hemi-ablation or focal ablation with no intention to treat||29||64; 7.2 (mean; SD)||24.5; 18.8 (mean; SD)||NR||NR|
|Beerlage 1999||HIFU||1||Retrospective case series||TRUS standard||MRI||NR||Hemi-ablation with no intention to treat||14||62; 55–69 (mean; range)||10.8; 3.5–20 (mean; range)||NR||NR|
|Muto 2008||HIFU||2a||Prospective case series||TRUS extended||MRI||Unilateral||Dog-leg ablation||29||72; 62–80 (median; range)||5.4; 1.8–25.1 (median; range)||6: 55.2% (n = 16); 7: 20.7% (n = 6); 8+: 17.2% (n = 5); unknown: 6.9% (n = 2)||NR|
|Ahmed 2011||HIFU||2a||Prospective development study||Template mapping||MRI||Unilateral||Hemi-ablation||20||60.4; 5.4 (mean; SD)||7.3; 2.8 (mean; SD)||NR||Low: 25% (5/20); intermediate: 75% (15/20)|
|El Fegoun 2011||HIFU||2a||Retrospective case series||NR||NR||Unilateral||Hemi-ablation||12||70; 4.8 (mean; SD)||7.3; 2.6–10 (mean; range)||3+3: 83.3% (n = 10); 3+4: 16.7% (n = 2)||NR|
|Ahmed 2012||HIFU||2b||Prospective development study||Template mapping||MRI||Unifocal or multifocal||Focal ablation||41||63; 58–66 (median; IQR)||6.6; 5.4–7.7 (median; IQR)||3+3: 31.7% (n = 13); 3+4: 58.6% (n = 24); 4+3: 9.8% (n = 4)||Low: 26.8% (n = 11); intermediate: 63.4% (n = 26); high: 9.8% (n = 4)|
|Chopra 2012||HIFU||1||Proof of concept||NR||MRI||NR||Focal ablation with no intention to treat||8||60; 49–70 (mean; range)||6.2; 2.7–13.1 (median; range)||3+3: 25% (n = 2); 3+4: 50% (n = 4); 4+3: 25% (n = 2)||NR|
|Dickinson 2013||HIFU||1||Proof of concept||Template mapping||MRI||Unilateral, unifocal, or multifocal||Index lesion ablation or hemi-ablation||26||61; 40–79 (mean; range)||7.7; 1.5–14.2 (mean; range)||3+3: 34.6% (n = 9); 3+4: 65.4% (n = 17)||Low: 11.5% (n = 3); intermediate: 42.3% (n = 11); high: 46.2% (n = 12)|
|Napoli 2013||MR-HIFU||1||Prospective development study||NR||MRI||Unifocal||Index lesion ablation||5||65.4; 50–75 (median; range)||8.8 (median; IQR and range NR)||3+3: 60% (n = 3); 3+4: 40% (n = 2)||NR|
|Van Velthoven 2013||HIFU||2a||Prospective development study||NR||MRI||Unifocal||Hemi-ablation||31||71; 55–83 (median; range)||5.3; 0.3–11.0 (median; range)||≤6: 61.3% (n = 19); 7: 32.2% (n = 10); ≥8: 6.5% (n = 2)||Low: 54.8% (n = 17); intermediate: 38.7% (n = 12); high: 6.5% (n = 2)|
|Ahmed 2015||HIFU||2b||Prospective development study||TRUS standard and/or template mapping||MRI||Unifocal||Index lesion ablation||56||63.9; 5.8 (mean, SD)||7.4; 5.6–9.5 (median, IQR)||NR||Low: 12.5% (n = 7); intermediate: 83.9% (n = 47); high: 3.6% (n = 2)|
|Feijoo 2015||HIFU||2b||Prospective case series||TRUS extended or template mapping||MRI||Unilateral||Hemi-ablation||71||70.2; 6.8 (mean; SD)||6.1; 1.6–15.5 (median; IQR)||3+3: 86.6% (n = 58); 3+4: 13.4% (n = 9); NR: 4 lost to follow-up||NR|
|Ghai 2015||MR-HIFU||1||Prospective development study||TRUS extended + targeted||MRI||Unifocal or multifocal||Index lesion ablation||4||63; 56–68 (median; range)||4.7; 0.9–6.7 (median, IQR)||3+3 (100%)||Low: 100% (4/4)|
|Total||HIFU or MR-HIFU||1–2b||Proof of concept to prospective development studies||Combination (see above)||MRI||Unilateral, unifocal, or multifocal||Combination (see above)||346||63 (IQR 62–70)||7.3 (IQR 5.8–8.3)||3+3 to ≥8||Low, intermediate or high|
|Bahn 2006||Cryotherapy||2a||Retrospective case series||TRUS standard + targeted||Color-Doppler||Unilateral||Hemi-ablation||31||63; 51–75 (mean; range)||4.9 (mean; IQR NR)||6: 84.3% (n = 23); 7: 25.8% (n = 8)||NR|
|Ellis 2007||Cryotherapy||2a||Retrospective case series||NR||NR||Unilateral||Dog-leg ablation||60||69 ± 7.8 (mean ± SD)||7.2 ± 4.7 (mean ± SD)||Gleason 6: 78.3%; Gleason 7: 20%; Gleason 8–10 1.7%||Low: 66.7%; intermediate: 23.3%; high: 10%|
|Onik 2007||Cryotherapy||2a||Retrospective case series||TRUS standard or template mapping||NR||Unilateral||Focal ablation||55||NR||8.3 (mean; IQR NR)||NR||Low: 47.3% (n = 26); intermediate: 36.4% (n = 20); high: 16.4% (n = 9)|
|Truesdale 2010||Cryotherapy||2b||Retrospective case series||TRUS standard||NR||Unilateral||Hemi-ablation||77||69.5 ± 6.7 (mean ± SD)||6.5 ± 4.9 (mean ± SD)||Gleason 6: 64.9% (n = 50); Gleason 7: 32.5% (n = 25); Gleason 8: 2.6% (n = 2)||Low: 57.1% (n = 44); intermediate: 40.3% (n = 31); high: 2.6% (n = 2)|
|Bahn 2012a||Cryotherapy||2b||Retrospective case series||TRUS standard + targeted||Color-Doppler||Unilateral||Hemi-ablation||73||64; 47–79 (median; range)||5.4; 0.01–20 (median; range)||3+3: 41% (n = 30); 3+4: 34% (n = 25); 4+3: 25% (n = 18)||Low: 33% (n = 24); intermediate: 67% (n = 49)|
|Ward 2012||Cryotherapy||2b||Retrospective case series||NR||NR||Organ-confined||NR||1160||67.8 ± 7.8 (mean ± SD)||NR||Gleason 6: 73.6%; Gleason 7: 20.9%; Gleason ≥8: 5.6%||Low: 46.8%; intermediate: 40.9%; high: 12.4%|
|Hale 2013||Cryotherapy||2a||Retrospective case series||Template mapping||NR||Organ-confined||Hemi-ablation or subtotal||26||65; 55–74 (median; range)||NR||3+3: 96.2% (n = 25); 3+4: 3.8% (n = 1)||Low: 88.5% (n = 23); intermediate: 11.5% (n = 3)|
|Al Barqawi 2014||Cryotherapy||2b||Prospective development study||Template mapping||NR||Organ-confined||Focal ablation||62||60.5 ± 6.8 (mean ± SD)||5.1 ± 2.2 (mean ± SD)||Gleason 3+3 or Gleason 3+4||Low to intermediate risk|
|Durand 2014||Cryotherapy||2b||Prospective case series||TRUS standard||MRI||Unilateral||Hemi-ablation||48||67; 50–77 (median; IQR)||6.1; 3.1–9.7 (mean; range)||Gleason 3+3: 100%||Low: 100%|
|Lian 2015||Cryotherapy||2b||Retrospective case series||NR||NR||Unilateral||Hemi-ablation||41||67; 56–76 (median; IQR)||7.1; 2.6–14.1 (median; range)||3+3: 58.5% (n = 24); 3+4: 24.4% (n = 10); 4+3: 17.1% (n = 7)||Low: 56.1% (n = 23); intermediate: 43.9% (n = 18)|
|Mendez 2015||Cryotherapy||2b||Retrospective case series||NR||NR||NR||NR||317||66.5 ± 6.6 (mean ± SD)||NR||Gleason 3+3: 100%||Low: 100%|
|Total||Cryotherapy||2a–2b||Retrospective case series to prospective development study||Combination (see above)||MRI or color-Doppler||Unilateral or organ-confined||Combination (see above)||1950||66.8 (IQR 63.8–68.1)||6.3 (IQR 5.2–7.2)||3+3 to ≥8||Low, intermediate or high|
|Moore 2006||PDT||1||Prospective development study||TRUS standard||MRI||Unilateral||Focal ablation||6||66; 61–71 (mean; range)||1.9–15 (range)||3+3 (100%)||Low: 50%; intermediate: 50%|
|Azzouzi 2013||PDT||2b||Prospective development study||NR||NR||Organ-confined||Hemi-ablation||68||62.7; 5.5 (mean; SD)b||6.4; 2.3 (mean; SD)b||3+3: 97.1% (n = 66); 3+4: 2.9% (n = 2)||NR|
|Moore 2014||PDT||2b||Prospective development study||TRUS standard or template mapping||MRI||Organ-confined||NR||42||63.9; 5.3 (mean; SD)||NR||3+3: 97.6% (n = 41); 3+4: 2.4% (n = 1)||Low: 100%|
|Total||PDT||1–2b||Prospective development studies||TRUS standard or template mapping||MRI||Unilateral or organ-confined||Focal or hemi-ablation||116||63.9 (IQR NA)||6.4 (IQR NA)||3+3 or 3+4||Low to intermediate risk|
|Lindner 2009||LITT||2a||Prospective development study||TRUS standard||MRI||Unifocal||Focal ablation||12||56.5; 51–52 (median; range)||5.7 ± 1.1 (mean ± SD)||3+3: 100%||Low: 100%|
|Lindner 2010||LITT||1||Proof of concept||TRUS standard||MRI||Unifocal||Focal ablation||4||66; 61–73 (median; range)||4.2; 2.9–14.8 (median; range)||3+3: 50% (n = 2); 4+3: 50% (n = 2)||NR|
|Oto 2013||LITT||2a||Prospective development study||TRUS standard||MRI||Unifocal||Focal ablation||9||61–52–77 (median–range)||5.5 ± 2.6 (mean ± SD)||3+3: 88.9% (n = 8); 3+4: 11.1% (n = 1)||NR|
|Lepor 2015||LITT||2a||Prospective development study||NR||MRI||Unifocal or multifocal||Focal ablation||25||66; 49–84 (median; range)||5.3; 2–9.4 (median; range)||3+3: 44% (n = 11); 3+4: 52% (n = 13); 4+3: 4% (n = 1)||NR|
|Total||LITT||1–2a||Proof of concept to prospective development studies||TRUS standard||MRI||Unifocal or multifocal||Focal ablation with or without intention to treat||50||63.5 (IQR 57.6–66)||5.4 (IQR 4.5–5.7)||3+3 to 4+3||Low|
|Nguyen 2012||Brachytherapy||2b||Retrospective case series||NR||MRI||Organ-confined||Peripheral zone ablation||318||NR||5; 3.8–6.9 (median; IQR)||3+3: 88% (n = 280); 3+4: 12% (n = 38)||Low: 83% (n = 265); intermediate: 17% (n = 53)|
|Cosset 2013||Brachytherapy||2a||Retrospective case series||TRUS extended||MRI||Unilateral||Focal ablation||21||62.3; 56–75 (mean; range)||6.9; 3.6–13.9 (mean; range)||3+3: 9.5% (n = 2); 3+4: 90.5% (n = 19)||NR|
|Total||Brachytherapy||2a–2b||Retrospective case series||TRUS extended||MRI||Unilateral or organ-confined||Focal or peripheral zone ablation||339||62.3 (IQR NA)||6 (IQR NA)||3+3 or 3+4||Low to intermediate risk|
|Valerio 2014||IRE||2a||Retrospective case series||Template mapping and/or targeted||MRI||Organ-confined||Index lesion ablation||34||65 ± 6 (mean ± SD)||6.1; 4.3–7.7 (median; IQR)||3+3: 26% (n = 9); 3+4: 56% (n = 19); 4+3: 15% (n = 5); 4+4: 3% (n = 1)||Low: 26% (n = 9); intermediate: 71% (n = 24); high: 3% (n = 1)|
|Ting 2015c||IRE||2a||Retrospective case series||Template mapping or targeted||MRI||Organ-confined||Index lesion ablation||25||67; 60–71 (median; IQR)||6; 4.3–8.6 (median; IQR)||3+3: 8% (n = 2); 3+4: 60% (n = 15); 4+3: 32% (n = 8)||Low: 8% (n = 2); intermediate: 92% (n = 23)|
|Van den bos 2015||IRE||1||Proof of concept||TRUS standard||NR||Organ-confined||Focal ablation with no intention to treat||16||60; 44–75 (median; range)||9; 3.6–25 (median; range)||3+3: 50% (n = 8); 3+4: 18.8% (n = 3); 4+3: 18.8% (n = 3); 4+4: 12.5% (n = 2)||NR|
|Total||IRE||1–2a||Proof of concept to retrospective case series||Combination (see above)||MRI||Organ-confined||Index lesion or focal ablation with no intention to treat||66||65 (IQR NA)||6.1 (IQR NA)||3+3 to 4+4||Low to intermediate risk|
|Zlotta 1998||RFA||1||Proof of concept||NR||NR||NR||Focal ablation with no intention to treat||15||NR||NR||NR||NR|
|Total||RFA||1||Proof of concept||NR||NR||NR||Focal ablation with no intention to treat||15||NR||NR||NR||NR|
a Partial overlap with Bahn et al., 2006.
b Data referring to the whole population including bilateral ablation.
c Partial overlap with Valerio et al., 2014.
HIFU = high-intensity focused ultrasound; IDEAL = Idea, Development, Exploration, Assessment, Long-term study; IRE = irreversible electroporation; IQR = interquartile range; LITT = laser-induced interstitial thermotherapy; MRI = magnetic resonance imaging; NA = not applicable; NR = not reported; PDT = photodynamic therapy; PSA = prostate-specific antigen; Ref. = Reference; RFA = radiofrequency ablation; SD = standard deviation; TRUS = transrectal ultrasound.
Length of follow-up, ablation, and oncological results of the 37 series included
|Ref.||Length follow-up (d)||Lost to follow-up (%)||Length of hospital stay (d)||Postfocal histology||Type of histology||Overall significant cancer (%)||Overall any cancer (%)||Significant cancer treated area (%)||Any cancer treated area (%)||Significant cancer untreated area (%)||Any cancer untreated area (%)||Any secondary local treatment (%)||Secondary focal ablation (%)||Radical treatment (%)||Hormonal treatment (%)||Metastatic disease (%)||Overall survival (%)||Disease-specific survival (%)|
|Madersbacher 1995||NA||NR||Mandatory||Radical prostatectomy||NR||70a||NR||70a||NR||NR||NA||NA||NA||NA||NA||NR||NR|
|Beerlage 1999||NR||NR||NR||Mandatory||Radical prostatectomy||NR||92.9a||NR||28.6a||NR||92.9a||NA||NA||NA||NA||NA||100a||100a|
|Muto 2008||34; 8–45 (median; range)||NR||1 (median and IQR)||Mandatory||NR||NR||23.5||NR||NR||NR||NR||NR||NR||NR||NR||NR||100||100|
|Ahmed 2011||12 (median and range)||1 (median and IQR)||Mandatory||Targeted||10.5)||10.5||5||5||100||100|
|El Fegoun 2011||127; 90–133 (median; range)||NR||Mandatory||TRUS standard||8.3||NR||NR||NR||NR||8.3||8.3||NR||33.3||NR||83||100|
|Ahmed 2012||12 (median and range)||1; 1–2 (median; IQR)||Mandatory||Targeted||7.7||23||7.7||23||10.3||10.3||100||100|
|Chopra 2012||NA||NR||Mandatory||Radical prostatectomy||75a||100a||NR||NR||NR||NR||NA||NA||NA||NA||NA||100a||100a|
|Dickinson 2013||NA||NR||Mandatory||Template mapping + targeted||NA||NA||NA||NA||NA||NA||NA||NA||NA||NA||NA||NR||NR|
|Napoli 2013||NA||NR||Mandatory||Radical prostatectomy||40||100||40||100||NA||NA||NA||NA||NA||100||100|
|Van Velthoven 2013||38; 12–61 (median; range)||6.5||4; 2–6 (median; range)||For cause||TRUS standard||NR||10.3||NR||NR||10.3||10.3||10.3||6.9||100||100|
|Ahmed 2015||12 (median and range)||1 (median and IQR)||Mandatory||Targeted||19.2||42.3||15.4||34.6||3.8||7.7||7.2||3.6||3.6||100||100|
|Feijoo 2015||12; 6–50 (median; IQR)||6||NR||Mandatory||TRUS standard||NR||25.4||NR||16.4||NR||10.5||NR||NR||NR||NR||NR||NR||NR|
|Ghai 2015||6 (median and range)||NR||Mandatory||TRUS extended + targeted||100||25||100||100||100|
|Total HIFU||12 (IQR 0–28.5)||0 (IQR 0–6)||1 (IQR 1–2.5)||Mandatory or for cause||Combination (see above)||0 (IQR 0–13.5)||23.3 (IQR 10.4–38.1)||0 (IQR 0–11.6)||16.4 (IQR 0–25)||0 (IQR 0–21.9)||10.3 (IQR 0–100)||7.8 (IQR 3.8–10.3)||6.7 (IQR 2.7–10.3)||0 (0–1.8)||0 (IQR 0–13.5)||0 (IQR 0–0)||100 (IQR 100–100)||100 (IQR 100–100)|
|Bahn 2006||70; 2–107 (median; range)||3.2||NR||Mandatory||TRUS standard + targeted||NR||4%||NR||4||3.3||3.3||100||100|
|Ellis 2007||12; 3–36 (median; range)||1.7||NR||For cause||NR||NR||23.7||NR||1.7||NR||22||18.6||18.6||100||100|
|Onik 2007||43.2 (mean; IQR NR)||NR||NR||For cause||TRUS standard||NR||7.3||NR||7.3||7.3||7.3||NR||NR||100||100|
|Truesdale 2010||24; 0–87 (median; range)||NR||1 (median and range)||For cause||TRUS standard||NR||13||NR||3.9||NR||10.4||NR||NR||NR||NR||NR||100||100|
|Bahn 2012||44; 12–102 (median; range)||4.1||1 (median and range)||For cause||TRUS standard + targeted||4.3||17.1||1.4||1.4||2.9||15.7||5.7||2.9||1.4||1.4||100||100|
|Ward 2012||21.1 ± 19.7 (mean ± SD)||NR||NR||For cause||NR||NR||3.7||NR||NR||NR||NR||NR||NR||NR||NR||NR||NR||NR|
|Hale 2013||19.1; 2–52 (mean; range)||NR||1; 1–2 (median; range)||For cause||TRUS standard||7.7||NR||NR||NR||NR||7.7||7.7||100||100|
|Al Barqawi 2014||28; 26–31 (median; IQR)||NR||Mandatory||TRUS standard||NR||19.4||NR||12.9||NR||8.1||11.3||8.1||3.2||NR||100||100|
|Durand 2014||13.2; 7.4–26.5 (median; IQR||3.4; 2–32 (median; range)||Mandatory||TRUS standard||6.5||26.1||6.5||13||2.2||15.2||14.6||6.3||6.3||2.1||100||100|
|Lian 2015||63; 12–92 (median; IQR||2.4||NR||For cause||TRUS standard||7.5||17.5||2.5||5||5||12.5||7.5||5||2.5||5||100||100|
|Mendez 2015||NR||NR||NR||For cause||NR||NR||2.5||NR||NR||NR||NR||NR||NR||NR||NR||NR||NR||NR|
|Total cryotherapy||26 (IQR 17.6–48.8)||2.1 (IQR 0–3.4)||1 (IQR 1–2.8)||Mandatory or for cause||TRUS standard +/– targeted||5.4 (IQR 1.1–7.3)||13 (IQR 4–19.4)||1.4 (0–4.5)||2.8 (IQR 0.4–10.9)||2.9 (IQR NA)||11.5 (IQR 7.5–15.6)||7.6 (IQR 6.1–13.8)||4 (IQR 0–7.7)||3.3 (IQR 1.7–7.1)||0% (IQR 0–2.1)||0% (IQR 0–0)||100 (IQR 100–100)||100 (IQR 100–100)|
|Moore 2006||NR||NR||1–4 (range)||Mandatory||TRUS standard||NR||100||NR||NR||NR||NR||83.3||NR||83.3||100||100|
|Azzouzi 2013||6 (median and range)||1.5||NR||Mandatory||TRUS standard||NR||23.9||NR||NR||NR||NR||NR||NR||NR||NR||NR||100||100|
|Moore 2014||6 (median and range)||11.9||NR||Mandatory||TRUS standard||NR||45.9||NR||NR||NR||NR||NR||NR||NR||NR||NR||100||100|
|Total PDT||6 (IQR 6–6)||6.7 (IQR NA)||NR||Mandatory||TRUS standard||NR||45.9 (IQR NA)||NR||NR||NR||NR||83.3 (IQR NA)||NR||83.3 (IQR NA)||0 (IQR NA)||0 (IQR NA)||100 (IQR 100–100)||100 (IQR 100–100)|
|Lindner 2009||6 (median and range)||0%||1; 1–2 (median; range)||Mandatory||TRUS standard + targeted||16.7||50||16.7||33.3||16.7||8.3||8.3||100||100|
|Lindner 2010||1 wk (median and range)||NR||Mandatory||Radical prostatectomy||NR||NR||NR||NR||NA||NA||NA||NA||NA||100||100|
|Oto 2013||6 (median and range)||NR||Mandatory||Targeted||22.2||22.2||100||100|
|Lepor 2015||3 (median and range)||NR||Mandatory||Targeted||4.8||4.8||4.8||4.8||100||100|
|Total LITT||4.5 (IQR 0.8–6)||0 (IQR 0–0)||1 (IQR NA)||Mandatory||Combination (see above)||4.8 (IQR NA)||22.2 (IQR NA)||2.4 (IQR 0–13.7)||13.5 (IQR 1.2–30.5)||0 (IQR 0–0)||0 (IQR NA)||0 (IQR NA)||0 (IQR 0–0)||0 (IQR NA)||0 (IQR 0–0)||0 (IQR 0–0)||100 (IQR 100–100)||100 (IQR 100–100)|
|Nguyen 2012||61; 33–88 (median; IQR)||NR||NR||For cause||TRUS standard||3.5||5.3||NR||NR||NR||NR||NR||NR||NR||NR||0.3||NR||99.7|
|Cosset 2013||NR||NR||NR||Mandatory||TRUS standard||4.8||4.8||NR||100|
|Total brachytherapy||61 (IQR NA)||NR||NR||Mandatory or for cause||TRUS standard||1.8 (IQR NA)||5.1 (IQR NA)||0 (IQR NA)||0 (IQR NA)||0 (IQR NA)||4.8 (IQR NA)||0 (IQR NA)||0 (IQR NA)||0 (IQR NA)||0 (IQR NA)||0.2 (IQR NA)||NR||99.9 (IQR NA)|
|Valerio 2014||6; 1–23 (median; range)||1; 1–2 (median; range)||For cause||Targeted||2.9||2.9||2.9||2.9||11.8||8.8||2.9||100||100|
|Ting 2015||7 (median; range NR)||NR||1; 1–5 (median; range)||Mandatory||Template mapping||23.8||61.9||19.0||19.0||4.8||NR||12||8||4||100||100|
|Van den bos 2015||1 (median; range NR)||NR||Mandatory||Radical prostatectomy||NR||NR||NR||NR||NR||NR||NR||NR||NA||NA||NA||NR||NR|
|Total IRE||6 (IQR NA)||0 (IQR 0–0)||1 (IQR 1–1)||Mandatory or for cause||Combination (see above)||13.4 (IQR NA)||32.4 (IQR NA)||11 (IQR NA)||11 (IQR NA)||2.4 (IQR NA)||0 (NA)||11.9 (IQR NA)||8.4 (IQR NA)||3.5 (IQR NA)||0 (IQR 0–0)||0 (IQR 0–0)||100 (IQR 100–100)||100 (IQR 100–100)|
|Zlotta 1998||NR||NR||NR||Mandatory||Radical prostatectomy||NR||100a||NR||NR||NR||NR||NR||NA||NA||NA||NA||NR||NR|
|Total RFA||NR||NR||NR||Mandatory||Radical prostatectomy||NA||NA||NA||NA||NA||NA||NA||NA||NA||NA||NA||NR||NR|
a Not included in cumulative analysis as there was no intention to treat.
HIFU = high-intensity focused ultrasound; IRE = irreversible electroporation; IQR = interquartile range; LITT = laser-induced interstitial thermotherapy; MRI = magnetic resonance imaging; NA = not applicable; NR = not reported; PDT = photodynamic therapy; PSA = prostate-specific antigen; Ref. = Reference; RFA = radiofrequency ablation; SD = standard deviation; TRUS = transrectal ultrasound.
Morbidity and functional outcomes of the 37 series included
|Ref.||Serious AE, % (scale)||PROM for continence||Leak-free (%)||Pad-free (%)||PROM for erectile function||Potency preservation (%)||Stability||New use of PDE-5 inhibitors (%)||PROM for urinary symptoms||Change||Catheterization time (min)||Stricture rate (%)||Urinary retention rate (%)||UTI rate (%)||PROM for bowel symptoms (%)||Change||Recto-urethral fistula (%)||PROM for quality of life||Change|
|Muto 2008||NR||UCLA-EPIC||NR||NR||NR||NR||NR||NR||IPSS||Stable||19.7; 7.6 (mean; SD)||4||NR||4||NR||NR||NR||NR||NR|
|El Fegoun 2011||NR||NR||NR||100||NR||NR||NR||NR||IPSS||Stable||NR||8.3||16.7||NR||NR||NR||NR||NR|
|Ahmed 2012||NR||UCLA-EPIC||100||100||IIEF-15||88.6||Deterioration||NR||IPSS||Stable||8.5; 8.0–15.0 (median; IQR)||2.4||17.1||NR||NR||2.4 (suspicion)||FACT-P||Deterioration|
|Napoli 2013||0 (Dindo-Clavien)||NR||NR||NR||NR||NR||NR||NR||NR||NR||3 (median and range)||NR||NR||NR||NR||NR||NR||NR||NR|
|Van Velthoven 2013||3.2 (Dindo-Clavien)||NR||NR||100||NR||80||NR||13.8||NR||NR||2; 2–21 (median; range)||3.4||3.4||10.3||NR||NR||NR||NR|
|Ghai 2015||0 (Dindo-Clavien)||ICS||NR||100||IIEF-5||100||Deterioration||IPSS||Stable||6; 0–7 (median; range)||NR||NR||NR||SF-12HS||Stable|
|Ahmed 2015||NR||UCLA-EPIC||92.6||92.6||IIEF-15||76.9||Deterioration||29.6||IPSS||Stable||9; 7–14 (mdeian; IQR)||7.1||NR||17.9||NR||NR||FACT-P||Stable|
|Feijoo 2015||3 (Dindo-Clavien)||ICS||100||100||IIEF-5||NR||Deterioration||NR||IPSS||Stable||NR||9.0||6.0||NR||NR||NR||NR|
|Total HIFU||1.5 (IQR 0–3.2)||UCLA-EPIC or ICS||96.3 (IQR 90.7–100)||100 (IQR 95–100)||IIEF||88.6 (IQR 78.5–97.5)||Deterioration or stable||13.8 (IQR NA)||IPSS||Stable||7.3 (IQR 2.8–11.7)||3.4 (IQR 0–5)||2.9 (IQR 0–8.5)||8.2 (IQR 1–17)||NR||NR||0 (0–0)||FACT-P or SH-12HS||Stable or deterioration|
|Al Barqawi 2014||0 (NR)||NR||NR||100||SHIM||NR||Stable||NR||IPSS||Improvement||7 (median; IQR NR)||NR||NR||NR||NR||NR||NR|
|Durand 2014||4.2 (Dindo-Clavien)||NR||NR||100||IIEF-5||NR||Stable||NR||IPSS||Stable||3.5; 1–34 (median; range)||2.1||14.6||NR||NR||2.1||NR||NR|
|Lian 2015||2.5 (Dindo-Clavien)||NR||NR||100||IIEF-5||76.9||NR||17.1||NR||NR||NR||NR||2.5||NR||NR||NR||NR||NR|
|Total cryotherapy||2.5 (IQR NA)||NR||98 (IQR NA)||100 (IQR 100–100)||IIEF, SHIM, or BMFSI||81.5 (IQR 69.3–88.2)||Stable||26.9 (IQR NA)||IPSS||Improvement or stable||5.3 (IQR NA)||1.1 (IQR NA)||3.8 (IQR 1.8–9.8)||0% (IQR NA)||NR||NR||0 (IQR 0–0.3)||NR||NR|
|Moore 2006||NR||NR||83.3||NR||BMSFI||NR||Stable||NR||IPSS||Stable||1–4 (range)||NR||33.3||16.7||NR||NR||NR||NR|
|Azzouzi 2013||9.3 (CTCAE)a||NR||NR||NR||IIEF-5||88.6a||Deterioration||NR||IPSS||Improvement||NR||1.2a||12.8a||14a||NR||NR||NR||NR|
|Moore 2013||11.9 (CTCAE)||NR||NR||NR||IIEF-5||88.2||Stable||NR||IPSS||Improvement||NR||NR||5||NR||NR||NR||NR||NR|
|Total PDT||10.6 (IQR NA)||NR||83.3 (IQR NA)||NR||IIEF or BMSFI||88.4 (IQR NA)||Stable or deterioration||NR||IPSS||Improvement or stable||NR||1.2 (IQR NA)||12.8 (IQR NA)||15.4 (IQR NA)||NR||NR||0 (IQR 0–0)||NR||NR|
|Lindner 2009||0 (NR)||NR||100||100||IIEF-5||100%||Stable||NR||IPSS||Stable||0; 0–1 (median; range)||16.7||NR||NR||NR||NR|
|Lindner 2010||0 (NR)||NR||NR||NR||NR||NR||NR||NR||NR||NR||NR||NR||NR||NR||NR||NR||NR||NR||NR|
|Oto 2013||0 (CTCAE)||NR||NR||100||SHIM||100||Stable||NR||IPSS||Stable||NR||NR||NR||NR||NR||NR||NR||NR|
|Lepor 2015||0%(NR)||NR||NR||100||SHIM||NR||Stable||NR||IPSS||Stable||0; 0–3 (median; range)||28||NR||NR||NR||NR|
|Total LITT||0 (IQR 0–0)||NR||100 (IQR NA)||100 (IQR 100–100)||SHIM or IIEF||100 (IQR 100–100)||Stable||NR||IPSS||Stable||0 (IQR 0–0)||0 (IQR 0–0)||22.4 (IQR NA)||0 (IQR 0–0)||NR||NR||0 (IQR 0–0)||NR||NR|
|Total brachytherapy||NR||ICS||NR||95.2 (IQR NA)||IIEF||NR||Stable||NR||IPSS||Stable||NR||NR||4.8 (IQR NA)||NR||NR||NR||0 (IQR NA)||NR||NR|
|Valerio 2014||0 (CTCAE)||NR||NR||100||NR||95||NR||NR||NR||NR||3; 0–9 (median; range)||5.9||14.7||NR||NR||NR||NR|
|Ting 2015||4 (Dindo-Clavien)||UCLA-EPIC||100||100||UCLA-EPIC||NR||Stable||NR||IPSS||Stable||2; 2–5 (median; range)||NR||20||NR||UCLA-EPIC||Stable||SF-12HS||Stable|
|Van den bos 2015||0 (NR)||NR||NR||NR||NR||NR||NR||NR||NR||NR||NR||NR||NR||NR||NR||NR||NR||NR|
|Total IRE||0 (IQR NA)||UCLA-EPIC||100 (IQR NA)||100 (IQR 100–100)||UCLA-EPIC||95 (IQR NA)||Stable||NR||IPSS||Stable||2.5 (IQR NA)||0 (IQR NA)||13 (IQR NA)||14.7 (IQR NA)||UCLA-EPIC||Stable||0 (IQR 0–0)||SF-12HS||Stable|
a Data referring to the whole population including bilateral ablation.
BMSFI = Brief Male Sexual. Function Inventory; CTCAE = Common Terminology Criteria for Adverse Events; EPIC = Expanded Prostate Cancer Index Composite; FACT-P = Functional Assessment of Cancer Therapy-Prostate; HIFU = high-intensity focused ultrasound; ICS = International Continence Society; IIEF = International Index of Erectile Function; IRE = irreversible electroporation; IPSS = International Prostate Symptom Score; IQR = interquartile range; LITT = laser-induced interstitial thermotherapy; NA = not applicable; NR = not reported; PDT = photodynamic therapy; PROM = patient-reported outcomes measures; Ref. = Reference; RFA = radiofrequency ablation; SD = standard deviation; SF-12HS = Short Form-12 Health Survey; SHIM = Sexually Health Inventory for Men; TRUS = transrectal ultrasound; UCLA = University of California, Los Angeles; UTI = urinary tract infection.
Design of ongoing clinical trials
|Registration no.||Name||Source of energy||Sample size (n)||Open||Close||City||Stage||Target population risk||Primary outcome||Primary outcome measure||Secondary outcomes||Secondary outcome measures||Follow-up|
|NCT01226576||Focal MR-Guided Focused Ultrasound Treatment of Localized Low-Intermediate Risk Prostate Cancer: Feasibility Study||HIFU||80||2010||2015||Multicenter||2a||Low-intermediate||Safety at 6 mo|
Effectiveness at 6 mo
Template mapping biopsy
|Safety at 24 mo|
Effectiveness at 24 mo
Genito-urinary toxicity & quality of life at 24 mo
Template mapping biopsy
IPSS, SF12, UCLA-EPIC
|NCT02016040||Focal Therapy Using HIFU for Localized Prostate Cancer||HIFU||25||2013||2016||Montreal (Canada)||2a||Low-intermediate||Cancer control||MRI targeted biopsy||Safety|
Genito-urinary toxicity & quality of life
|NCT01657942||Focal MR-Guided Focused Ultrasound Treatment of Localized Low and Intermediate Risk Prostate Cancer||HIFU||40||2013||2016||Multicenter||2a||Low-intermediate||Safety||Adverse events||Cancer control||Template mapping biopsy||6 mo|
|NCT02265159||Intervention Trial Evaluating Focal Therapy Using High Intensity Focused Ultrasound for the Treatment of Prostate Cancer||HIFU||100||2014||2020||Zurich (Switzerland)||2b||Low-intermediate||Cancer control||Template mapping biopsy||Biochemical failure|
Genito-urinary toxicity & quality of life
Secondary intervention rate
Template mapping biopsy
IPSS, IIEF-15, UCLA-EPIC, FACT-P V4, Memorial Anxiety Scale for Prostate Cancer
Transition to other treatments
|ISRCTN99760303||Partial prostate Ablation versus Radical prosTatectomy||HIFU||100||2015||2017||Oxford|
|2b||Intermediate||Feasibility of RCT||Uptake of ≥50% eligible patients||Cancer control|
Genito-urinary toxicity & quality of life
|TRUS biopsy, MRI|
IPSS, IIEF-15, UCLA-EPIC, EQ-5D-5L, FACT-P V4, The Modified 18-term Memorial Anxiety Scale for Prostate Cancer, Resource Utilization Questionnaire
|NCT01094665||MRI Targeted Focal Laser Thermal Therapy of Prostate Cancer||LITT||60||2009||2016||Toronto (Canada)||1||Low-intermediate||Safety||NR||Cancer control||TRUS biopsy||4 mo|
|NCT02243033||Laser Interstitial Thermal Therapy of Prostate Cancer||LITT||100||2010||2016||Indian Wells (USA)||2a||Low-intermediate||Safety||Adverse events||Cancer control|
Genito-urinary toxicity & quality of life
|MRI targeted biopsy|
No patients undergoing the procedure
IPSS, SHIM, and PHQ-9
|NCT02200809||MR-guided Focal Laser Ablation of the Prostate||LITT||20||2014||2019||Nijmegen (Netherlands)||2a||Low-intermediate||Cancer control||MRI targeted biopsy||NR||NR||3 yr|
|NCT02357121||Focal Laser Ablation of Prostate Tissue (FLA)||LITT||12||2015||2016||Los Angeles (USA)||1||Low-intermediate||Safety||Adverse events||Efficacy||MRI||1 yr|
|NCT02600156||Focal Laser Ablation of Prostate Cancer Tumors||LITT||20||2015||2018||Rochester (USA)||1||Low-intermediate||Feasibility|
|Target, access, monitor, and ablate tissue|
|Cancer control||MRI||3 yr|
|NCT01830166||Focal Therapy for Prostate Cancer - A Pilot Study of Focal Low Dose Rate Brachytherapy||Brachytherapy||10||2013||2018||Vancouver (Canada)||2a||Low||Develop treatment plans||NR||Quality of life|
MRI, mapping biopsy
|NCT01902680||Phase II Study of Feasibility of Focal Therapy for Prostate Cancer of Good Prognosis With Permanent I125 Localized Implant||Brachytherapy||17||2013||2015||Toulouse (France)||2a||Low||Feasibility||Dosimetry study by CT/MRI||Progression-free survival|
Genito-urinary toxicity & quality of life
IPSS, IIEF, EORTC-QLQ
|NCT02391051||Focal Brachytherapy in Patients With Selected Low-risk Prostate Cancer - A Phase-II-trial||Brachytherapy||50||2014||2017||Erlangen (Germany)||2a||Low||Safety||Adverse events at 6 wk||Cancer control|
Genito-urinary toxicity & quality of life at 6 wk
IPSS, IIEF, EORTC-QLQ, ICIQ
|6 wk for primary outcome|
10 yr overall
|NCT02290366||Prospective Evaluation of Focal Brachytherapy Using Cesium-131 For Patients With Low Risk Prostate Cancer||Brachytherapy||100||2014||2020||Pittsburgh (USA)||2b||Low||Disease-free survival||NR||Genito-urinary toxicity & quality of life||NR||5 yr|
|NCT02303054||MRI-Targeted Focal Ablation of the Prostate in Men With Prostate Cancer||RFA||21||2014||2016||New York (USA)||2a||Low-intermediate||Cancer control||MRU fusion targeted biopsy||Genito-urinary toxicity & quality of life||IPSS, IIEF-15, UCLA-EPIC, SF-12 QoL||6 mo|
|NCT02328807||Focal Prostate Radio-Frequency Ablation||RFA||30||2014||2016||Tampa|
|2a||Low-intermediate||Cancer control||Biopsy (type NR)||Safety|
Genito-urinary toxicity & quality of life
IPSS, IIEF-5, UCLA-EPIC, and RAS
|NCT02294903||Focal Prostate Radiofrequency Ablation||RFA||20||2015||2016||London|
|2a||Low-intermediate||Cancer control||Template mapping biopsy||Safety|
Genito-urinary toxicity & quality of life
EPIC = Expanded Prostate Cancer Index Composite; FACT-P = Functional Assessment of Cancer Therapy-Prostate; HIFU = high-intensity focused ultrasound; IIEF = International Index of Erectile Function; IRE = irreversible electroporation; IPSS = International Prostate Symptom Score; LITT = laser-induced interstitial thermotherapy; MRI = magnetic resonance imaging; NR = not reported; PHQ-9 = Patient Health Questionnaire-9; PSA = prostate-specific antigen; QoL = quality of life; RAS = Relationship Assessment Scale; RFA = radiofrequency ablation; SF-12HS = Short Form-12 Health Survey; SHIM = Sexually Health Inventory for Men; TRUS = transrectal ultrasound; UCLA = University of California, Los Angeles.
HIFU is a form of thermal energy that leads to tissue ablation by raising the temperature over 60° using focused high-intensity ultrasound. Tissue ablation is the consequence of two mechanisms: (1) coagulative necrosis due to extreme temperature, and (2) internal cavitation due to the interaction between water and ultrasounds. Modern devices delivering HIFU to the prostate are transurethral or transrectal, and use in-bore guidance or MR-transrectal ultrasound (TRUS) fusion, respectively.
Of the 13 series evaluating focal HIFU in 346 men, six were considered Stage 1, four Stage 2a, and three Stage 2b. Two studies were retrospective case series; the others were prospective proof of concept, case series, or development studies. Two series evaluated in-bore transurethral HIFU; the others transrectal focal HIFU. Five series did not clearly report the type of entry biopsy; in the remaining, TRUS standard biopsy, TRUS extended protocols, targeted biopsy, and/or template mapping biopsy were performed. MRI was used in 11 series (84.6%). The study population included low, intermediate and high risk patients with median age of 63 yr (IQR: 62–70 yr) and median PSA of 7.3 ng/ml (IQR: 5.8–8.3 ng/ml).
Median follow-up was 12 mo (IQR: 0–28.5 mo) with 12 series including mandatory sampling and one study including biopsy only for cause. Apart from four Stage I studies in which men underwent radical prostatectomy soon after focal HIFU, the remaining studies employed targeted biopsy, TRUS standard or extended biopsy, and/or template mapping biopsy. In the series with intention to treat, the overall presence of significant and insignificant cancer was 0% (IQR: 0–13.5%) and 23.3% (IQR: 10.4%–38.1%), respectively. However, the first outcome was reported only in five series. The probability of transition to secondary local treatment was 7.8% (IQR: 3.8–10.3%); overall and disease-specific survival were 100% (IQR: 100–100%) and 100% (IQR: 100–100%), respectively. Significant adverse events (SAE) occurred in 1.5% of patients (IQR: 0–3.2%). Pad-free continence and potency preservation were achieved in 100% (IQR: 95–100%) and 88.6% (IQR: 78.5–97.5%), respectively.
Cryotherapy is a thermal form of energy relying on extreme cold temperature leading to tissue ablation by a number of mechanisms such as osmotic injury, cytolysis, apoptosis, and vascular damage. The procedure is performed through cryo-needles positioned in the target area through the perineum. A given distance is maintained between the needles is order to form a homogeneous ice ball with no skip lesion in the middle.
Of the 11 series evaluating focal cryotherapy in 1950 patients, four were considered Stage 2a, and seven Stage 2b. All studies were retrospective except one prospective case series and one prospective development study. Four series did not clearly report the type of entry biopsy; in the remaining, TRUS standard +/- targeted biopsy, or template mapping biopsy were performed. The study population included low, intermediate and high risk patients with median age of 66.8 yr (IQR: 63.8–68.1 yr) and median PSA of 6.3 ng/ml (IQR: 5.2–7.2 ng/ml).
Median follow-up was 26 mo (IQR: 17.6–48.8 mo) with three series including mandatory sampling and 18 including biopsy only for cause. Control biopsy included TRUS standard +/- targeted biopsy. Overall presence of significant and insignificant cancer were at 5.4% (IQR: 1.1–7.3%) and 13% (IQR: 4–19.4%), respectively. However, the first outcome was reported only in four series. The probability of transition to secondary local treatment was 7.6% (IQR: 6.1–13.8%); overall and disease-specific survival were 100% (IQR: 100–100%) and 100% (IQR: 100–100%), respectively. SAE occurred in 2.5% patients (IQR: not applicable [NA]), although only two series reported these using a standardized classification. Pad-free continence and potency preservation were achieved in 100% (IQR: 100–100%) and 81.5% (IQR: 69.3–88.2%), respectively.
PDT ablation relies on the activation of a vascular photosensitiviser within the target area, which leads to the formation of reactive oxygen species causing vessels thrombosis, apoptosis, and necrosis. In the prostate, laser activating fibers are positioned transperineally, and the photosensitiviser is administered intravenously.
Three prospective development studies on Stage 1 to 2b evaluating focal PDT in 116 patients have been reported in the literature. TRUS standard or template mapping biopsy and MRI were used to identify eligible patients. The study population included low and intermediate risk patients with a median age of 63.9 yr (IQR: NA) and median PSA of 6.4 ng/ml (IQR: NA).
When reported, median follow-up was homogeneous at 6 mo (IQR: 6–6 mo) with all three studies including mandatory sampling using TRUS standard biopsy. The presence of significant cancer was reported by none of the studies; insignificant cancer was present in 45.9% (IQR: NA). The probability of transition to secondary local treatment was reported only in the Stage 1 study, and was at 83.3% (IQR: NA). Overall and disease-specific survival were 100% (IQR: 100–100%) and 100% (IQR: 100–100%), respectively. SAE occurred in 10.6% of patients (IQR: NA). Pad-free continence rates were not available. Potency preservation was achieved in 88.4% (IQR: NA), respectively.
LITT is another thermal energy leading to ablation by raising the temperature directly within the target tissue. As opposite to PDT, LITT is a direct thermal energy, and does not employ photosensitivisers. The laser fibers are positioned transperineally or transrectally; the number of fibers is dependent by the volume of the target tissue.
Four prospective Stage 1 to 2a studies evaluating focal LITT in 50 patients have been reported in literature. TRUS standard and MRI were systematically used to identify eligible patients. One study included only men with low-risk disease, whereas the other studies included also Gleason ≤4+3, although risk stratification was not clearly reported. The median age was 63.5 yr (IQR: 57.6–66 yr); median PSA was 5.4 ng/ml (IQR: 4.5–5.7 ng/ml).
Median follow-up was 4.5 mo (IQR: 0.8–6 mo) with all series including mandatory sampling after treatment. In the Stage 1 study, all men underwent radical prostatectomy, whereas in the other three studies men underwent TRUS standard and/or targeted biopsy. Overall, the presence of significant and insignificant cancer were 4.8% (IQR: NA) and 22.2% (IQR: NA), respectively. The probability of transition to secondary local treatment was 0% (IQR: NA); overall and disease-specific survival were 100% (IQR: 100–100%) and 100% (IQR: 100–100%), respectively. No SAE were reported in any study. Pad-free continence and potency preservation were achieved in 100% (IQR: 100–100%) and 100% (IQR: 100–100%), respectively.
Brachytherapy is an established whole-gland treatment in prostate cancer. Sealed radiating seeds are inserted through the perineum in the prostate. When used as a focal option, brachytherapy is used as a monotherapy with no conjunction of external beam radiation, and only a part of the prostate is planned to receive the radiation dose needed to achieve complete treatment.
Two retrospective Stage 2a–b case series evaluating focal brachytherapy in 339 patients have been reported in literature. Both series used MRI at the outset. One series did not report the type of entry biopsy; in the other, all men underwent TRUS extended biopsy. The study population included low and intermediate risk patients with a median age of 62.3 yr (IQR: NA) and a median of PSA of 6 ng/ml (IQR: NA).
One series did not report the length of follow-up, while the other had a median follow-up of 61 mo (IQR: 33–88 mo). Both series incorporated TRUS standard biopsy, although in one sampling was mandatory, whereas in the other it was for cause. Overall, the presence of significant and insignificant cancer were 1.8% (IQR: NA) and 5.1% (IQR: NA), respectively. No patient had secondary local treatment (IQR: NA). Overall survival was not reported by any study, whilst disease-specific survival was 99.9% (IQR: NA). SAE were reported by no series using a standardized classification. Pad-free continence was reported only by one series and was at 95.2%. Potency preservation was not reported by any series.
IRE ablation delivers high voltage low energy electric current within the target tissue. In the prostate, this is achieved by positioning electro-needles through the perineum under TRUS guidance.
One proof of concept Stage 1 and two retrospective cases series Stage 2a studies evaluating focal IRE in 66 patients have been reported in literature. TRUS standard, template mapping biopsy and/or targeted were used to identify eligible patients. The study population included low and intermediate risk patients with a median age of 65 yr (IQR: NA) and a median PSA of 6.1 ng/ml (IQR: NA).
Median follow-up was 6 mo (IQR: NA) with different follow-up strategies and triggers for biopsy. The only Stage I study with no intention to treat incorporated mandatory radical prostatectomy after treatment. One Stage 2a incorporated mandatory template mapping biopsy after treatment. Overall, the presence of significant cancer and insignificant cancer were 13.4% (IQR: NA) and 32.4%. The probability of transition to secondary local treatment was 11.9%. Overall and disease-specific survival were 100% (IQR: 100–100%) and 100% (IQR: 100–100%), respectively. SAE occurred in 0% of patients (IQR: NA). Pad-free continence and potency preservation were achieved in 100% (IQR: 100–100%) and 95% (IQR: NA), respectively.
RFA is another thermal procedure delivering medium frequency alternating current in order to generate killing heat within the target area. Similarly to all other sources of energy except HIFU of the prostate, it is delivered by inserting specific needles transperineally.
Only one proof of concept Stage 1 study evaluating focal RFA prior to radical prostatectomy in 15 men has been reported. No details on the study population were available. None of the other oncological and functional outcomes could be extrapolated. Residual tumor was found in all men, although there was no intention to treat in this study.
This systematic review shows that seven sources of energy have been delivered as focal strategies in a clinical setting. HIFU, cryotherapy, PDT, and brachytherapy have been assessed in up to Stage 2b studies including 346, 1950, 116, and 339 patients, respectively. LITT and IRE have been evaluated in up to Stage 2a studies in 50 and 66 patients, respectively. RFA has been evaluated in one Stage 1 study including 15 patients. Overall, this systematic review shows that focal therapy rarely causes significant morbidity and seems to have a minor impact on quality of life, although the oncological effectiveness in the long-term needs to be further evaluated.
While this systematic review was comprehensive, there are key aspects that need to be debated prior to further discuss the results. The assessment of novel sources of energy should be distinguished from the evaluation of the strategy itself, namely focal therapy. The success of sources of energy delivered in a focal manner is strictly dependent on our ability to select eligible patients. Although multiparametric MRI has a high performance to rule in and rule out clinically significant disease at a regional level, the strategy is not perfect and some relevant cancers might be missed. The issue is even more relevant as the definition of clinically significant disease is debated, and varying the threshold of significance has a substantial impact on the performance of our diagnostic tests  and . Also, the high performance reported in literature comes from high volume expert centers; reproducibility needs to be verified yet.
Further, no study had a comparator arm represented by a standard treatment approach, and most focused on safety, feasibility, functional outcomes, and short- to mid-term outcomes. Therefore, while the results should be considered with respect to the evaluation of these sources of energy within early stage studies, oncological effectiveness of focal therapy is yet to be defined for different reasons. Firstly, if we consider that the aim of focal therapy is to treat only significant disease, some series included a number of men harboring what is currently considered insignificant disease, and there was a wide variation in the definition of clinically significant disease. Secondly, while short- to mid-term oncological outcome, as measured by negative-biopsy rate and/or avoidance of other local treatments, seems encouraging, it should be emphasized that some studies used discordant tools for selecting and following eligible men. For instance, intensive sampling was employed to select suitable patients, but only random systematic sampling was employed to diagnose local recurrence. There is awareness about this limitation in the research community, and recent trials incorporate the same precise diagnostic tools at the outset and in the follow-up . Finally, heterogeneity in study design including target population, risk stratification, type of focal ablation, follow-up schedule, as well as outcome measures of morbidity and ablation do not allow a formal meta-analysis to be performed or to draw a reliable comparison between the different sources of energy. In this setting, with the intent to summarize these limited and heterogeneous data, we chose to use simple descriptive statistics. For instance, although focal therapy has been lately defined as ablation of the index lesion only by a group of experts, there was intrastudy and interstudy variability in the ablation strategy with many early series using pragmatic template such as hemiablation . Also, in the case of lesion-only ablation, the location of the tumor has a great impact on functional outcomes; in particular the distance from the sphincter and neurovascular bundles is likely to influence continence and potency, respectively. There is room for improvement also in the use of validated PROMs. While most studies included did not use PROMs to elicit functional outcomes, recent prospective studies and ongoing trials do employ these outcome measures.
Focal HIFU and cryotherapy have been the most investigated sources of energy so far in terms of number of studies, stage of assessment, and length of follow-up. Whilst the evidence regarding focal HIFU relies on a number of prospective studies, most studies investigating focal cryotherapy are retrospective, but it should be noted that these have longer follow-up. Additional studies are ongoing and will further add essential evidence to move forward in the evaluation of these technologies. Two studies, one evaluating focal HIFU and one evaluating focal cryotherapy have fully recruited the expected sample size of 272 and 100 men, respectively, and results will be available in the upcoming months (NCT01194648 and NCT00877682). Both studies incorporate mandatory control biopsy of the treated as well as of the untreated area after 3 yr of follow-up. These studies will verify not only the ablation results of these two modalities in the midterm, but will also verify the natural course of untreated areas after focal therapy. The multicenter design and the prospective nature with validated outcome measures will also clarify the reproducibility of these procedures and the impact of quality of life, respectively, with longer follow-up.
Focal PDT has been offered to patients only within prospective clinical trials, the phase of assessment is 2b, but a Phase 3 RCT has completed accrual, and results are awaited (NCT01310894). Across 12 European countries, 400 patients with low-risk disease were randomized to focal PDT against active surveillance. Absence of residual cancer at the 2-yr control biopsy and treatment failure were the primary end-points. This study represents the first randomized study including a focal therapy arm against a standard arm, represented by active surveillance. Although the results will provide high quality evidence in this setting and will clarify the outcomes of focal PDT within a multicenter trial, further trials will be needed in order to consider focal therapy as a legitimate option. High quality evidence at present shows the study population does not benefit from immediate treatment, and can be safely managed by active surveillance. Future trials will need to incorporate mainly—if not exclusively—men harboring clinically significant disease who are likely to benefit from treatment, and in whom an oncological benefit can be measured.
Focal LITT is in the early Stage 2a of assessment. The results seem encouraging with a safe toxicity profile, although the short monitoring after treatment up to 6 mo points to further assessment needed. This is under the way in three Stage 1 to 2a trials with longer monitoring up to 3 yr. Focal brachytherapy is currently recruiting in four Stage 2a to 2b prospective studies. While the oncological outcome and toxicity profile of whole-brachytherapy are well defined, the ongoing studies are very important as the available evidence in the focal setting is based exclusively on retrospective data. Focal IRE is another novel source of energy accounting for one Stage 1 study and two Stage 2a retrospective studies. The procedure seems well tolerated; however, reliable evidence of ablation efficacy is lacking. One Stage 2a prospective development study evaluating focal IRE will be soon reported, and another Stage 2b trial supported by the Endourological society will start soon in six European centers. These trials are awaited in order to further evaluate this technology in a rigorous manner. Only one Stage 1 study is at present available for RFA, and it is impossible to make any comments about this source of energy in prostate cancer. However, three Stage 2a prospective development studies are recruiting men for focal RFA in order to evaluate this technology in a rigorous manner.
The PART trial is a key study to push the evaluation of focal therapy forward. In a multicenter RCT, 100 men will be randomized between radical prostatectomy (control arm) against focal HIFU (interventional arm). The hypothesis is that the effectiveness of treatment would be comparable, although focal therapy will reduce treatment-related toxicity, as measured by validated outcome measures. The main aim is to assess the feasibility of a RCT in this setting with the primary outcome being to recruit over 50% eligible men. In case of positive results, a Stage III trial powered to show statistically significant results would be planned.
Delivering a RCT in focal therapy against a standard option will be challenging . In the area of prostate cancer, there are few examples of success, and many examples of failures. Many trials in the areas were preemptively closed for two reasons: patients’ unwillingness to be randomized in different treatments and clinicians’ lack of equipoise . These challenges are very likely to be encountered in a RCT comparing focal therapy with a standard option in light of the different toxicity profiles of the two arms, as well as the debate surrounding the legitimacy of focal therapy among clinicians. If such trial would be revealed unfeasible, an alternative way of randomization should be explored—such as what the researchers have applied within the ProtecT trial—or alternative trial designs should be considered in order to evaluate in a rigorous and timely manner a focal therapy option . Alternative trial designs are more easily embedded in clinical practice, and allow measuring the effectiveness of a given intervention in the real world rather than its efficacy in a trial setting. Examples of alternative trial designs which might be adopted in this field are: cohort-embedded multiple RCT, cluster RCT, patient preference trials, and parallel prospective cohort studies.
Seven sources of energy have been delivered in a focal manner in men with localized prostate cancer. HIFU, cryotherapy, PDT, and brachytherapy have been investigated in up to Stage 2b trials, LITT, and IRE in up to Stage 2a trials, and RFA in only one Stage 1 trial. Focal therapy seems safe and appears to offer good preservation of genito-urinary function. Cancer control in studies with intention to treat is encouraging, although this needs to be verified against standard of care in high quality comparative effectiveness trials.
Author contributions: Massimo Valerio had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Valerio, Cerantola, Eggener, Lepor, Polascik, Villers, Emberton.
Acquisition of data: Valerio, Cerantola.
Analysis and interpretation of data: Valerio, Cerantola.
Drafting of the manuscript: Valerio, Cerantola.
Critical revision of the manuscript for important intellectual content: Eggener, Lepor, Polascik, Villers, Emberton.
Statistical analysis: Valerio, Cerantola.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Eggener, Lepor, Polascik, Villers, Emberton.
Financial disclosures: Massimo Valerio certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Emberton receives funding from USHIFU, GSK, AngioDynamics, and Advanced Medical Diagnostics for clinical trials. Emberton is a paid consultant to AngioDynamics, Steba Biotech, and SonaCare Medical (previously called USHIFU). He has previously received consultancy payments from Oncura/GE Healthcare and Steba Biotech. None of these sources had any input whatsoever into this article.
Funding/Support and role of the sponsor: None.
Acknowledgments: The SICPA foundation supports the ongoing fellowship and PhD program of Valerio. Emberton would like to acknowledge funding from the Medical Research Council (UK), the Pelican Cancer Foundation charity, Prostate Cancer UK, St Peters Trust charity, Prostate Cancer Research Center, the Wellcome Trust, National Institute of Health Research-Health Technology Assessment program, and the US National Institute of Health-National Cancer Institute. Emberton receives funding in part from the UK National Institute of Health Research UCLH/UCL Comprehensive Biomedical Research Centre. Emberton is a NIHR senior investigator.
-  M. Valerio, H.U. Ahmed, M. Emberton, et al. The role of focal therapy in the management of localised prostate cancer: A systematic review. Eur Urol. 2014;66:732-751 Crossref
-  G. Giannarini, G. Gandaglia, F. Montorsi, A. Briganti. Will focal therapy remain only an attractive illusion for the primary treatment of prostate cancer?. J Clin Oncol. 2014;32:1299-1301 Crossref
-  M. Valerio, M. Emberton, H.U. Ahmed. Focal therapy will become a standard option for selected men with localized prostate cancer. J Clinical Oncol. 2014;32:3680-3681 Crossref
-  A.M. Wise, T.A. Stamey, J.E. McNeal, J.L. Clayton. Morphologic and clinical significance of multifocal prostate cancers in radical prostatectomy specimens. Urology. 2002;60:264-269 Crossref
-  F. Algaba, R. Montironi. Impact of prostate cancer multifocality on its biology and treatment. J Endourol. 2010;24:799-804 Crossref
-  H.U. Ahmed, M. Arya, A. Freeman, M. Emberton. Do low-grade and low-volume prostate cancers bear the hallmarks of malignancy?. Lancet Oncol. 2012;13:e509-e517 Crossref
-  J.J. Futterer, A. Briganti, P. De Visschere, et al. Can clinically significant prostate cancer be detected with multiparametric magnetic resonance imaging?. A systematic review of the literature. Eur Urol. 2015;68:1045-1053
-  D. Moher, A. Liberati, J. Tetzlaff, D.G. Altman. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Ann Intern Med. 2009;151:265-269
-  P. McCulloch, D.G. Altman, W.B. Campbell, et al. No surgical innovation without evaluation: the IDEAL recommendations. Lancet. 2009;374:1105-1112 Crossref
-  S. Madersbacher, M. Pedevilla, L. Vingers, M. Susani, M. Marberger. Effect of high-intensity focused ultrasound on human prostate cancer in vivo. Cancer Res. 1995;55:3346-3351
-  H.P. Beerlage, S. Thuroff, F.M. Debruyne, C. Chaussy, J.J. de la Rosette. Transrectal high-intensity focused ultrasound using the Ablatherm device in the treatment of localized prostate carcinoma. Urology. 1999;54:273-277 Crossref
-  S. Muto, T. Yoshii, K. Saito, Y. Kamiyama, H. Ide, S. Horie. Focal therapy with high-intensity-focused ultrasound in the treatment of localized prostate cancer. Jpn J Clin Oncol. 2008;38:192-199 Crossref
-  H.U. Ahmed, A. Freeman, A. Kirkham, et al. Focal therapy for localized prostate cancer: A phase I/II trial. J Urol. 2011;185:1246-1254
-  A.B. El Fegoun, E. Barret, D. Prapotnich, et al. Focal therapy with high-intensity focused ultrasound for prostate cancer in the elderly. A feasibility study with 10 years follow-up. Int Braz J Urol. 2011;37:213-219
-  H.U. Ahmed, R.G. Hindley, L. Dickinson, et al. Focal therapy for localised unifocal and multifocal prostate cancer: A prospective development study. Lancet Oncol. 2012;13:622-632
-  R. Chopra, A. Colquhoun, M. Burtnyk, et al. MR imaging-controlled transurethral ultrasound therapy for conformal treatment of prostate tissue: Initial feasibility in humans. Radiology. 2012;265:303-313 Crossref
-  L. Dickinson, Y. Hu, H.U. Ahmed, et al. Image-directed, tissue-preserving focal therapy of prostate cancer: a feasibility study of a novel deformable magnetic resonance-ultrasound (MR-US) registration system. BJU Int. 2013;112:594-601 Crossref
-  A. Napoli, M. Anzidei, C. De Nunzio, et al. Real-time magnetic resonance-guided high-intensity focused ultrasound focal therapy for localised prostate cancer: Preliminary experience. Eur Urol. 2013;63:395-398 Crossref
-  R. Van Velthoven, F. Aoun, K. Limani, K. Narahari, M. Lemort, A. Peltier. Primary zonal high intensity focused ultrasound for prostate cancer: results of a prospective Phase IIa feasibility study. Prostate Cancer. 2014;2014:756189
-  H.U. Ahmed, L. Dickinson, S. Charman, et al. Focal ablation targeted to the index lesion in multifocal localized prostate cancer: A prospective development study. Eur Urol. 2015;68:927-936
-  E.R. Feijoo, A. Sivaraman, E. Barret, et al. Focal high-intensity focused ultrasound targeted hemiablation for unilateral prostate cancer: A prospective evaluation of oncologic and functional outcomes. Eur Urol. 2016;69:214-220
-  S. Ghai, A.S. Louis, M. Van Vliet, 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:W177-W184 Crossref
-  D.K. Bahn, P. Silverman, F. Lee Sr., R. Badalament, E.D. Bahn, J.C. Rewcastle. Focal prostate cryoablation: Initial results show cancer control and potency preservation. J Endourology. 2006;20:688-692 Crossref
-  D.S. Ellis, T.B. Manny Jr., J.C. Rewcastle. Focal cryosurgery followed by penile rehabilitation as primary treatment for localized prostate cancer: Initial results. Urology. 2007;70(Suppl 6):9-15
-  G. Onik, D. Vaughan, R. Lotenfoe, M. Dineen, J. Brady. Male lumpectomy”: Focal therapy for prostate cancer using cryoablation. Urology. 2007;70(Suppl 6):16-21
-  M.D. Truesdale, P.J. Cheetham, G.W. Hruby, et al. An evaluation of patient selection criteria on predicting progression-free survival after primary focal unilateral nerve-sparing cryoablation for prostate cancer: Recommendations for follow up. Cancer J. 2010;16:544-549 Crossref
-  D. Bahn, A.L. de Castro Abreu, I.S. Gill, et al. Focal cryotherapy for clinically unilateral, low-intermediate risk prostate cancer in 73 men with a median follow-up of 3.7 years. Eur Urol. 2012;62:55-63
-  J.F. Ward, J.S. Jones. Focal cryotherapy for localized prostate cancer: A report from the national Cryo On-Line Database (COLD) Registry. BJU Int. 2012;109:1648-1654 Crossref
-  Z. Hale, M. Miyake, D.A. Palacios, C.J. Rosser. Focal cryosurgical ablation of the prostate: A single institute's perspective. BMC Urol. 2013;13:2 Crossref
-  A.B. Barqawi, D. Stoimenova, K. Krughoff, et al. Targeted focal therapy for the management of organ confined prostate cancer. J Urol. 2014;192:749-753 Crossref
-  M. Durand, E. Barret, M. Galiano, et al. Focal cryoablation: A treatment option for unilateral low-risk prostate cancer. BJU Int. 2014;113:56-64 Crossref
-  H. Lian, J. Zhuang, R. Yang, et al. Focal cryoablation for unilateral low-intermediate-risk prostate cancer: 63-month mean follow-up results of 41 patients. Int Urol Nephrol. 2016;48:85-90
-  M.H. Mendez, N.M. Passoni, J. Pow-Sang, J.S. Jones, T.J. Polascik. Comparison of outcomes between preoperatively potent men treated with focal versus whole gland cryotherapy in a matched population. Journal Endourol. 2015;29:1193-1198
-  C.M. Moore, T.R. Nathan, W.R. Lees, et al. Photodynamic therapy using meso tetra hydroxy phenyl chlorin (mTHPC) in early prostate cancer. Lasers Surg Med. 2006;38:356-363 Crossref
-  A.R. Azzouzi, E. Barret, C.M. Moore, et al. TOOKAD Soluble vascular-targeted photodynamic (VTP) therapy: Determination of optimal treatment conditions and assessment of effects in patients with localised prostate cancer. BJU Int. 2013;112:766-774 Crossref
-  C.M. Moore, A.R. Azzouzi, E. Barret, et al. Determination of optimal drug dose and light dose index to achieve minimally invasive focal ablation of localised prostate cancer using WST11-vascular-targeted photodynamic (VTP) therapy. BJU Int. 2015;116:888-896
-  U. Lindner, R.A. Weersink, M.A. Haider, et al. Image guided photothermal focal therapy for localized prostate cancer: Phase I trial. J Urol. 2009;182:1371-1377 Crossref
-  U. Lindner, N. Lawrentschuk, R.A. Weersink, et al. Focal laser ablation for prostate cancer followed by radical prostatectomy: validation of focal therapy and imaging accuracy. Eur Urol. 2010;57:1111-1114 Crossref
-  A. Oto, I. Sethi, G. Karczmar, et al. MR imaging-guided focal laser ablation for prostate cancer: phase I trial. Radiology. 2013;267:932-940 Crossref
-  H. Lepor, E. Llukani, D. Sperling, J.J. Futterer. Complications, recovery, and early functional outcomes and oncologic control following in-bore focal laser ablation of prostate cancer. Eur Urol. 2015;68:924-926
-  P.L. Nguyen, M.H. Chen, Y. Zhang, et al. Updated results of magnetic resonance imaging guided partial prostate brachytherapy for favorable risk prostate cancer: Implications for focal therapy. J Urol. 2012;188:1151-1156 Crossref
-  J.M. Cosset, X. Cathelineau, G. Wakil, et al. Focal brachytherapy for selected low-risk prostate cancers: A pilot study. Brachytherapy. 2013;12:331-337 Crossref
-  M. Valerio, P.D. Stricker, H.U. Ahmed, et al. Initial assessment of safety and clinical feasibility of irreversible electroporation in the focal treatment of prostate cancer. Prostate Cancer Prostatic Dis. 2014;17:343-347 Crossref
-  F. Ting, M. Tran, M. Bohm, et al. Focal irreversible electroporation for prostate cancer: functional outcomes and short-term oncological control. Prostate Cancer Prostatic Dis. 2016;19:46-52
-  W. van den Bos, D.M. de Bruin, R.R. Jurhill, et al. The correlation between the electrode configuration and histopathology of irreversible electroporation ablations in prostate cancer patients. World J Urol. 2016;34:657-664
-  A.R. Zlotta, B. Djavan, C. Matos, et al. Percutaneous transperineal radiofrequency ablation of prostate tumour: Safety, feasibility and pathological effects on human prostate cancer. Br J Urol. 1998;81:265-275 Crossref
-  N. Arumainayagam, H.U. Ahmed, C.M. Moore, et al. Multiparametric MR imaging for detection of clinically significant prostate cancer: A validation cohort study with transperineal template prostate mapping as the reference standard. Radiology. 2013;268:761-769 Crossref
-  E. Rud, D. Klotz, K. Rennesund, et al. Detection of the index tumour and tumour volume in prostate cancer using T2-weighted and diffusion-weighted magnetic resonance imaging (MRI) alone. BJU Int. 2014;114:E32-E42 Crossref
-  B.G. Muller, W. van den Bos, M. Brausi, et al. Follow-up modalities in focal therapy for prostate cancer: results from a Delphi consensus project. World J Urol. 2015;33:1503-1509
-  I.A. Donaldson, R. Alonzi, D. Barratt, et al. Focal therapy: Patients, interventions, and outcomes—A report from a consensus meeting. Eur Urol. 2015;67:771-777 Crossref
-  H.U. Ahmed, V. Berge, D. Bottomley, et al. Can we deliver randomized trials of focal therapy in prostate cancer?. Nat Rev Clin Oncol. 2014;11:482-491 Crossref
-  J.A. Lane, J.L. Donovan, M. Davis, et al. Active monitoring, radical prostatectomy, or radiotherapy for localized prostate cancer: Study design and diagnostic and baseline results of the ProtecT randomized phase 3 trial. Lancet Oncol. 2014;15:1109-1118 Crossref
a Division of Surgery and Interventional Science, University College London, London, UK
b Department of Urology, University College London Hospitals NHS Foundation Trust, London, UK
c Department of Urology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
d Section of Urology, University of Chicago, Chicago, IL, USA
e Department of Urology, New York University School of Medicine, New York, NY, USA
f Division of Urology, Duke University Medical Center, Durham, NC, USA
g Department of Urology, Lille University Medical Center, Lille University, France
Corresponding author. Division of Surgery and Interventional Science, University College London, 74 Huntley Street, London W1P 7NN, UK. Tel. +44 (0)20 3447 9194; Fax: +44 (0)20 3447 9303.
These authors are joint first authors.
☆ Please visit www.eu-acme.org/europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically.
© 2016 Published by Elsevier B.V.