There is a growing body of focal therapy clinical data. Trying to draw definitive conclusions from the existing literature is challenging. Studies vary greatly in inclusion and evaluation criteria, treatment technique, endpoints, definition of failure, posttreatment assessment protocols, and measures of toxicity. A great deal of insight can still be gleaned, though, from the existing literature. The largest study to date investigating focal therapy was recently updated by Nguyen et al. (Nguyen et al. 2012). 318 patients were treated using intraoperative MRI guidance to deliver low dose rate brachytherapy using ¹²⁵I (minimum dose 137 Gy) to the peripheral zone only. Entry criteria included being T1c, having a PSA < 15 ng/mL and a biopsy Gleason score 3 + 4 or less. 88 % of patients had Gleason score 3 + 3 and 83 % of the patient cohort was low risk. With a median follow-up of 5.1 years 91.5 % of patients had PSA control by nadir + 2 and 78.1 % at 8 years. Nadir + 2 for low risk patients at 5 and 8 years was 95.1 % and 80.4 % but this improved to 95.6 % and 90.0 % using nadir + 2 and PSA velocity >0.75 ng/mL per year. For intermediate risk patients PSA failure-free survival was 73 % at 5 years and 66.4 % at 8 years. When looking at the cohort of 36 patients who failed by the nadir + 2 definition 16/22 with a PSA velocity >0.75 ng/mL per year had a suspicious lesion on MRI that was biopsy positive for a local recurrence (Gleason 3 + 3 in 5, Gleason 3 + 4 in 2, Gleason 4 + 3 in 2, Gleason 4 + 4 in 1, Gleason 3 + 5 in 1, and Gleason 4 + 5 in 2). For the 10 patients with nadir + 2 failure but PSA velocity <0.75 ng/mL per year only 2 had suspicious lesions on MRI. Both underwent 12 core biopsy and one Gleason score 3 + 3 = 6 disease was found. Based on this data PSA velocity greater than 0.75 ng/mL per year in addition to nadir + 2 better predicts failure in this less than whole gland treatment setting. While this provides some evidence-based guidance, PSA kinetics post partial gland therapy are ultimately not well understood. Our limited understanding of PSA changes post partial gland treatment serves as an impediment to defining ideal follow-up and definitions of failure.

Other focal therapy radiation approaches have used intensity modulated radiation therapy to spare the urethra in a more focused therapy approach. A randomized phase II study of urethra sparing treatment versus standard whole gland therapy for NCCN low risk patients was recently published (Vainshtein et al. 2012). The prescription dose was 75.6 Gy and for the urethral sparing plans the mean proximal and distal urethral doses were limited to 65 Gy and 74 Gy, respectively. Patients had to have no visible lesion within 5 mm of the prostatic urethra seen on MRI. The primary endpoint was a change in urinary health related quality of life at 3 months using the Expanded Prostate Cancer Index (EPIC) quality of life questionnaire. 16 patients were randomized and the trial was subsequently halted as no significant differences in EPIC urinary health related quality of life at 3 months was observed. At a median follow-up of 4.7 years three patients had PSA failure in the urethral sparing group but there were none in the standard treatment group. Two out of the three patients with PSA failure had biopsy proven local failure contralateral to the original site of disease. It is likely that using a 1.5T MRI with no multiparametric sequences that the MRI understaged some of these patients.

Outside of radiation therapy there are a number of important focal therapy studies. HIFU and cryoablation are the most developed techniques, however, multiple other techniques are emerging (Bozzini et al. 2013). The most important non-radiation data comes from a group in the United Kingdom that focuses on the use of HIFU (Ahmed et al. 2011). They conducted a Phase I/II trial in men with either low or intermediate risk disease (PSA ≤ 15, Gleason score ≤4 + 3, stage ≤T2b). They had to have unilateral disease as assessed by TRUS guided biopsies, mp-MRI, and TPM biopsies. Hemi-gland treatment with the urethra defining the mid-gland was delivered using the Sonablate 500. The trial was powered to see if focal therapy significantly reduces the risk of erectile dysfunction at 12 months post-treatment. 20 patients were enrolled and 75 % of them had D’Amico based intermediate risk disease. mp-MRI at 6 months showed residual cancer in the treated lobe in 2 men but no suspicious lesions in the untreated lobe in any. There was an 80 % decrease in PSA seen at 3 months that persisted at 12 months (7.3 vs. 1.5 ng/mL). 2 patients with positive mp-MRI at 6 months had biopsies. Both had low volume disease with 1 mm Gleason 3 + 3 in 1 of 4 and 1 of 5 biopsies. One patient elected to undergo active surveillance and the other was retreated with HIFU. 89 % of patients achieved the trifecta status of pad-free, leak-free continence, and erections sufficient for intercourse. This same group subsequently published the first study using an ultra-focal HIFU approach (Ahmed et al. 2012). Low risk patients (PSA ≤ 15, Gleason score ≤4 + 3, stage ≤T2a) were included and evaluated using 1.5T mp-MRI and transperineal template mapping biopsies. The edges of the ablative zone needed to be at least 10 mm from a neurovascular bundle or at least 5 mm from both neurovascular bundles if disease was bilateral. Untreated areas could not have any histological evidence of prostate cancer. A maximum of two areas could be treated and were treated with at least 3–5 mm margins. Primary outcomes were feasibility, patient acceptability, and side-effect profile. Secondary outcomes were histological and imaging measures of cancer control. 41 men were treated with 49 % receiving unilateral one area ablation, 37 % receiving bilateral two area ablation, and 15 % receiving a midline one area ablation. Median PSA level at baseline was 6.6 ng/mL and at 12 months follow-up was 1.9 ng/mL. 39 patients had a biopsy at 6 months with a mean of 6 cores taken. mp-MRI at 6 months showed signs of residual cancer in the treated areas in nine men and was confirmed on biopsy in seven of them. Two men had negative mp-MRIs but positive biopsies. Both demonstrated clinically insignificant disease. Of the men with positive biopsies five chose active surveillance and four chose retreatment with HIFU. Of the 31 men with good baseline function 84 % achieved the trifecta status of being leak-free, pad-free, erections sufficient for intercourse, and with no evidence of clinically significant disease on mp-MRI at 12 months. Cryotherapy is another very common focal therapy technique and the largest cohort of patients treated with this modality was reported from the Cryo On-Line Database (COLD) registry (Ward and Jones 2012). Focal therapy to a portion of the gland was performed in 1,160 patients (47 % low risk and 41 % intermediate risk) with biochemical control (old ASTRO definition) at 36 months of 75.7 %. This is similar to the biochemical recurrence-free survival of patients treated with whole gland cryotherapy treatment at 75.1 %. Toxicity rates were either similar or better in the focal versus whole gland cryotherapy group: urinary incontinence 1.6 versus 3.1 %, new-onset erectile dysfunction 41.9 versus 67.6 %, rectourethral fistula 0.1 versus 0.4 %, urinary retention 1.2 versus 1.6 %. Definitive conclusions from this data are limited because of the lack of defined criteria for treating patients.