Transperineal Targeted Microwave Ablation (TMA) of localized prostate cancer guided by MRI-Ultrasound fusion and organ-based tracking: a pilot study

To investigate the efficacy of transperineal targeted microwave ablation (TMA) in treating localized prostate cancer (PCa). This is a single-centre prospective phase 2 trial recruiting men with low to intermediate-risk localized PCa to undergo transperineal TMA. TMA was performed with MRI-Ultrasound fusion guidance and organ-based tracking. A per-protocol 6-month MRI and biopsy were performed for all patients. The primary outcome was any cancer detected on biopsy of each ablated area. Secondary outcomes included per-patient analysis of positive biopsy, complications, urinary symptom score, erectile function and quality of life (QOL) scores. In the first 15 men, 23 areas were being treated. The median age was 70 years, number of TMA ablations were 5 (range 2–8), and the total ablation time and operating time was 22 (IQR 14–28) and 75 (IQR 65-85) minutes, respectively. PSA level dropped from a median of 7.7 to 2.4 ng/mL. For the primary outcome, 91.3% (21/23) ablated area had no cancer in 6-month biopsy. In per-patient analysis, 33.3% (5/15) had in or out-of-field positive biopsy at 6 months. Among these five cases, four of them were amenable to active surveillance and 1 (6.7%) case with out-of-field ISUP grade group 2 cancer received radiotherapy. The urinary symptoms, uroflowmetry, erectile function, and QOL scores had no significant difference at 6 months. One patient (out of five patients with normal erection) in the cohort complained of significant worsening of erectile function after TMA. Grade 1 complications including hematuria (33.3%), dysuria (6.7%), and perineal discomfort (13.4%) were observed. In this first pilot study, transperineal TMA guided by MRI-Ultrasound fusion guidance and organ-based tracking was shown to be effective, safe, and easily applicable in men with localized PCa.


INTRODUCTION
Prostate cancer is the second most common male cancer worldwide and contribute to a significant proportion of cancer death and disease burden.As the diagnosis of prostate cancer is based more and more on MRI prostate-guided biopsies, the chances of diagnosing prostate cancer in a focal region have increased considerably.Although radical prostatectomy and radiotherapy are still the two most recommended first-line treatments for localized clinically significant prostate cancer [1], the long-term treatment-related adverse events of these treatments including erectile dysfunction, urinary incontinence, irradiation cystitis and irradiation proctitis can significantly reduce the quality of life.In men diagnosed with low-risk prostate cancer, active surveillance (AS) is a recommended management option in order to safely defer radical treatment and its harms [1][2][3].
Focal therapy has emerged as a middle ground between active surveillance and radical treatment for men with focal low to intermediate-risk prostate cancers.The treatment-related adverse events of various focal therapies like high-intensity focused ultrasound (HIFU) and cryotherapy were significantly less than radical treatment, and a significant proportion of patients can remain free from radical treatment for many years.Although local recurrence rate can reach up to 30-40% in the long run, most of these recurrences were amenable to repeated focal treatment and only a small proportion requiring radical treatment.Cohorts with follow-up time up to 8 years have shown up to 85-90% radical treatment-free survival [4].A propensity score weighted comparison of radical treatment versus focal therapy showed that 6 to 8-year cancer control of low to intermediate-risk prostate cancers were similar [5,6].Therefore, focal therapy is definitely an option for well-selected patients with strong desire for preservation of continence and sexual function [7].As robust data comparing focal therapy with standard treatments like radical prostatectomy or radiotherapy is lacking, the EAU guidelines for prostate cancer recommend focal therapy to be performed in the context of a clinical trial setting or well-designed prospective cohort study.
Targeted microwave ablation (TMA) is a new form of focal therapy for prostate cancer delivered via precise needle ablations using microwave energy.Precise TMA needle ablations are enabled under MRI-Ultrasound fusion guidance and Organbased tracking mechanism similar to that in fusion prostate biopsy.There was only one pilot study published on the safety and feasibility of transrectal microwave needle ablations in 10 cases, showing that the necrosis region on 7-day MRI corresponded well to the predicted ablation zone [8].
This study is the first phase 2 clinical trial investigating early oncological and functional outcomes of transperineal Baseline demographic data and parameters were collected before and after treatment up to 1 year.Serum PSA, urine culture, and various questionnaires including The Expanded Prostate Cancer Index Composite (EPIC-26), International Prostate Symptom Score (IPSS), the International Index of Erectile Function short form (IIEF-5), and Quality of Life assessment questionnaires: EuroQol-5 Dimension (EQ-5D) and EORTC QLQ-C30 were assessed at baseline and at 1 month, 3 months, 6 months and 12 months after TMA.Uroflowmetry was performed at baseline and at 1 month, 6 months, and 12 months after TMA.MRI prostate with contrast was performed at 7-14 days and 6 months after treatment.
A compulsory per-protocol MRI-Ultrasound fusion transperineal prostate biopsy was performed for every patient at 6 months guided by 6-month MRI scan, including targeted biopsies to prior treated area (whether or not there is MRI evidence of recurrence) and any new lesion, followed by 18-core systematic biopsies.
The primary outcome was any cancer detected on biopsy of each ablated area 6 months after treatment.The secondary outcomes included per-patient analysis of any cancer detected on biopsy at 6 months, any cancer detected on biopsy of MRI-visible and MRI-invisible lesion at 6 months, out-of-field cancer detection on systematic biopsy at 6 months, and complications of treatment using Common Terminology Criteria for Adverse Events (CTCAE).
Targeted Microwave Ablation (TMA) treatment TMA was performed under general or spinal anaesthesia with the patient placed in lithotomy position (Fig. 1).The Biomedical TATO3® Microwave needle thermoablation (Koelis, Grenoble, France) was performed under Organ-based Tracking® (OBT) mechanism of the Koelis Trinity® machine.Both Koelis Trinity and TATO3 were CE (European Conformity) marked in Europe.A transrectal sideview ultrasound probe was used for real-time imaging and tracking of the prostate.
The 17G Microwave needle was inserted transperineally via a full (brachytherapy) grid or mini-grid (Fig. 1).The Microwave needle was directed to the target under MRI-Ultrasound fusion OBT guidance with predicted treatment zone shown on the screen before the start of treatment.(Fig. 1) The MRI-visible lesion(s) and MRI invisible lesions mapped on organ-based tracking technology during fusion biopsy were treated.The treatment time was 1.5-5 min per ablation zone at the power of 12 W (Fig. 2), with sequential ablations using a single microwave needle [9].Targeted focal ablation of the index lesions in the prostate was performed with 5-10 mm intra-prostatic margin from the lesion border.A Foley urethral catheter was routinely inserted after TMA.All patients were discharged within 24 h from treatment.

Statistical analyses
The data related to the patient and perioperative parameters and outcomes were analyzed using IBM SPSS Statistics 26.0 (Chicago, Illinois, US).Descriptive statistics were used to characterize the demographic data and perioperative patient characteristics.Comparison of continuous data between pre-operative and post-operative was done with paired T test or ANOVA if the data was normally distributed or with Mann-Whitney U test or Kruskal-Wallis test if the data was ordinal or skewed.

RESULTS
Between October 2019 to March 2021, 17 men with prostate cancer (PCa) who fit the inclusion and exclusion criteria were offered TMA.Two cases were excluded from analysis due to patient withdrawal from study before treatment, and both eventually received radical prostatectomy.Fifteen patients received TMA treatment and were included in analysis, with seven patients having one lesion and eight patients having two lesions.The first 15 patients included 10 intermediate and 5 lowrisk (with lesion size ≥6 mm) PCa patients.The baseline mean and median PSA was 8.2 (standard deviation, SD, 3.6) and 7.7 (interquartile range [IQR] 5.6-11.4)ng/mL, respectively.The median MRI lesion size was 9.5 (IQR 5.0-13.0)mm.The baseline characteristics were shown in Table 1.
A total of 23 areas were being treated in 15 patients, of which 20 were MRI-visible and 3 were MRI-invisible (PI-RADS 1) and mapped on systematic biopsy using organ-based tracking technology.(Table 2) The median number of microwave needle ablations was 5 (range 2-8), and the median total ablation time and operating time were 22 (IQR 14-28) and 75 (IQR 65-85) min, respectively.Brachytherapy grid was used in the first 10 cases, and the Minigrid was used in the last 5 cases.(Fig. 1) All patients were discharged same day or within 24 h after treatment.Foley catheter was kept for a median of 7 days (IQR 4-7 days).A multiparametric MRI prostate scan was done at 6 months for all patients, and a per-protocol MRI-Ultrasound fusion transperineal biopsy was performed for all patients at 6 months including treated areas, new lesion areas, and systematic biopsies.The median total core number of 6-month biopsy was 22 (IQR 20-24) cores.

Primary outcome
For the primary outcome of any cancer at 6 months in treated area, 91.3% (21/23) had no cancer.(Table 2) The two cases with cancer detected on 6-month biopsy were the first (TMA001) and third patient (TMA003) in the cohort.Patient TMA001 had 6-month MRI showing contrast-enhancing small lesion at the lateral edge of the treated tumor, and biopsy showed 4 mm ISUP grade group 1 cancer.Patient TMA003 had 1 mm ISUP grade group 1 cancer in treated area.

Secondary outcomes
For the secondary outcomes, the PSA level dropped from a median of 7.7 to 2.4 ng/mL (68.8% reduction by median, paired t test, p < 0.001).Out-of-field cancer at 6-month biopsy was detected in 5 out of 15 patients, and only one of them (TMA011) was ISUP grade group 2. (Table 2) Two (TMA003, TMA011) of these five patients had a single new MRI lesion far away from the treated area and biopsy reviewed ISUP grade group 1 (5 mm) and 2 (6 mm), respectively.Patient TMA003 should be feasible for active surveillance or repeated focal therapy, but patient opted for radical prostatectomy.Patient TMA011 had new ISUP grade group 2 lesion and received external beam radiotherapy.The other three patients had systematic biopsies in nontreated areas showing small foci of ISUP grade group 1 cancers and were put on active surveillance.In per-patient analysis, only 6.7% (1/15) patients with ISUP grade group 2 in a new MRI lesion were indicated for repeated treatment.There was no statistically significant change in urinary symptoms (IPSS and QOL), uroflowmetry (maximal flow rate [Qmax]), erectile function (IIEF-5), and in other quality of life assessments including EPIC-26, QLQC-30, and EQ5D at 6 months.(Table 1) The median prostate volume estimated on MRI prostate scans reduced significantly from 35.6 to 27.0 ml (paired t test, p < 0.001) at 6 months.

Complications
Mild visible hematuria (grade 1) after TMA was observed in 33.3% (5/15) patients, and all subsided within 14 days without the need of medical attendance.Dysuria (Grade 1) was reported by 6.7% (1/ 15) patients and lasted for 14 days.Perineal discomfort (Grade 1) was reported by 13.4% (2/15) patients and lasted for 14 and 30 days.In terms of erectile dysfunction, 66.7% (10/15) patients had pre-operative erectile dysfunction that failed penetrative sex.Among the five patients with preoperative erectile function adequate for penetrative sex, one of them had significant worsening of erection function which required PDE5 inhibitors.

DISCUSSION
This is the first phase 2 trial on the efficacy of transperineal TMA in treating localized prostate cancer, and this paper described the outcome in the first 15 patients.In terms of treatment efficacy in treated area, 91.3% (21/23) treated areas had no cancer on 6-month MRI and 3-core biopsy at treated area, and the two patients with in-field recurrence showed ISUP grade group (GG) 1 cancers (4 mm and 1 mm).No ISUP GG ≥ 2 cancer or high volume (≥6 mm) ISUP GG 1 cancer was found in treated areas.
There was only 1 out of 15 (6.7%) patients who had 6-month biopsy showing a ISUP grade group 2 recurrence which was out of treatment field.Overall, there was 33.3% (5/15) patients with outof-field recurrence at 6-month biopsy.In per-patient analysis, four out of five recurrences were suitable for active surveillance (AS), and one of the four men opt for radical prostatectomy instead of AS or repeated focal therapy.The men with a new 5 mm MRI lesion at a non-treated area showing ISUP GG2 tumor was amendable for repeated focal treatment but the patient opted for radiotherapy.
The positive biopsy rates in this study were comparable to different series using various focal therapies [10].A large HIFU series with 625 patients by reported negative in-field follow-up biopsy rate of 75% (56/222) [11], compared with 48% in a cryotherapy series [12], 76% in an irreversible electroporation series [13], and 76% in a vascular-targeted photodynamic therapy series [14].
One prior feasibility study on transrectal microwave needle ablation of prostate cancer showed that the technology was safe and the post-treatment MRI changes corresponded well to the predicted treatment zones [8].The quoted pilot study used mainly 1 needle ablation per patient, and therefore minimal margin was achieved.Further, there was also no dedicated navigation software to guide needle ablation.
In the current study, a dedicated navigation software using organ-based tracking mechanism is available in the Koelis Trinity machine (Koelis, Grenoble, France), combining elastic fusion and live needle tracking between every needle insertion as in usual fusion biopsy.Therefore, the microwave needles can be directed to the planned site with high level of precision (<2 mm error) with needle position confirmed again before the actual ablation [15].The navigation software also provides a predicted treatment zone on live 3D ultrasound image according to the selected ablation time (1.5, 2, 3, 4, or 5 min).This allows the operator to visualize the treatment zone before actual ablation and avoid damage to vital structures like rectum and external urinary sphincter.
A 5-10 mm intra-prostatic margin of the MRI-visible tumor was achieved with repeated needle ablations.This was made feasible with the relatively short microwave ablation time (a few minutes per ablation), software recording of each needle and ablated zone, and easy navigation using MRI-Ultrasound fusion guidance.In addition to the MRI-visible lesions that can be marked with the navigation software, the MRI-invisible positive cores which were diagnosed on mapping systematic biopsy done with the same fusion system could be shown on the treatment screen.With sequential needle ablations, the treatment zone can be easily sculpted to fit tumors of different sizes and locations and to cover the desired margin.The surgeon would have minimal resistance to add one more ablation as the additional time is just a few minutes.
Both brachytherapy grid and mini-grid can be used to guide TMA needles during treatment.Using a brachytherapy grid can reach most sites in a relatively small prostate, but for anterior lesions which are at midline or very close to midline, risk of bulbous urethral injury can be an issue.For anterolateral lesions in a larger prostate, the pubic bone interference may prevent the needle from reaching the most optimal site.With a mini-grid, each TMA needle can be inserted from a different angle by deviating the TRUS probe before each ablation, for example, by inserting the  needle from lateral to medial for an anterior midline lesion (Figs.1b, 3c, d) to avoid hitting the bulbous urethra.The authors prefer using the mini-grid as it is more versatile.During TMA, hyperechoic ultrasound changes similar to the "pop-corn" phenomenon during HIFU focal therapy were observed in the predicted treatment zone, and this could serve as a visual guide to the extent of treatment.When the ultrasonic changes in the treatment zone extends near to the posterior prostate capsule, hydrodissection could be performed by injecting cold saline using a spinal needle, via lower grid holes, to the space between prostate and rectum.The ablation time (22 min) and total operating time (75 min) of TMA were shorter than most HIFU or cryotherapy treatment, and four TMA cases can be comfortably done within one operating day.Hopefully, these early experiences on the use of TMA can provide some insights and set a standard for subsequent TMA treatment in the future.
Among the 15 patients in the current cohort, 10 had intermediate risk disease, and 5 had low risk disease.In the 5 low-risk disease patients (Table 2), the lesion sizes were 15 mm (Patient 1), 2 lesions of 5 mm each (Patient 3), 10 mm and 13 mm lesions (Patient 4), 9 mm (Patient 12), and 14 mm (Patient 13).Therefore, although the five patients had ISUP grade group 1 disease, most of them had significant tumor volume or involvement of more than 1 area in the prostate.While most low-risk patients are encouraged to have active surveillance in our centre, the five patients in this cohort requested active treatment instead, and therefore focal therapy was discussed among radical treatment options.
Most of the cases in this series were mid to anterior tumors, and among them the prostatic urethra on one or even both lobes was within the ablated area.Light hematuria persisted for 1 to 14 days in five patients, and none of them required additional medical attendance or Foley catheter insertion.This appeared to be similar to the duration of gross hematuria after fusion prostate biopsy for para-urethral lesions.Only 1 patient had mild dysuria for 14 days which did not require analgesics.All 15 patients had similar IPSS, IPSS-QOL and Maximal flow rate at 6 months compared to baseline, and there was no suspicion of bladder neck stenosis.
There was no de-novo incontinence in all patients.For erectile function, the IIEF-5 score had no significant deterioration, and only one out of five patients who could perform penetrative sex before treatment reported worsening of erectile function after treatment.As erectile function may improve beyond 6-12 months after radical prostatectomy, the authors are keen to follow-up the patient further to see if erection function will improve in the future.Nevertheless, the sample size of patients with preoperative normal erection was too small to draw a conclusion on the effect of TMA on erectile function, and studies on TMA with larger sample size and longer follow-up are awaited.Before these data are available, patients should be warned that TMA can still cause erection dysfunction in a small proportion of patients.Quality of life measures including EPIC-26, QLQ-C30, and EQ5D were similar before and 6 months after treatment.
The strengths of the study include the first pilot study to evaluate treatment efficacy in transperineal TMA treatment for localized prostate cancer, and compulsory per protocol MRI and MR-guided biopsy at 6 months.Limitation includes the lack of longer-term data on oncological and functional outcomes.
In conclusion, from the first 15 cases in this first trial of transperineal TMA, TMA guided by MRI-Ultrasound fusion guidance and organ-based tracking was shown to be effective, safe, accurate, and easily applicable in men with localized prostate cancer.

Fig. 2
Fig. 2 Size of microwave ablation treatment zone in relation to ablation time.

Fig. 3
Fig. 3 Targeted microwave ablation (TMA) treatment.A Ultrasound image Before TMA treatment.B Ultrasound image at the end of a 5-min TMA treatment, C Recording of ablated zone after 1 treatment, D Recording of multiple sequential TMA treatment zones.E Post-TMA 1-week MRI T2W image showing needle tracks.F Post-TMA 1-week contrast MRI image showing ablated region.
TMA treatment in low to intermediate-risk focal prostate cancer.Here we report the outcomes of the first 15 cases in this trial.METHODOLOGYThis is a single-centre prospective phase 2 trial recruiting men with localized prostate cancer to undergo focal treatment in the form of Targeted Microwave Ablation (TMA).The study was conducted according to the Declaration of Helsinki.Approval from The Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (CREC 2019.347) and registration in Clinicaltrials.gov(NCT04113811)were done before recruitment of the first patient.Study consent was obtained before inclusion and consent to use intraoperative videos and photos have been obtained before the procedure.The inclusion and exclusion criteria are listed below:

Table 1 .
Patient characteristics at baseline and 6-month after treatment.

Table 2 .
Per-lesion prostate tumor characteristics on MRI and biopsy at baseline and at 6-month after targeted microwave ablation (TMA).