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FOCAL THERAPY Transurethral Ultrasound Ablation as a Promising Focal Therapy Option for Prostate Cancer

By: Joseph Chin, MD, FRCSC, Western University, London, Ontario, Canada; Xiaosong Meng, MD, PhD, University of Texas Southwestern, Dallas; Stephen Scionti, MD, Scionti Prostate Center, Sarasota, Florida; Laurence Klotz, MD, FRCSC, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada | Posted on: 09 Jun 2023

Magnetic resonance imaging (MRI)–guided transurethral ultrasound ablation via the transurethral ultrasound ablation (TULSA)-PRO device (Profound Medical, Mississauga, Canada) has emerged as a promising new option for targeted treatment of localized prostate cancer (PCa). This technology was developed at Sunnybrook Health Sciences Centre in Toronto and is based on a closed-loop control system using real time thermal mapping (a standard MRI feature). Practically, this means the amount of energy delivered to a specific slice of tissue is precisely determined by the tissue temperature achieved during the procedure. The goal is to heat all tissue in the target region to 57 °C, a temperature that is 100% lethal to epithelial cells. TULSA integrates quantitative image-based planning, monitoring, and treatment control with transurethral delivery to ablate prostate tissue through thermal coagulation via 10 ultrasound transducers that emit directional (planar, not focused) ultrasound energy into the adjacent prostate.1 These ten 5-mm transducers correspond to ten 5-mm MRI slices, each of which is imaged continuously throughout the procedure. TULSA combines the diagnostic, visualization, and real-time thermal dosimetry capabilities of MRI with the accuracy of feedback-controlled ultrasound ablation, and delivers ablative treatment, tailored to patient-specific anatomy and pathology.

The development of this technology began around 2000, with in silico and gel studies followed by canine acute treat-and-resect and chronic studies.2 This led to a first-in-man treat-and-resect study in 15 patients, who were treated to a defined region immediately prior to radical prostatectomy.3 These studies demonstrated that the accuracy of targeting was ± 1.5 mm, and the distance between ablated and healthy unaffected tissue was 1.3 mm. Subsequently, the first primary ablation Phase 1 trial of 30 low-risk patients was conducted in London, Canada; Heidelberg, Germany; and Royal Oak, Michigan,4 and then a 13-center Phase 2 study (including Toronto and London, Canada, plus 11 U.S. sites) on 115 patients with low- and intermediate-risk disease.5 The intent was subtotal ablation, with a clinical safety end point. The ablation volume was contoured on intraprocedural magnetic resonance images intentionally sparing a 3-mm rim of prostate tissue, thus leaving about 10% of the prostate volume untreated. This study reported no severe adverse events. Urinary and bowel function remained stable from early on. Erectile function recovered by 1 year and was stable at 3 years. The PSA level decreased 95% to a median nadir of 0.33 ng/mL, and was stable to 0.8 ng/mL at 3 years. Serial biopsies identified clinically significant disease in 34% and “any cancer” in 59%, in large part due to the study design on restricted treatment target volume. In the Phase 2 study, median PSA reduction was also 95% and median nadir was 0.34 ng/mL. Of 111 men with 12-month biopsy data, 65% had no evidence of cancer. Notably, the treatment was accompanied by a 90% volume reduction as measured by pre- and posttreatment MRI, from a median of 40 to 4 mL posttreatment. Among a subset with pretreatment Grade Group (GG) 2 disease, 79% were free of ≥GG2 disease. Erectile function was maintained or eventually regained in 75%. Five-year and 4-year oncologic and functional follow-up data are available from the Phase 1 and 2 patients, respectively, showing maintenance of response trends.6 At 4 years, 16% of patients required salvage therapy.

Most patients with intermediate-risk disease are candidates for TULSA and comprised about 75% of the patients undergoing TULSA last year. The remainder was split between men undergoing salvage ablation for local recurrence after radiation or other ablation modalities, men with low-grade disease and concurrent lower urinary tract symptoms, and select men with well-characterized GG4 disease (data provided via Profound). Contraindications include tight urethral strictures (preventing insertion of the 19F urethral applicator), inability to undergo MRI due to anatomic issues or implanted devices, prostatic calcifications >3 mm in the area of the index cancer, and a distance from the lateral margin of the urethra to the target margin of >3 cm. One of the benefits of TULSA is the ability to tailor the extent of treatment based on the disease and patient considerations, ranging from focal to hemi-ablation to whole-gland, with roughly half of the treatments in the U.S. last year categorized as whole-gland. Figure 1 is an example of ablation of a right anterior transition zone lesion at apex to mid gland, sparing the apical sphincter, neurovascular bundles, and bladder neck. Figure 2 depicts a right anterior transition zone lesion from mid gland to base, ablated focally from 9 o’clock to1 o’clock, sparing apex and neurovascular bundles. TULSA can be flexibly adapted to treatment of patients with multifocal disease, or concurrent ablation of the transition zone in men with prostatomegaly and lower urinary tract symptoms.7

Figure 1. Sixty-year-old male with PSA 10.6 ng/mL, 53 cc prostate, Prostate Imaging Reporting & Data System 5 lesion in right anterior transition zone with 5/14 cores positive for Grade Group 2 disease at the right apex and right mid gland. Normal erectile function, moderate lower urinary tract symptoms. A, Planning images of anterior ablation including lesion and transition zone with sparing of apical sphincter, neurovascular bundles and bladder neck. B, Maximum (Max) temperature map demonstrating achievement of target temperature in the ablation zone. C, Posttreatment contrast enhanced (CE) MRI with corresponding ablation cavity for treatment plan.

Figure 2. Forty-nine–year-old male with PSA 6.3 ng/mL, 30 cc prostate, Prostate Imaging Reporting & Data System 5 lesion right anterior transition zone, right mid gland to base. Transperineal fusion biopsy: Grade Group 2 disease in region of interest only. Normal erectile function, mild lower urinary tract symptoms. Focal ablation 9 o’clock to 1 o’clock. A, Treatment planning images of focal ablation zone sparing apex, neurovascular bundles. B, Maximum temperature map demonstrating excellent temperature coverage in ablation zone. C, Thermal dose map demonstrating concordance of effective thermal dose and maximum temperatures. D, Posttreatment contrast-enhanced MRI images confirming ablation zone.

TULSA is theoretically appealing as a salvage therapy for patients with local failure post-irradiation (Figure 3). Because no energy is directed through the rectum, and anatomic tissue temperature control is precise, TULSA appears to reduce the risk of prostato-rectal fistula and incontinence risks. To date, no prostato-rectal fistulae have occurred in over 3,000 patients treated for primary PCa worldwide. Currently, aside from anecdotal reports, there is only a single case series of post-irradiation TULSA, in 11 patients, reporting no significant adverse events. Eradication of disease in the treated zone occurred in 10/11 patients.8 While further validation is required, this appears to be an attractive option for the radio-recurrent patient cohort.

Figure 3. Sixty-three–year-old male with history of external beam radiotherapy in 2015 for Grade Group 3 prostate cancer (initial PSA 6.7 ng/mL, PSA nadir 0.6 ng/mL). Had progressive rise in PSA in 2018 from 2.2 ng/mL to 17 ng/mL in 2022. Workup with prostate MRI demonstrated Prostate Imaging Reporting & Data System 5 lesion at the right base anterior peripheral zone extending into anterior transition zone. Concordant prostate-specific membrane antigen positron emission tomography (PSMA PET)/CT without evidence of metastatic disease. Biopsy proven recurrent Grade Group 3 disease. A, Workup demonstrating recurrent lesion on PSMA PET/CT and multiparametric prostate MRI. B, Near whole gland treatment plan with sparing of bilateral neurovascular bundle (NVB). Maximum temperature and thermal dose map of treatment. Note effects of fiducial markers on thermometry data. Posttreatment contrast-enhanced MRI with corresponding ablation zone from near whole gland ablation. DCE indicates dynamic contrast-enhanced; DWI, diffusion-weighted imaging.

TULSA may also have a role in the treatment of patients with marked prostatomegaly. In one study of 11 men with a mean prostate volume of 53 cc, International Prostate Symptom Score improved by 82% and maximum flow rate by 101%.9 This corroborated with the significant prostate volume reduction (90%) observed in the aforementioned Phase 2 study. Five of 6 men preserved antegrade ejaculation.

Limitations of TULSA include the technical complexity and potential for prolonged treatment time (up to 4-5 hours). However, experience to date suggests that with streamlined workflow from practice, appropriate patient selection, and preparation, treatment time decreases considerably to 2-3 hours.

TULSA is a new technology with several potential advantages over existing alternatives. A randomized trial comparing TULSA to radical prostatectomy is currently underway, and should provide further evidence for the emerging role of this treatment modality.

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