MRI Guided Transurethral HIFU for Various Prostate Diseases

This study assesses feasibility and safety, the primary outcomes, of MRI guided transurethral high intensity focused ultrasound (HIFU) ablation for prostate diseases (PD). We will enrol 10 patients to each group with criteria as follows: localised prostate cancer (PC); locally advanced PC; locally recurrent PC after external beam radiation therapy (EBRT); benign prostatic hyperplasia (BPH). Secondary outcomes are both oncologic and functional outcomes and imaging based follow up after HIFU therapy will be also assessed.

Prostate cancer (PC) is the most common cancer among men in Finland with the highest incidence of all cancers. Benign prostate hyperplasia (BPH) also has high prevalence, increasing with age. BPH may cause harmful lower urinary tract symptoms (LUTS) and it is demonstrated that by the age of 60, over 50 % of men have clinically significant prostate BPH and up to 40 % of men over age 60 suffer from LUTS.

Currently curative intended therapies for PC, radiation therapy (RT) and radical prostatectomy (RP), offer desirable oncologic local control but have major impact on genitourinary function and quality of life (QoL). Some patients are unfit for surgical procedures or cannot tolerate RT due to concomitant medical conditions or prior therapies. At present lower risk PC is increasingly managed with active surveillance. However, diagnosis of PC and active surveillance itself may both lead to notable psychological and emotional burden impairing QoL. Further, significant amount of cases in some point end up in radical treatment resulted from either risk profile upgrade or patients preference. For these patients optimal treatment might be a focal therapy with sufficient oncologic control and minor impact on QoL.

There is controversy related to optimal treatment in local recurrence after RT. 45% of patients will have local recurrence after RT within 8 years after treatment. Androgen deprivation therapy (ADT) decelerate disease only temporarily and salvage RP includes major risks and is technically demanding, but can provide long-term cure in selected patients.

On the aspect of palliation, there is an eminent need for less invasive supplementary therapies since patients presenting with metastatic or locally advanced PC, generally have low performance status.

Management of benign prostatic obstruction has also faced challenges with conventional treatment modalities, since ageing and profuse co-morbidities among patients have increased. Transurethral resection of prostate (TURP) is still the standard treatment in severe LUTS caused by BPH.

Recently the major development of magnetic resonance imaging (MRI) has been achieved improving PC diagnosis and local staging. Even though PC is often multifocal, evidence indicates that both clinical outcome and prognosis of PC is determined predominantly by index lesion. Because of the notable risk of morbidities involving radical treatments and significant evolution of MRI, focal therapies have attained wide interest. One of the most interesting focal mini-invasive treatment is high intensity focused ultrasound (HIFU). HIFU technique exploits thermal energy; by raising target temperature over 55°C target volume is destroyed due to acute coagulation necrosis. Modern devices delivering HIFU to the prostate are transurethral and emit directional high intensity ultrasound to the focused regions utilising superior MRI guidance compared to older generation ultrasound guidance. Magnetic resonance thermometry technique utilizes noninvasive measurement of tissue temperature allowing monitoring real time temperature changes during treatment. The MRI treatment system is equipped with active dynamic temperature feedback control designed to maintain a constant temperature inside the target volume and at the boundary of the target area. By this way conformal three-dimensional ablative volumes with great spatial accuracy and precision can be achieved simultaneously avoiding damages to the surrounding sensitive tissues. Therapy verification is confirmed instantaneously after treatment by acquiring contrast enhanced MRI (CE-MRI) that visualise the non-perfused-volume (NPV) describing the success of total ablation of the target prostate volume.

This prospective clinical single center feasibility and safety study will evaluate the role of MRI guided transurethral HIFU ablation for various PD and clinical settings. All enrolled patients have prostate pathology and different clinical situation with need of definitive interventions and they are divided to four arms/groups according to specific inclusion criterion. Group 1 localised PC prior to RP, group 2 symptomatic locally advanced PC in need of palliative surgical intervention, group 3 locally recurrent PC after EBRT and group 4 symptomatic BPH in need for intervention.

The hypothesis is that MRI guided transurethral HIFU is feasible and safe in various prostate diseases and clinical settings. If hypothesis is proven for certain or for all groups, the investigators will continue with that group or groups to phase 2 clinical multi-institutional studies.

Eligibility Criteria:
Shared inclusion criteria for all groups:

* Language spoken: Finnish, English or Swedish
* Mental status: Patients must be able to understand the meaning of the study
* Informed consent: The patient must sign the appropriate Ethics Committee (EC) approved informed consent documents in the presence of the designated staff.
* Potential prostate biopsies obtained \> 6 weeks before HIFU/TULSA-PRO treatment (or at the discretion of PI)
* Eligible for MRI
* Eligible for spinal or general anesthesia (ASA 3 or less)
* Succession of urethral catheterization/Patency of prostatic urethra confirmed if needed with pre-HIFU cystoscopy

Group-specific inclusion criteria

Group 1. Localized PC prior to RP

* All localized PC patients planned for robot assisted laparoscopic prostatectomy (RALP) with normal standards of care are eligible for this study (EAU guidelines)
* MRI-visible biopsy proven PC (biopsies obtained \< 6 months before treatment)

Group 2. Locally symptomatic locally advanced and/or metastatic prostate cancer in need of palliative surgical intervention

* gross recurrent hematuria
* bladder outlet obstruction with intractable symptoms
* urinary retention

Group 3. Locally recurrent PC after EBRT as a salvage approach

* Phoenix criteria of biochemical relapse (PSA nadir + 2 ng/ml)
* MRI-visible, biopsy proven local recurrence
* No evidence of distant metastasis in PSMA-PET/CT

Group 4. Symptomatic BPH with need for intervention

* Patients planned for surgical procedure (e.g. TURP, laservaporization or open adenomectomy) with normal standards of care are eligible for this study
* Bilobular hyperplasia (enlarged transition zone lobes) without dominant enlargement of periurethral zone "median lobe" assessed in cystoscopy and TRUS
* No suspicion of cancer on baseline MRI (PI-RADS v2 lesion \< 3)

Shared exclusion criteria for all groups:

* Prostate calcifications \>1cm in largest diameter located in the anticipated treatment sector on baseline TRUS or MRI
* Prostate cysts \>1cm in largest diameter located in the anticipated treatment sector on baseline TRUS or MRI
* History of chronic inflammatory conditions (e.g. inflammatory bowel disease) affecting rectum (also includes rectal fistula and anal/rectal stenosis)
* Contraindications for MRI (cardiac pacemaker, intracranial clips etc.)
* Uncontrolled serious infection
* Claustrophobia
* Hip replacement surgery or other metal in the pelvic area
* Severe kidney failure (glomerular filtration rate (GFR) \<30ml/min/1.73m2) exclude usage of gadolinium in contrast-enhanced imaging unless justifiable based on the clinical judgment of the responsible radiologist and/or urologist.
* Known allergy to gadolinium
* Known allergy or contraindication to GI anti-spasmodic drug (e.g. glucagon, buscopan)
* Inability to insert urinary catheter (i.e. urethral stricture disease)
* Patients with artificial urinary sphincter, urethral sling or any penile implant
* Any other conditions that might compromise patient safety, based on the clinical judgment of the responsible urologist