MRI Guided Transurethral HIFU for Various Prostate Diseases (HIFU-PRO)

Feasibility and Safety of Transurethral HIFU in Various Prostate Diseases; Particularly Prostate Cancer

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.

Localised Prostate Cancer, Locally Advanced Prostate Cancer, Locally Recurrent Prostate Cancer, Benign Prostatic Hyperplasia

prostate cancer, benign prostatic hyperplasia, benign prostatic obstruction, high intensity focused ultrasound, real-time temperature feedback control, magnetic resonance imaging

This study is an early phase 1 non-randomized prospective single-institutional and four arm study to determine the applicability, feasibility and safety of MRI guided transurethral HIFU ablation of prostate separately in each pre-specified group/arm (10 patients per group). Due to the encouraging feasibility and safety results, an amendment was made to the original study protocol to increase the amount of salvage group patients and BPH group patients. With the approval of the ethics committee, the sample size of the salvage group and BPH group was increased to a total of 40 patients and 30 patients, respectively.

MRI guided transurethral HIFU ablation is targeted to MRI visible, biopsy proven, index lesion(s) within prostate and if possible with 5mm angular extension (imaging based healthy tissue marginal) to both sides from the tumour boundary in transverse plane and 5 mm in coronal plane. The ablative effect is aimed to reach prostate capsule by heating the control boundary (3 mm from capsule) to temperature 57 °C. The focal approach is intended to be radical as for index lesion.

MRI guided transurethral HIFU ablation is targeted to main prostatic malignant tumour squeezing and/or invading the prostatic urethra and/or bladder neck. The approach is intended to be palliative.

MRI guided transurethral HIFU ablation is targeted to MRI visible, biopsy proven, local recurrent index lesion(s) within and/or surrounding prostate and if possible with 5 mm angular extension to either side from the tumour boundary in transverse plane and 5 mm in coronal plane. The approach is intended to be focal and salvage. The whole-gland HIFU ablation approach will be considered in case of extensive organ confined recurrent prostate cancer (positive biopsies for malignancy from extensive/multiple area in prostate and/or extensive/multiple lesion(s) at baseline MRI) to cover whole prostate.

MRI guided transurethral HIFU ablation is targeted to adenomas of the prostate. The HIFU sector encompasses bilateral (anterolateral) transitional zones between bladder neck and verumontanum (colliculus seminalis).

The technology is developed to ablate targeted benign and malignant prostate tissue through transurethrally inserted probe that transmit ultrasound energy under MRI guidance and control. The therapeutic endpoint of this method is thermal coagulation of prostate tissue.

Quantitative analysis of targeting accuracy is defined as spatial difference between target prostate region in treatment planning phase and the target temperature isotherm (57°C) at the end of HIFU treatment on MRI thermometry. The measure used is dice similarity coefficient (DSC - unitless from 0 to 1) which is a statistical validation metric to measure the degree of spatial overlap between two regions. The measure is a composite outcome measure reported as single value for each arm/group.

Quantitative analysis of targeting accuracy volume illustrates over- and under-treatment representing the amount of tissue ≥ target temperature 57°C outside the target volume and < target temperature 57°C inside the target volume, respectively. Over- and under-treatment volumes are expressed as a % of the target volume. The measure is a composite outcome measure reported as single value for each arm/group.

Quantitative analysis of radiologically verified treatment accuracy; determined by comparing targeting volumes on MRI during treatment planning to immediate, 1 and 3 week NPV in CE-MRI following HIFU therapy. The ratio in percentage (%) between target prostate volume (ml) and NPV (ml) will be measured.

Qualitative analysis of treatment accuracy; determined by comparing both targeting volume on MRI during treatment planning and immediate, 1 and 3 weeks NPV following HIFU therapy separately to histopathologically verified coagulation necrosis volume from the removed prostate at 3 week after HIFU therapy. The ratio in percentage between target prostate volume (ml) and NPV (ml) to coagulative necrosis volume (ml) will be measured.

Quantitative analysis of treatment accuracy; determined by comparing targeting volume on MRI during treatment planning to immediate, 1 week and 12 months NPV in CE-MRI following HIFU therapy. The ratio in percentage between target prostate volume (ml) and NPV (ml) will be measured.

Radiologically determined treatment accuracy of HIFU ablation in locally recurrent PC after EBRT arm/group.

Quantitative analysis of treatment accuracy; determined by comparing targeting volume on MRI during treatment planning to immediate, 1 week and 12 months NPV in CE-MRI following HIFU therapy. The ratio in percentage between target prostate volume (ml) and non-perfused volume (ml) will be measured.

Quantitative analysis of treatment accuracy; determined by comparing targeting volume on MRI during treatment planning to immediate, 1 week and 12 months NPV in CE-MRI following HIFU therapy. The ratio in percentage between target prostate volume (ml) and NPV (ml) will be measured.

Safety is determined in each group and all group together by evaluation of the frequency and severity of device/treatment related adverse events associated with the use of TULSA-PRO system to ablate prostate tissue. The severity of the adverse events are graded according to the Clavien-Dindo Classification of surgical complications. The measure is a composite outcome measure reported as single value for each arm/group.

Preliminary efficacy of HIFU ablation to achieve sufficient tumour control in patients having local recurrent PC after EBRT

Histopathological evaluation of the treatment response is based on 2-6-core biopsy results obtained from HIFU treated region/volume at 12 months. The number of biopsies taken is depended on the size and extension of the primary lesion treated with HIFU. The cognitive transrectal ultrasound guided biopsy method will be used to confirm histologically anticipated treatment success; coagulative necrosis/fibrosis/scar tissue of the prostate tissue. The outcome of biopsies (negativity/positivity for prostate cancer) will be measured. The proportion of patients with negative prostate biopsy will be measured at 12 months follow-up visit.

Evaluation and characterisation of image based follow up with repetitive mpMRI (Arm/group 1: immediate, 1 and 3 week, Arms/Groups 2, 3 and 4: immediate, 1 week, 12 month) after HIFU treatment. Image based follow up will be focused on modifications and development of the rim of enhancement surrounding NPV and the evolution of NPV following HIFU treatment.

Preliminary efficacy of MRI guided transurethral HIFU ablation in locally recurrent PC after EBRT in terms of serum PSA response.

Explore and characterise short- and medium-term pattern of S-PSA response following HIFU ablation. Serum PSA will be measured before HIFU ablation and predetermined interval during follow up protocol after HIFU ablation. The serum PSA trend and nadir following HIFU ablation will be demonstrated.

Evaluate voiding function by using uroflowmetry before and after HIFU ablation separately in each arm/group.

Voiding function is assessed separately in each group/arm by: - measuring the rate of flow of voided urine using a flowmeter, a device that measures the quantity of urine (volume) voided per unit time (uroflowmetry). The measurement is expressed in millilitres per second (ml/s). The data from uroflowmetry before and after HIFU ablation will be compared.

Evaluate voiding function by measuring PVR before and after HIFU ablation separately in each arm/group.

Voiding function is assessed separately in each group/arm by: - post-voided residual urine (PVR) (volume in ml), which estimates the completeness of bladder emptying using a handheld ultrasonic bladder scanner. The PVR before and after HIFU ablation will be compared.

Evaluation of QoL using standardised questionnaire: - 26-item short-form version of EPIC, The Expanded Prostate Index Composite QoL questionnaire before and after HIFU ablation are compared. The measure is a composite outcome measure reported as single value for each arm/group.

Quality of life questionnaire, International Prostate Symptom Score (IPSS), is used to assess urinary symptoms following HIFU therapy. IPSS consists of seven question concerning urinary symptoms (points from 0 to 5) and one separate question concerning quality of life (points from 0 to 6). The total score of questions related to urinary symptoms can range from 0 to 35. The baseline IPSS score is compared to IPSS scores obtained from predetermined follow up protocol following HIFU therapy to characterise HIFU therapy´s short- (1 week, 3 and 6 months) and medium-term (12 months) impact on lower urinary tract function. A significant change in IPSS is defined as a change of > 3 points. The change in total points of IPSS between baseline and most recent follow up visit is measured.

Quality of life questionnaire, International Index of Erectile Function (IIEF-15), is used to assess sexual function following HIFU therapy. A score of 0-5 is awarded to each of the 15 questions that examine 4 main domain of male sexual function: erectile function, orgasmic function, sexual desire and intercourse satisfaction. Change in total score and each domain of IIEF-15 separately are measured between the baseline and most recent follow-up visit.

The pain is assessed predetermined interval during follow up using Visual Analog Scale for pain (VAS for pain, numerical rating scale 1-10). The measure is a composite outcome measure reported as single value for each arm/group.

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

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