EvaluatioN of HIFU Hemiablation and Short Term AndrogeN Deprivation Therapy Combination to Enhance Prostate Cancer Control.

• ClinicalTrials.gov Identifier: NCT03845751
• Recruitment Status: Unknown
• First Posted: February 19, 2019
• Last Update Posted: September 27, 2019
• Sponsor: Institut Mutualiste Montsouris
• Collaborator: University of Turin, Italy
• Information provided by (Responsible Party): Institut Mutualiste Montsouris

Study Description

Brief Summary:

The current study aims to examine the hypothesis that combining the focal effects of HIFU with the systemic effects of androgen deprivation therapy might eradicate the prostatic cancer cells by targeting the 'visible' index focus (by HIFU) and the tumour surrounding microenvironment which may contain 'invisible' foci and aberrant PCa related signalling (by androgen deprivation therapy) to enhance oncological outcomes of HIFU hemi-ablation in men with localized PCa, and consequently reducing treatment failures.

Condition or disease	Intervention/treatment	Phase
Prostate Cancer; Androgen Deprivation Therapy	Drug: HIFU hemi-ablation combined with ADT.	Phase 2

Detailed Description:

Prostate Cancer (PCa) is a multifocal disease in up to 90% of men with heterogeneity among different cancer foci in the same prostate gland. An index/dominant lesion has been proposed, namely the largest tumor nodule that often correlates with the highest Gleason score (GS) and, consequently, with the clinical behavior of the tumor. However, this concept is not always applicable as highest GS, largest tumor volume and extraprostatic extension may be present in different PCa foci in up to 10% of the cases.

Focal therapies (FT) for localized PCa emerged to reduce the adverse effects of radical treatments,including a30-90% for erectile dysfunction and 5-20% for incontinence and rectal toxicity, while maintaining comparable oncological efficacy. Amongst organ-sparing strategies, high-intensity focused ultrasound (HIFU) is widely used and yields promising cancer control rates and relatively low morbidity.

In our recently published prospective study of HIFU hemiablation for localized PCa with one year follow up, 25.4% of patients demonstrated PCa cores at 12 months post-treatment biopsy (Feijo et al, Eur Urol, 2016). Among them 11.5% of patients showed cancer in the contralateral untreated lobe. At 3 months, all patients were continent and 11 out of 21 preoperatively potent patients maintained adequate sexual functions. Minor adverse effects were reported in 8%, while 2.8% of patients experienced Clavien-Dindo grade-3 events.

Although FT has proven to be effective and less morbid treatment for localized PCa, an area for improvement still exists and a gap in cancer control needs to be filled by adding additional form of treatment so as to improve oncological outcomes and minimize treatment failures.

Research Rationale Previous studies have shown approximately 20% of men continue to harbour cancer at 12 months after HIFU FT for localized PCa. This finding could be in part attributed to undetectable (invisible) remote cancer foci owing to limitations of the currently available imaging and biopsy techniques and representing an appealing argument against FT.

Another point is tumor microenvironment, defined as the myriad of multiple interactions amongst tumour and surrounding cells including immune cells, stromal fibroblasts, mesenchymal stem cells and blood vessels.

It is not completely clear whether at least part of FT recurrences may be related to non-aggressive lesions taking the position of an index PCa focus and/or PCa index lesion signalling altering benign tissues behaviour.

Androgen deprivation therapy (ADT) modifies tumour microenvironment and suppresses PCa growth and progression.

Short-term ADT has been reported to increase the overall survival in men with localized intermediate- to high-risk PCa when combined with external beam radiation therapy (EBRT) or RP.

Short term ADT has been also investigated in the context of active surveillance; other trials are under way.

However, to date, there is no prospective data assessing the role of HIFU/ADT combination therapy for the treatment of localized PCa in terms of cancer control.

The current study aims to examine the hypothesis that combining the focal effects of HIFU with the systemic effects of androgen deprivation therapy might eradicate the prostatic cancer cells by targeting the 'visible' index focus (by HIFU) and the tumour surrounding microenvironment which may contain 'invisible' foci and aberrant PCa related signalling (by androgen deprivation therapy) to enhance oncological outcomes of HIFU hemi-ablation in men with localized PCa, and consequently reducing treatment failures, without significantly increasing toxicity and/or complications.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: EvaluatioN of High-intensity Focused Ultrasound (HIFU) Hemiablation and Short Term AndrogeN Deprivation Therapy Combination to Enhance Prostate Cancer Control for Low and Intermediate Risk Localized Prostate Cancer (PCa): the ENHANCE Prospective Feasibility Trial.
• Estimated Study Start Date: December 1, 2019
• Estimated Primary Completion Date: September 1, 2021
• Estimated Study Completion Date: December 1, 2021

Arms and Interventions

Arm

Intervention/treatment

Experimental: ADT protocol; ADT protocol is administered as a single subcutaneous injection of 3-month depot of 22.5 mg of leuprolide acetate (luteinizing hormone-releasing hormone [LHRH] agonist). Additionally, oral antiandrogen bicalutamide 50 mg once per day is given for 3 months, starting the same day of LHRH agonist injection. ADT protocol starts one month prior to the scheduled HIFU session. The intervention of the study is HIFU hemi-ablation combined with ADT.

Drug: HIFU hemi-ablation combined with ADT.; Hemi-ablation of the cancer-harbouring prostatic lobe will be carried out using HIFU energy. Short-term 3-month ADT will be administered concomitantly.- Short-term ADT is administered as a single subcutaneous injection of 3-month depot of 22.5 mg of leuprolide acetate (luteinizing hormone-releasing hormone [LHRH] agonist). Additionally, oral antiandrogen bicalutamide 50 mg once per day is given for two weeks, starting one week before the LHRH agonist injection. The ADT protocol starts within 1 month prior to the scheduled HIFU session

Outcome Measures

Primary Outcome Measures :

1. Oncological outcome [ Time Frame: 12 months after the HIFU session ]

   Number of treatment failures determined after prostatic biopsy and defined as:

   • Any Gleason pattern ≥4.
   • Any Gleason score ≥7.
   • High-volume (>1.3 cc) Gleason score 6 (3+3).
   • ≥7 mm of PCa in any core
   • ≥20% of positive cores
2. Erectile function [ Time Frame: 12 months post-treatment ]
   Rate of men maintaining potency after treatment. Erectile function changes will be assessed using the IIEF-5 and considering potency as IIEF-5 ≥22 without need of any medication (PDE-5 inhibitors and/or others).
3. Urinary continence [ Time Frame: 12 months post-treatment ]
   Rate of men maintaining continence and becoming incontinent after treatment. Continence is defined as >0pad/day being used. Incontinence is defined conversely.
4. Treatment toxicity and complications [ Time Frame: 12 months ]
   Rate of men experiencing treatment related complications and toxicity. Surgical complications will be graded using the Clavien-Dindo classification. Treatment related toxicity and adverse events will be graded using the Common Terminology Criteria for reporting Adverse Events (CTCAE v5).

Secondary Outcome Measures :

1. PSA variation [ Time Frame: at 3, 6, and 12 months post-treatment, as compared to baseline. ]
   Serum free and total PSA levels changes
2. testosterone variation [ Time Frame: at 3, 6, and 12 months post-treatment, as compared to baseline ]
   Serum Testosterone levels changes .
3. erectile function variation [ Time Frame: at 3 and 6 months post-treatment ]

   Erectile function as compared to baseline using:

   • IIEF-5 score changes at different time points post-treatment, as compared to baseline.
   • Proportion of men who are potent at baseline and then sustain erectile dysfunction, at 12 months. Potency is defined as an IIEF score ≥22 without requiring any medication.
4. urinary continence variation [ Time Frame: at 3 and 6 months post-treatment ]
   Variation of ICSmale SF score in incontinence domains (international continence society male short form questionnaire - incontinence domain is composed by six questions going from 0 (total continence) to 24 (severe incontinence).
5. urinary continence proportion [ Time Frame: 3, 6, and 12 months post-treatment ]
   Variation in continence category according to the number of pads used/day due to continence problems compared to baseline. Categories will be (full continence= 0 pads/day or security pad, mild incontinence =1pad/day, moderate incontinence= 2pads/day, severe incontinence >2pads/day).
6. urinary voiding function variation [ Time Frame: 3, 6, and 12 months post-treatment ]

   Urinary voiding function variation (compared to baseline) assessing changes of the IPSS (International Prostatic Symptoms Score).

   The IPSS score measures if the subject has significant problems/symptoms in passing the urine/voiding the bladder. The scale goes from 0 (no symptoms or bother) to 35 (extremely severe symptoms).

7. additional treatment due to recurrent or persistent prostate cancer [ Time Frame: 12 months ]
   Rate (%) of men needing to undergo further prostate cancer active treatment due to treatment failure due to biochemical recurrence according to the Phoenix criteria and biopsy proving persistence/recurrence of clinically significant PCa (defined as previously described - see Oncological outcome).

Eligibility Criteria

• Ages Eligible for Study: 50 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Men aged 40-80 years (upper age limit is defined according to a life expectancy estimate being <10 years for men >80).
• Localized, intermediate- or low-risk PCa (according to the most recent version of the European Association of Urology Prostate Cancer Guidelines).
• Unilateral (unifocal or multifocal) PCa or bilateral disease allowing unilateral GS 3+3 up to 1mm in the non-treated side.
• Histopathologically verified PCa by any mpMRI-targeted prostate biopsy (3 cores per each target lesion + 12 random cores performed) or systematic prostate biopsy (in case of a negative mpMRI), performed transperineally or transrectally).
• ≤3 biopsy cores demonstrating cancer involvement.
• <50% cancer involvement of any cancer harbouring core.
• Any Gleason score 7 (3 + 4) OR high-volume (>1.3 cc) Gleason score 6 (3+3).
• Prostate specific antigen (PSA) ≤15 ng/ml.
• Clinical stage T1c-T2a with no evidence of extra-prostatic extension/seminal vesicle invasion, N0M0 disease. (EAU guidelines)
• Prostate volume ≤ 50 ml.
• Treatment-naive patients (received no previous treatments for PCa, apart from active surveillance).
• World Health Organization (WHO) performance status of grade 0-2.
• Life expectancy of ≥10 years (G8 score ≥14 will be required in men >70 years)

Exclusion Criteria:

• Low-volume (<1.3 cc) Gleason score ≤6 (3 + 3) OR any Gleason score > 3+4
• Prostatic calcifications or cysts whose location may interfere with effective delivery of HIFU energy.
• Metal implants/stents in the urethra.
• Active urinary tract infection.
• Men who have previously received any form of PCa treatment (e.g. external beam radiation therapy (EBRT), brachytherapy, HIFU, cryosurgery, thermal or microwave therapy and/or hormonal therapy including 5 α-reductase inhibitors).
• Men who have undergone surgery for benign prostatic hyperplasia in the previous 6 months; i.e. a transurethral resection of the prostate (TURP), holmium laser enucleation (HOLEP), greenlight laser vaporization, others.
• Men with an inability to tolerate a transrectal ultrasound probe or have undergone prior significant rectal surgery preventing insertion of transrectal HIFU probe.
• Men unable to have MRI scanning (e.g. men with severe claustrophobia, permanent cardiac pacemaker or metallic implant which may likely contribute to significant image artefacts).
• Men with renal impairment and a glomerular filtration rate (GFR) of <35 ml/min (unable to tolerate Gadolinium dynamic contrast enhanced MRI).
• WHO performance status of grade 3-4 / men unfit for surgery
• Language barriers that might hinder the communications, understanding of written and verbal information about the trial, consenting process, or completing the questionnaires.
• Men refusing to sign an informed consent to participate in the trial.
• Concomitant cancers or previous cancers without a 5 years cancer free-status follow up.
• Men not reaching an androgen castration status at three months post-ADT administration will be included in the trial but not in the final analysis.
• Men with relative and/or absolute contraindications to androgen deprivation therapy.

Contacts and Locations

Contacts

Contact: Rafael SANCHEZ, Doctor; +33156616263; rafael.sanchez-salas@imm.fr

Contact: Giancarlo Marra, Doctor; drgiancarlomarra@gmail.com

Sponsors and Collaborators

Institut Mutualiste Montsouris

University of Turin, Italy

More Information

• Responsible Party: Institut Mutualiste Montsouris
• ClinicalTrials.gov Identifier: NCT03845751
• Other Study ID Numbers: URO-01-2019
• First Posted: February 19, 2019
• Last Update Posted: September 27, 2019
• Last Verified: September 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Institut Mutualiste Montsouris:

HIFU; hemi ablation; focal therapy

Additional relevant MeSH terms:

Prostatic Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Prostatic Diseases