FOCALE: Efficacy Evaluation of Focused HIFU (High Intensity Focused Ultrasound) Therapy in Patients With Localized Intermediate Risk Prostate Cancer

Sponsor

Hospices Civils de Lyon (Other)

Overall Status

Recruiting

CT.gov ID

NCT03568188

Collaborator

(none)

170

Enrollment

Locations

Arm

Anticipated Duration (Months)

11.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The aim of the focal treatment HIFU is to destroy the cancer without causing side effects in contrast to radical treatments. Radical treatments (surgery or radiation therapy) are the standard therapies for patient with intermediate risk localized prostate cancer and good life expectancy (prostatectomy if life expectancy10 years) By destroying only the part of the gland that harbors cancer, it may indeed be possible to provide efficient cure of the disease while minimizing treatment-induced morbidity (incontinence and loss of potency). Around 20% of patients presented with a unilateral tumor: this patients are currently treated radically. No study published papers reported outcomes of a large population (>100) with intermediate risk cancers treated with Focal-HIFU (conducted with the Focal One® device). Focal therapy must be only offer within clinical trial setting (EAU (European Association of Urology) Guidelines ). The aim of this cohort will be to determine the success rate of Focal-HIFU in this intermediate risk population. The result the study will be used for calculation the arms of a future random study

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer	Procedure: treatment with focal HIFU Biological: PSA dosage Device: MRI Other: Questionnaires Procedure: Prostatic biopsies Biological: blood test Biological: urine test	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

170 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase 2, Multicenter, Prospective Cohort Study, Estimating the Efficacy of Focused HIFU Therapy in Patients With Localized Intermediate Risk Prostate Cancer

Actual Study Start Date :

Sep 28, 2018

Anticipated Primary Completion Date :

Sep 28, 2022

Anticipated Study Completion Date :

Sep 28, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: HIFU treatment 170 patients with prostate cancer of intermediate risk receive the immediate treatment with focal HIFU. The treatment area will be defined using MRI data and 3D biopsies. A safety distance of at least 9 mm will be defined around the tumor. An intraoperative contrast echocardiographic control will be performed to evaluate the necrotic area. If necessary, additional HIFU lesions will be performed during the same session. In case of residual tumor demonstrated during control biopsies, additional treatment of this tumor with focal HIFU may be proposed. Patients will also have PSA (Prostate-Specific Antigen) dosage, MRI (Magnetic Resonance Imaging) exam, questionnaires and prostatic biopsies during their follow up. If the patient decides to participate in the ancillary study, a blood test (for immunological analyzes and detection of CTC (circulating tumor cells)) and a urine test (for PCA3 (The prostate cancer antigen 3 gene) test) will be performed during their follow up.	Procedure: treatment with focal HIFU HIFU treatment will be conducted with the Focal One® device. The treatment area will be defined using MRI data and 3D biopsies. A safety distance of at least 9 mm will be defined around the tumor. An intraoperative contrast echocardiographic control will be performed to evaluate the necrotic area. If necessary, additional HIFU lesions will be performed during the same session. In case of residual tumor demonstrated during control biopsies, additional treatment of this tumor with focal HIFU may be proposed. Biological: PSA dosage PSA dosage will be regularly performed during patient follow up thanks to blood sampling. Device: MRI MRI exam will be regularly performed during patient follow up. Other: Questionnaires Patients will have to complete five questionnaires during their follow up : QLQ-C30 (Quality of Life questionnaire), EPIC-26 (The Expanded Prostate Cancer Index Composite), IPSS (International Prostate Score Symptom), IIEF-5 (The International Index of Erectile Function). Procedure: Prostatic biopsies Prostatic biopsies will be regularly performed during patient follow up. Biological: blood test if the patient decides to participate in the ancillary study, a blood test (for immunological analyzes and detection of CTC (circulating tumor cells)) will be performed during their follow up. Biological: urine test if the patient decides to participate in the ancillary study, a urine test (for PCA3 test) will be performed during their follow up.

Arm

Intervention/Treatment

Experimental: HIFU treatment

170 patients with prostate cancer of intermediate risk receive the immediate treatment with focal HIFU. The treatment area will be defined using MRI data and 3D biopsies. A safety distance of at least 9 mm will be defined around the tumor. An intraoperative contrast echocardiographic control will be performed to evaluate the necrotic area. If necessary, additional HIFU lesions will be performed during the same session. In case of residual tumor demonstrated during control biopsies, additional treatment of this tumor with focal HIFU may be proposed. Patients will also have PSA (Prostate-Specific Antigen) dosage, MRI (Magnetic Resonance Imaging) exam, questionnaires and prostatic biopsies during their follow up. If the patient decides to participate in the ancillary study, a blood test (for immunological analyzes and detection of CTC (circulating tumor cells)) and a urine test (for PCA3 (The prostate cancer antigen 3 gene) test) will be performed during their follow up.

Procedure: treatment with focal HIFU

HIFU treatment will be conducted with the Focal One® device. The treatment area will be defined using MRI data and 3D biopsies. A safety distance of at least 9 mm will be defined around the tumor. An intraoperative contrast echocardiographic control will be performed to evaluate the necrotic area. If necessary, additional HIFU lesions will be performed during the same session. In case of residual tumor demonstrated during control biopsies, additional treatment of this tumor with focal HIFU may be proposed.

Biological: PSA dosage

PSA dosage will be regularly performed during patient follow up thanks to blood sampling.

Device: MRI

MRI exam will be regularly performed during patient follow up.

Other: Questionnaires

Patients will have to complete five questionnaires during their follow up : QLQ-C30 (Quality of Life questionnaire), EPIC-26 (The Expanded Prostate Cancer Index Composite), IPSS (International Prostate Score Symptom), IIEF-5 (The International Index of Erectile Function).

Procedure: Prostatic biopsies

Prostatic biopsies will be regularly performed during patient follow up.

Biological: blood test

if the patient decides to participate in the ancillary study, a blood test (for immunological analyzes and detection of CTC (circulating tumor cells)) will be performed during their follow up.

Biological: urine test

if the patient decides to participate in the ancillary study, a urine test (for PCA3 test) will be performed during their follow up.

Outcome Measures

Primary Outcome Measures

patient proportion with controlled disease (Control of the pathology) [12 months]
The main objective is the estimation of FOCAL HIFU treatment efficacy defined as the percentage of positive biopsies in the treated lobe at 12 months after inclusion.

Secondary Outcome Measures

proportion of patients needing additional treatment [12 months]
The objective is to determine the proportion of patients needing additional treatment (focal or radical) at 12 months. This includes patients who wish or require radical treatment (prostatectomy, radiotherapy), total focal treatment, or additional focal treatment.
proportion of patients needing additional treatment [48 months]
The objective is to determine the proportion of patients needing additional treatment (focal or radical) at 48 months. This includes patients who wish or require radical treatment (prostatectomy, radiotherapy), total focal treatment, or additional focal treatment.
proportion of patients needing additional radical treatment [12 months]
The objective is to determine the proportion of patients needing additional radical treatment at 12 months. This includes patients who wish or require prostatectomy or radiotherapy total focal treatment.
proportion of patients needing additional radical treatment [48 months]
The objective is to determine the proportion of patients needing additional radical treatment at 48 months. This includes patients who wish or require prostatectomy or radiotherapy total focal treatment.
rate of positive biopsies [12 months]
The rate of positive biopsies in the untreated lobe and treated lobe evaluated and will be used to evaluate the carcinologic evolution at 12 months.
rate of positive biopsies [24 months]
The rate of positive biopsies in the untreated lobe and treated lobe evaluated and will be used to evaluate the carcinologic evolution at 24 months.
rate of positive biopsies [48 months]
The rate of positive biopsies in the untreated lobe and treated lobe evaluated and will be used to evaluate the carcinologic evolution at 48 months.
clinically significant cancer rate [48 months]
The clinically significant cancer rate (Gleason 7 or invasion of more than 3 biopsies or invasion> 3 mm regardless of Gleason) in the untreated lobe and the treated lobe will be measured and will be used to evaluate the carcinologic evolution at 48 months.
Gleason score [12 months]
Evolution of the Gleason score (appearance of Gleason ≥7) will be measured and will be used to evaluate the carcinologic evolution at 12 month. The Gleason score is a prognosis factor for prostate cancer. It is based prostate cancer cells architecture from biopsies. The more the architectures of prostate cancer cell is destroyed, the worse is the prognosis. The score grades from 3 to 5, 5 being the more destroyed, the score 1 and 2 being normal cells. When there is more than one tumor cells population in the prostate, the score is composed of the sum of the most 2 frequents grade. For example a Gleason 7 tumor could be 3+4 or 4+3, the 4+3 being more aggressive.
Gleason score [24 months]
Evolution of the Gleason score (appearance of Gleason ≥7) will be measured and will be used to evaluate the carcinologic evolution at 24 month. The Gleason score is a prognosis factor for prostate cancer. It is based prostate cancer cells architecture from biopsies. The more the architectures of prostate cancer cell is destroyed, the worse is the prognosis. The score grades from 3 to 5, 5 being the more destroyed, the score 1 and 2 being normal cells. When there is more than one tumor cells population in the prostate, the score is composed of the sum of the most 2 frequents grade. For example a Gleason 7 tumor could be 3+4 or 4+3, the 4+3 being more aggressive.
Gleason score [48 months]
Evolution of the Gleason score (appearance of Gleason ≥7) will be measured and will be used to evaluate the carcinologic evolution at 48 month. The Gleason score is a prognosis factor for prostate cancer. It is based prostate cancer cells architecture from biopsies. The more the architectures of prostate cancer cell is destroyed, the worse is the prognosis. The score grades from 3 to 5, 5 being the more destroyed, the score 1 and 2 being normal cells. When there is more than one tumor cells population in the prostate, the score is composed of the sum of the most 2 frequents grade. For example a Gleason 7 tumor could be 3+4 or 4+3, the 4+3 being more aggressive.
Appearance of another cancerous focus in the other half of the prostate [12 months]
Appearance of another cancerous focus in the other half of the prostate will be supervised and will be used to evaluate the carcinologic evolution at 12 months.
Appearance of another cancerous focus in the other half of the prostate [24 months]
Appearance of another cancerous focus in the other half of the prostate will be supervised and will be used to evaluate the carcinologic evolution at 24 months.
Appearance of another cancerous focus in the other half of the prostate [48 months]
Appearance of another cancerous focus in the other half of the prostate will be supervised and will be used to evaluate the carcinologic evolution at 48 months.
Appearance of metastases [12 months]
Appearance of metastases (lymph node or bone) will be supervised and will be used to evaluate the carcinologic evolution at 12 months.
Appearance of metastases [24 months]
Appearance of metastases (lymph node or bone) will be supervised and will be used to evaluate the carcinologic evolution at 24 months.
Appearance of metastases [48 months]
Appearance of metastases (lymph node or bone) will be supervised and will be used to evaluate the carcinologic evolution at 48 months.
Appearance of an extra capsular extension [12 months]
Appearance of an extra capsular extension will be supervised and will be used to evaluate the carcinologic evolution at 12 months.
Appearance of an extra capsular extension [24 months]
Appearance of an extra capsular extension will be supervised and will be used to evaluate the carcinologic evolution at 24 months.
Appearance of an extra capsular extension [48 months]
Appearance of an extra capsular extension will be supervised and will be used to evaluate the carcinologic evolution at 48 months.
Overall survival [48 months]
Overall survival at 48 months will be measured from the date of inclusion to the date of death, all causes of death combined or the date of last new or point date to 48 months.
Prostate cancer specific survival [48 months]
Prostate cancer specific survival at 48 months will be measured from the date of inclusion to the date of death related to prostate cancer or the date of last new or point date to 48 months
Recurrence free survival [48 months]
Prostate cancer specific survival at 48 months will be measured from the date of inclusion to the date of first metastasis , or the date of last new or point date to 48 months.
Proportion of serious adverse effect [48 months]
comparison of the proposition of serious adverse effect at 48 months
Quality of life score [over the 48 months]
quality of life will be assessed using the QLQC30 (Quality of Life questionnaire) questionnaire. It is a specific questionnaire to determine the quality of life a patient with cancer. It is composed of 30 questions with 4 potential answers going from: not at all, a little, enough or a lot, within 28 questions and with a visual scale going from 1 to 7 (7 being excellent and 1 being very bad) for the last 2 questions. The raw score is established by adding the score of each question and a linear transformation range it from 0 to 100. The higher the score, the better the quality of life.
EPIC-26 score [over the 48 months]
urinary function will be assessed using the EPIC-26 (The Expanded Prostate Cancer Index Composite) questionnaire. The EPIC-26 is a self-reported scale health-related quality of life questionnaire for prostate cancer patients . It is composed of 26 items in 4 different domains: urinary incontinence, urinary irritation/obstruction, bowel, sexual, and vitality/hormonal. Response options for each EPIC item form a Likert scale, and multi-item scale scores are transformed linearly to a 0-100 scale. Each items as a standardized value from 0 to 100. Then the average of the standardized value is determined in each domain to crate the summary score. The higher the score, the better the quality of life.
IPSS score [over the 48 months]
urinary function will be assessed using the IPSS (International Prostate Score Symptom) questionnaire. The IPSS questionnaire is based on the answers to seven questions concerning urinary symptoms and one question concerning quality of life. Each question concerning urinary symptoms allows the patient to choose one out of six answers indicating increasing severity of the particular symptom. The answers are assigned points from 0 to 5. The total score can therefore range from 0 to 35. The score is then categorized as follow: Mild (symptoms score less than or equal to 7), Moderate (symptom score range 8-19), Severe (symptom score range 20-35). The higher the score, the worse the symptoms.
IIEF-5 score [over the 48 months]
Sexual function will be assessed using the IIEF-5 (The International Index of Erectile Function) questionnaire. The IIEF-5 Questionnaire is composed of 5 items with 5 possible answers rating from 1 to 5 (very low, low, moderate, high, very high). The score is the sum of the ordinal responses to the 56 items. It is then categorized as follow: 22-25: No erectile dysfunction, 17-21: Mild erectile dysfunction, 12-16: Mild to moderate erectile dysfunction, 8-11: Moderate erectile dysfunction, 5-7: Severe erectile dysfunction. The higher the score, the better the sexual function.
patient proportion with controlled disease (Control of the pathology) [48 months]
The main objective is the estimation of FOCAL HIFU treatment efficacy defined as the percentage of positive biopsies in the treated lobe at 48 months after inclusion.
Ancillary study: Measure of anti-tumoral immunity induction [over the 48 months]
The consequences of HIFU treatment over immune anti-tumoral induction will be estimated by the description of Programmed death-ligand 1/ligand 2 (PDL1/L2) overexpression on immune cells and overexpression of Programmed cell death 1 (PD-1) on T lymphocytes (T-cells).
Ancillary study: Measure of Circulating Tumor Cells (CTC) number reduction [over the 48 months]
The consequences of HIFU treatment over Messenger RNA (mRNA) will be estimated by measure of CTC number reduction.
Ancillary study: Measure of ncRNA (non-coding RNA) PCA3 (Prostate cancer gene 3) level reduction. [over the 48 months]
The consequences of HIFU treatment over PCA3 will be estimated by measure of ncRNA PCA3 level reduction.

Eligibility Criteria

Criteria

Ages Eligible for Study:

50 Years to 80 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Inclusion Criteria:

Patient having been clearly informed of the study and having accepted, with sufficient reflection time, to participate by signing the informed consent form of the study.
Age between 50 and 80 years with a life expectancy of more than 5 years. Patients between the ages of 75 and 80 will need to have a G8 score > 14.
Initial diagnosis of localized prostate cancer (T1c or T2a) with the following characteristics:
A multiparametric MRI showing a single invasive tumor focus at most two contiguous sextants confirmed by biopsies (index tumor). Patients with multiple suspected MRI foci may be included if only one of these foci is confirmed by targeted biopsies.
Gleason score= 7 (3+4).
Tumor accessible to a Focal-HIFU treatment. For apical tumor, it must be localized more than 9 mm from the external sphincter
PSA ≤ 15ng / ml.
Patient affiliated with health insurance or beneficiary of an equivalent plan.

Exclusion Criteria:

Contraindications to treatment with HIFU-F:
Tumor not accessible.
Multiple intra prostatic calcifications inducing, on ultrasound, a shadow cone in the prostate preventing the penetration of ultrasound and thus the realization of the treatment.
History of pelvic irradiation
Presence of an implant (stent, catheter) located less than 1 cm from the treatment area.
Fistula of the urinary tract or rectum.
Anal or rectal fibrosis, anal or rectal stenosis or other abnormalities making it difficult to insert the Focal One® probe.
Anatomical abnormality of the rectum or rectal mucosa.
Patient with artificial sphincter, penile prosthesis or intra prostatic implant, eg stent.
History of intestinal inflammatory pathology.
Uro-genital infection in progress (the infection to be treated before HIFU treatment).
Anterior surgery at the level of the anus or rectum making the introduction of the probe impossible.
Allergy to latex.
Thickness of the rectal wall> 10mm.
TURP indication. Bladder neck incision is allowed.
Patient with a medical contraindication to Sonovue® injection.
Patient with a medical contraindication on MRI.
Patient already treated for prostate cancer (hormone therapy, radiotherapy, surgery).
History of uncontrolled cancer and / or treated for less than 5 years (with the exception of basal cell skin cancer).
History of pelvic radiotherapy.
History of sclerosis of the bladder neck or urethral stenosis.
Patient with a several bleeding risk according to medical advice (patient with oral anticoagulant therapy must receive an alternative therapy).
Patients with unstable neurological pathology.
Patient who has been treated for a therapeutic trial within 30 days of enrollment or who wishes to participate in an ongoing study that may interfere with this study.
Legal person protected by law.
Patient not able to understand the objectives of the study or refusing to comply with postoperative instructions.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Polyclinique du parc Rambot	Aix-en-Provence	France	13100
2	Clinique Saint-Vincent	Besançon	France	25044
3	Service d'Urologie, Clinique Tivoli Ducos	Bordeaux	France	33000
4	Groupe Hospitalier Pellegrin - CHU	Bordeaux	France	33076
5	Hôpital L. Pasteur, Hôpitaux Civils de Colmar	Colmar	France	68024
6	Service d'Urologie CHRU de Lille, Hôpital HURIEZ	Lille	France	59000
7	Service d'Urologie Générale de Santé - Hôpital Privé La Louvière	Lille	France	59000
8	Service d'Urologie et Chirurgie de la Transplantation, Hôpital Edouard Herriot,	Lyon	France	69437
9	Service d'urologie Assistance Publique - Hôpitaux de Marseille - Hôpital Marseille Nord	Marseille	France	13915
10	Département d'Urologie, Institut Montsouris	Paris	France	75014
11	Centre Hospitalier Lyon Sud - Hospices Civils de Lyon	Pierre-Bénite	France	69495
12	Clinique Urologique Nantes Atlantis	Saint-Herblain	France	44800
13	Service d'Urologie, Hôpital Foch	Suresnes	France	92150
14	CHU de Toulouse - Hôpital de Rangueil	Toulouse	France	31400
15	Clinique Générale Beaulieu - Swiss International Prostate Center	Geneva	Sweden	1206