Focal Therapy for Prostate Cancer Using HIFU (INDEX)

A Multi-Center Prospective Single Arm Intervention Trial Evaluating Focal Therapy Using High Intensity Focused Ultrasound (Sonablate 500) for Localized Prostate Cancer

RATIONALE: Prospective trials using hemi-ablation with high intensity focused ultrasound (HIFU) (Sonablate 500) have demonstrated feasibility, safety, and encouraging functional outcomes and early cancer control with 90% of men achieving trifecta status (no erectile dysfunction, leak-free pad-free continence, cancer control). However, these trials have involved small numbers of patients with men selected for good baseline function. A multi-centre prospective trial within a larger cohort of men that better represents the patient population with prostate cancer (external validity) is required.

Study Overview

• Status: Recruiting
• Conditions: Urinary Incontinence; Prostate Cancer; Male Erectile Disorder; Therapy-related Toxicity
• Intervention / Treatment: Other: questionnaire administration; Procedure: quality-of-life assessment; Procedure: multiparametric magnetic resonance imaging; Procedure: transperineal prostate biopsy; Procedure: transrectal prostate biopsy; Procedure: assessment of therapy complications; Procedure: high-intensity focused ultrasound ablation

Detailed Description

Verification of a new therapy as favourable, or equivalent, in outcome to 'standard' care is ideally sought through comparison with another matched control group. Randomised controlled trials (RCTs) offer the best method for minimising systematic bias and revealing the true effect of an intervention or drug. However, RCTs involving treatments of localised prostate cancer have had a historically poor patient uptake, as the reference 'gold' standard of care is not known. In addition, RCTs are expensive to run and involve huge infra-structural support. A number of trials in the USA have been forced to close due to lack of recruitment. The ProStart trial in the UK has also had to close for the same reason. It has been acknowledged by the Food and Drug Agency in the USA that comparative randomized trials will be problematic in this area due to lack of physician and patient equipoise. A randomized trial may be feasible if a pragmatic design is adopted but prior to acceptance of such a design, the number of centres with expertise in this complex intervention (mp-MRI, TTPM, focal HIFU) will need to be increased.

Observational studies are a commonly used alternative to ascertain the effectiveness of a treatment. They are used to observe a treatment effect in a selected group of patients who are presumed to derive benefit from the treatment given. Although methodologically not as robust, and therefore prone to bias, they have some benefits over RCTs. The principal ones are those of enhanced external validity (many patients do not wished to be randomised and therefore refuse participation), and more rapid accrual compared to a randomised design. For this reasons, a single arm medium term follow-up cohort intervention study has been designed. At the time of writing the safety and tolerability aspects of focal therapy by HIFU are known as a result of the Phase I/II studies carried out at UCLH. The results have been presented and exist in the public domain in abstract form but have not yet been published (presented in tables above). These early studies were powered to detect a change in the proportion of men who could obtain an erection sufficient for penetration compared to their status prior to their treatment. The very low event rate for both erectile dysfunction and incontinence indicates that the 'proof of concept' has been demonstrated for focal therapy. Moreover, we can be relatively confident that, in expert hands, focal HIFU is safe. Therefore, a multi-centre study is now required involving a larger group of patients for the following reasons:

1. To evaluate medium term cancer control using histological parameters. Stage two of INDEX will evaluate conversion to radical and systemic therapies and link men to national databases to determine survival in 5 and 10 years.
2. To confirm that focal therapy can lead to low rates of genitourinary and rectal toxicity and minimal impact on quality of life within a large and more representative cohort of patients (greater precision around outcome measures).
3. To demonstrate that the skills (characterization through template prostate mapping and MRI as well as the treatment related skills) acquired by the team at UCLH are indeed transferable to other providers.
4. To calculate costs of care and to model potential cost-effectiveness in comparison to alternative therapies. If this single arm intervention study demonstrates acceptable outcomes to support the findings of the Phase I/II studies, it is anticipated that this preliminary study will lead onto a Phase III evaluation of focal therapy, prior to more widespread use of this technology.

• Study Type: Interventional
• Enrollment (Anticipated): 354
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • England
    • London, England, United Kingdom, WC1E 6BT
      • Recruiting
      • University College London
      • Contact: SITU Trials Unit; Phone Number: +44207 679 9280; Email: situ.index@ucl.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 90 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

1. Histologically proven prostate cancer on trans-rectal or transperineal template prostate biopsies.

2. Prostate biopsy (either TRUS or MRI Targeted or Template):

   • TRUS biopsy: up to burden bilateral disease with maximum 3mm one biopsy on non-dominant side is allowable.
   • MRI targeted and/or Template biopsy within 12 months of entry showing:
   • unilateral disease minimum 3mm of Gleason 3+3 or any Gleason 3+4 or 4+3 but not exceeding Gleason 4+3 overall OR
   • bilateral disease presence of clinically significant cancer on only one side (as determined by histological rules described above) Gleason ≤7 which is concordant with the MRI findings.
3. Stage T1-T2cN0M0 disease, as determined by local guidelines (radiological T3a permitted).
4. Serum PSA </=20ng/ml
5. Life expectancy of >/=10 years.
6. Signed informed consent by patient.
7. An understanding of the English language sufficient to understand

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: High Intensity Focused Ultrasound; HIFU, the Intervention	Other: questionnaire administration; Procedure: quality-of-life assessment; Procedure: multiparametric magnetic resonance imaging; Procedure: transperineal prostate biopsy; Procedure: transrectal prostate biopsy; Procedure: assessment of therapy complications; Procedure: high-intensity focused ultrasound ablation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Conversion to radical therapy and/or requiring systemic therapy and/or developing metastases and/or dying of prostate cancer	To determine the proportion of men converting to radical therapy and/or requiring systemic therapy and/or developing metastases and/or dying of prostate cancer following focal therapy for localised prostate cancer using HIFU	5 years
Conversion to radical therapy and/or requiring systemic therapy and/or developing metastases and/or dying of prostate cancer	To determine the proportion of men converting to radical therapy and/or requiring systemic therapy and/or developing metastases and/or dying of prostate cancer following focal therapy for localised prostate cancer using HIFU	10 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
rate of erectile dysfunction	The presence of severe erectile dysfunction at 12 months, as measured by the IIEF-5 questionnaire with or without the use of phosphodiesterase-5 inhibitors, in those with absence of severe erectile dysfunction at baseline	12 months
rate of erectile dysfunction	The presence of severe erectile dysfunction at 24 months, as measured by the IIEF-5 questionnaire with or without the use of phosphodiesterase-5 inhibitors, in those with absence of severe erectile dysfunction at baseline	24 months
time to return of erectile function	Time to return of erectile function (absence of severe ED on IIEF-15 questionnaire)	24 months
rate of urinary incontinence (pad free, leak free and pad-free alone)	Presence of urinary incontinence (any pad usage plus any leakage of urine) as determined by the UCLA-EPIC urinary continence questionnaire, at 12 months, in those men with no urinary incontinence at baseline	12 months
rate of urinary incontinence (pad free, leak free and pad-free alone)	Presence of urinary incontinence (any pad usage plus any leakage of urine) as determined by the UCLA-EPIC urinary continence questionnaire, at 24 months, in those men with no urinary incontinence at baseline	24 months
time to return of continence (pad free, leak free and pad-free alone)	Time to return of urinary continence (as determined by UCLA-EPIC Urinary domain questionnaire)	24 months
rate of loss of ejaculation	rate of loss of ejaculation (as determined by IIEF-15 questionnaire)	24 months
rate of loss of orgasm	rate of loss of orgasm (as determined by IIEF-15 questionnaire)	24 months
rate of pain during intercourse	rate of pain during intercourse (as determined by IIEF-15 questionnaire)	24 months
number of men using phosphodiesterase-5 inhibitors to maintain erectile function	Need for phosphodiesterase-5 inhibitors to maintain erectile function sufficient for penetration up to 24 months	24 months
rate of lower urinary tract symptoms	Grading of lower urinary tract symptoms as determined by IPSS scores	24 months
rate of bowel toxicity	UCLA-EPIC Bowel Function Questionnaire	24 months
anxiety levels	EQ-5D Quality of Life Questionnaire	24 months
general health related quality of life	General and prostate health related quality of life measured using EQ-5D Quality of Life questionnaire	24 months
proportion of men achieving trifecta status at 12 months	Achievement of trifecta status (no severe ED, pad-free leak-free continence, cancer control with absence of clinically significant cancer) at 12 months in those men with good baseline function	12months
proportion of men achieving trifecta status at 24 months	Achievement of trifecta status (no severe ED, pad-free leak-free continence, cancer control with absence of clinically significant cancer) at 24 months in those men with good baseline function	24 months
rate of secondary prostate cancer intervention (prostatectomy, radiotherapy, androgen ablation, whole-gland HIFU or cryosurgery)	rate of secondary prostate cancer intervention (prostatectomy, radiotherapy, androgen ablation, whole-gland HIFU or cryosurgery)	24 months
risk factors for failure defined as a) presence of any cancer and b) clinically significant cancer at study end	risk factors for failure defined as a) presence of any cancer and b) clinically significant	24 months
biochemical (PSA) kinetics including determining the optimal biochemical definition of failure	biochemical (PSA) kinetics including determining the optimal biochemical definition of	24 months
describe composite outcomes of failure	describe composite outcomes of failure	24 months
Cost-effectiveness	To determine the costs of treatment and model potential cost effectiveness using comparative cancer control and functional outcomes at 5 years compared to other cohort trials involving the management of localized prostate cancer	5years
Cost-effectiveness	To determine the costs of treatment and model potential cost effectiveness using comparative cancer control and functional outcomes at 10 years compared to other cohort trials involving the management of localized prostate cancer	10 years

Collaborators and Investigators

• Sponsor: University College, London
• Investigators: Study Chair: Mark Emberton, MD, FRCS, MBBS, University College, London; Study Chair: Hashim Uddinn Ahmed, MD, FRCS, Imperial College London

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2011
• Primary Completion (Anticipated): December 1, 2028
• Study Completion (Anticipated): June 1, 2029

Study Registration Dates

• First Submitted: September 2, 2010
• First Submitted That Met QC Criteria: September 2, 2010
• First Posted (Estimate): September 3, 2010

Study Record Updates

• Last Update Posted (Actual): April 20, 2018
• Last Update Submitted That Met QC Criteria: April 18, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: stage I prostate cancer; stage IIB prostate cancer; stage IIA prostate cancer; male erectile disorder; urinary incontinence; therapy-related toxicity
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Lower Urinary Tract Symptoms; Urological Manifestations; Genital Neoplasms, Male; Prostatic Diseases; Urination Disorders; Sexual Dysfunctions, Psychological; Sexual Dysfunction, Physiological; Elimination Disorders; Prostatic Neoplasms; Urinary Incontinence; Erectile Dysfunction; Enuresis
• Other Study ID Numbers: CDR0000684020; 9945 (Other Identifier: Ohio State University Medical Center)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No