Clinical trial NCT06223295: Effectiveness of Focal Therapy in Men With Prostate Cancer
Official title: Effectiveness of Focal Therapy in Men With Prostate Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Prostate Cancer
Prostate Neoplasm
Keywords: prostate neoplasm
focal therapy
prostate cancer
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Isala
name: Amsterdam UMC, location VUmc
name: St. Antionius Hospital
name: Hifu kliniek
name: Dutch National Health Care Institute
name: ZonMw: The Netherlands Organisation for Health Research and Development
name: Nederlandse Vereniging voor Radiotherapie en Oncologie
name: Wetenschapscommissie interventieradiologie/Nederlandse vereniging voor interventieradiologie
name: Inspire2live
name: Prostaatkankerstichting
name: Nederlandse Vereniging voor Urologie
First posted: 2024-01-25
Enrollment: 356
Sex: MALE
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: In the Netherlands, most men with prostate cancer (PCa) are treated with radical whole-gland treatment, i.e. prostatectomy or radiotherapy. The burden of complications such as incontinence and erectile dysfunction associated with radical treatment is considerable. A recent systematic review by our group has shown that focal therapy of PCa seems to reduce the burden of treatment side-effects in men with intermediate-risk disease, maintaining their quality of life without compromising oncological effectiveness. The costs of side effects that can be prevented are estimated at €5456 per patient, resulting in total expected cost savings of about €22 million per year in The Netherlands. Furthermore, exploration of the benefit-risk balance under patients showed that they are willing to sacrifice some survival for an improvement in quality of life (QoL).

Focal therapy comprises a modern alternative to selectively treat a specific part of the prostate while preserving the rest of the gland. There is, however, a lack of high-quality evidence, and numerous papers therefore recommend to perform a multicenter randomized controlled trial (RCT). The RCT should have long-term follow-up, predefined assessment of cancer-specific and health-related QoL outcome measures, and economic evaluations to inform policymakers regarding cost-effectiveness. This RCT on focal therapy versus usual care is urgently needed to enable focal therapy to overgrow the experimental status, provide the evidence needed for guidelines, and make this available for selected patients who benefit from this strategy. Because of its promising results in other countries, focal therapy is increasingly requested by patients, but due to the lack of high-quality evidence, it is not reimbursed yet. This has been designated by both the PCa patient support group and physicians as a failure of both the market and the funding agencies. The investigators, therefore, aim to perform a high-quality multi-center RCT to provide the evidence needed to decide on reimbursement and implementation of focal therapy in patients with intermediate-risk, unilateral clinically localized PCa in the Netherlands.

Detailed description: In the Netherlands, most men with PCa are treated with radical whole-gland treatment, i.e. prostatectomy or a form of radiotherapy. The burden of complications such as incontinence and erectile dysfunction associated with radical treatment is considerable.

A recent systematic review by our group has shown that focal therapy of PCa seems to reduce the burden of treatment side-effects in men with intermediate-risk disease, maintaining their quality of life without compromising oncological effectiveness. The costs of side-effects that can be prevented are estimated at €5456 per patient, resulting in total expected cost savings of about €22 million per year in The Netherlands. Furthermore, exploration of the benefit-risk balance under patients showed that they are willing to sacrifice some survival for an improvement in quality of life (QoL).

Focal therapy comprises a modern alternative to selectively treat a specific part of the prostate while preserving the rest of the gland. There is, however, a lack of high-quality evidence, and numerous papers therefore recommend to perform a multicenter randomized controlled trial (RCT). The RCT should have long-term follow-up, predefined assessment of cancer-specific and health-related QoL outcome measures, and economic evaluations to inform policymakers regarding cost-effectiveness. This RCT on focal therapy versus usual care is urgently needed to enable focal therapy to overgrow the experimental status, provide the evidence needed for guidelines, and make this available for selected patients who benefit from this strategy. Because of its promising results in other countries, focal therapy is increasingly requested by patients, but due to the lack of high-quality evidence, it is not reimbursed yet. This has been designated by both the PCa patient support group and physicians as a failure of both the market and the funding agencies.

At present, all devices that are used in the proposed study are CE approved and no safety issues were reported in IDEAL stage 1 and 2a studies. For high-risk PCa, local radical therapy has been found to significantly improve oncological endpoints. However, for low- and intermediate-risk localized PCa, the different recommended options by guidelines (radical prostatectomy (RP), radiotherapy (RT), or active surveillance (AS)) have similar short- to medium-term oncological outcomes in randomized studies. A PROZIB database search and a KWF report showed that about 65% of the intermediate-risk patients that are eligible for focal therapy currently undergo either RP or RT. Furthermore, brachytherapy is only used to a limited extent (7%) in intermediate-risk patients in the Netherlands, and since it is not offered as a treatment option in the participating hospitals in this proposal, the investigators do not include this option in our study.

Active surveillance is mainly used for low-risk patients rather than for the intermediate-risk patients the investigators are aiming for in this study. Our systematic review concluded that more high-quality evidence is required before focal therapy can become available as a standard treatment. The majority of focal therapy studies were prospective development IDEAL stage 2a studies (feasibility studies), showing the limited adverse impact on functional outcomes and favorable oncological outcomes. Overall, focal therapy studies reported a median of 95% pad-free at 1-year and 85% of the patients had no clinically significant cancer in the treated area, respectively. High-quality multi-center comparative clinical trials, however, appear to be lacking. The appropriate management of patients with recurrent PCa following focal therapy has been an ongoing point of discussion. Marra et al. showed that evidence from assessments of salvage treatments after focal therapy failure is low and is derived from four retrospective salvage series. Available salvage options after focal therapy include RP and RT. Overall oncological outcomes are acceptable, although biochemical recurrence is slightly higher compared to primary PCa treatment, probably because of the higher aggressiveness of recurrent/persistent PCa. Functional outcomes and complications are not markedly worse compared to primary treatment. Salvage RP and salvage RT, therefore, seem feasible treatment options with acceptable oncological control and functional outcomes. Thus, re-treatment with salvage radiotherapy or salvage surgery remains a clinical option after focal therapy failure. Experience from other countries and our qualitative research on this topic taught us that many patients will consciously opt for an initial focal therapy to maintain their quality of life and because they can be treated later when deemed necessary with the other options.

All patients included in our trial will undergo intensive follow-up. Patients undergoing focal therapy will undergo quarterly PSA measurement and yearly prostate MRI, followed by a prostate biopsy after 12 months and thereafter if indicated based on the MRI. Since focal therapy is a one-time intervention, there will be no patients left in treatment or that require alternative fallback treatments. Ablation devices can be returned after the completion of the trial. The disposables are single-use and are depreciated. There are no specific costs associated with the discontinuation of focal treatment after the trial.

The investigators, therefore, aim to perform a high-quality multi-center RCT to provide the evidence needed to decide on reimbursement and implementation of focal therapy in patients with intermediate-risk, unilateral clinically localized PCa in the Netherlands. This study is funded by a national grant (Veelbelovende Zorg) from the Dutch Health Institute (Zorginstituut Nederland).

Eligibility criteria: Inclusion Criteria:

* Gleason score of 7 (3 + 4 or 4 + 3; ISUP grade 2/3)
* PSA level of ≤ 20 ng/ml
* Clinical stage ≤ T2b disease
* Life expectancy of ≥ 10 years
* Men with a prostate size ≤ 5 cm in sagittal length and ≤ 6 cm in axial length
* Fit, eligible, and normally destined for radical surgery or radiotherapy
* No concomitant cancer
* No previous treatment of their prostate
* An understanding of the Dutch language sufficient to receive written and verbal information about the trial, its consent process and the study questionnaires

Exclusion Criteria:

* Unfit for general anesthesia or radical surgery
* Low volume low-risk disease (≤4mm Gleason score of ≤ 6 / ISUP grade 1)
* High-risk disease (Gleason score of ≥ 8 / ISUP grade \>3)
* Clinical T3 disease (extracapsular PCa)
* Men who have received previous active therapy for PCa.
* Men with evidence of extraprostatic disease.
* Men with an inability to tolerate a transrectal ultrasound.
* Cardiac pacemaker
* Metal implants/stents in the urethra or prostate.
* ASA ≥4
* Prostatic calcification/cysts that interfere with effective delivery of TULSA/HIFU based on MRCT.
* Men with renal impairment and a glomerular filtration rate (GFR) of \< 30 ml/minute/1.73 m2.
* Unable to give consent to participate in the trial, as judged by the attending clinicians

Primary outcomes:
measure: Oncological effectiveness (non-inferiority) defined as treatment failure
timeFrame: 36 months
measure: Quality of life (superiority) measured with Functional Assessment of Cancer Therapy-Prostate questionnaire
timeFrame: 12 months
Secondary outcomes:
measure: Metastasis-free survival
timeFrame: at baseline, 3, 6, 12, 24, 36, 48 and 60 months
measure: Health-related quality of life using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for prostate cancer
timeFrame: at baseline, 3, 6, 12, 24, 36, 48 and 60 months
measure: Health-related quality of life using the International Consultation on Incontinence Questionnaire
timeFrame: at baseline, 3, 6, 12, 24, 36, 48 and 60 months
measure: Health-related quality of life regarding urinary symptoms using the International Prostate Symptom Score questionnaire
timeFrame: at baseline, 3, 6, 12, 24, 36, 48 and 60 months
measure: Health-related quality of life using the Sexual Health Inventory for Men International Index of Erectile Function-5 questionnaire
timeFrame: at baseline, 3, 6, 12, 24, 36, 48 and 60 months
measure: Health-related quality of life using the 5-dimension health-related quality of life from the uroQol group
timeFrame: at baseline, 3, 6, 12, 24, 36, 48 and 60 months
measure: Disease progression
timeFrame: 60 months
measure: Disease specific mortality
timeFrame: 60 months
measure: All-cause mortality
timeFrame: 60 months
measure: Operating time
timeFrame: Immediately after the procedure
measure: Hospital care stay
timeFrame: Immediately after procedure
measure: Pathology results after biopsy and/or radical prostatectomy
timeFrame: 60 months
measure: Adverse events
timeFrame: 60 months
measure: Cost-effectiveness will be measured using the iMTA Medical Consumption Questionnaire
timeFrame: 60 months
measure: Cost-effectiveness will be measured using the IMTA Productivity Cost Questionnaire
timeFrame: 60 months
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Centre
state: Gelderland
city: Etten-Leur
country: Netherlands
facility: Hifu kliniek
state: Noord-Brabant
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC
state: Noord-Holland
city: Zwolle
country: Netherlands
facility: Isala klinieken
state: Overijssel
city: Nieuwegein
country: Netherlands
facility: St. Antonius hospital
state: Utrecht
Study officials:
References:
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