<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03255135</url>
  </required_header>
  <id_info>
    <org_study_id>HIFU01</org_study_id>
    <nct_id>NCT03255135</nct_id>
  </id_info>
  <brief_title>Initial Experience in Brazilian Single Center With High Intensity Focalized Ultrasound (HIFU) Prostate Cancer Therapy: Morbidity, Oncological and Functional Outcomes.</brief_title>
  <official_title>Initial Experience in Brazilian Single Center With High Intensity Focalized Ultrasound (HIFU) Prostate Cancer Therapy: Morbidity, Oncological and Functional Outcomes.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hospital de Transplante Doutor Euryclides de Jesus Zerbini</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hospital de Transplante Doutor Euryclides de Jesus Zerbini</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Prostate cancer (PCa) is the most prevalent non cutaneous cancer in occidental countries. In&#xD;
      Brazil incidence was about sixty thousand new cases in 2016 and occupied second place as all&#xD;
      cancer mortality, just behind lung cancer. Literature shows than younger patients tend to&#xD;
      have more aggressive tumors rising cancer specific mortality scores. Main risk factors are&#xD;
      age, life style (sedentary, high meat and fat intake) and family history (gene inheritance).&#xD;
&#xD;
      Besides vast advances in precocious tumors detection, challenges remain in the definition of&#xD;
      the biological status of the tumor, which is highly variable and full of prognostic&#xD;
      implications. PCa heterogeneity is demonstrated by the uncertain natural history, varying&#xD;
      from indolent lesion to aggressive metastatic and fast progression cancer resistant to&#xD;
      conventional therapies. In an actual treatment scenario, prognostic identification is the&#xD;
      cornerstone of daily practice treatment considering the natural history variability cited&#xD;
      before and the discrepancy of long term slow growth (studies estimate eight to sixteen years&#xD;
      of tumor growth to achieve metastatic disease) to high grade aggressive cancer.&#xD;
&#xD;
      Considering all this background and taking in account the indolent evolution of low risk PCa&#xD;
      new therapies emerge with promising outcomes. High-Intensity Focused Ultrasound (HIFU) have&#xD;
      to be highlighted due to easy operation, good oncologic results and low complication profile.&#xD;
      The method is based on real-time imaging guided high intensity ultrasound (US) causing&#xD;
      overheat and cavitation in the focused tissue. Applied since 90's, mainly in German and&#xD;
      French groups, initially programmed to treat hole gland preserving only urinary sphincter and&#xD;
      bladder neck, showed recently some data on 1700 patients, 5 years biochemical recurrence free&#xD;
      survival of 80% and best results including morbidity profile in low risk, low prostate volume&#xD;
      and in the group with previous trans urethral prostate resection (TURP). This results are&#xD;
      very similar to other radical treatment options with median follow up of 8 years, cancer&#xD;
      specific survival 98% and metastasis free survival of 95% If local recurrence was identified&#xD;
      another HIFU ablation or even radical treatment achieved good results in local control with&#xD;
      acceptable morbidity profile.&#xD;
&#xD;
      Focal treatment is a new entity in PCa therapy. One randomized trial compared focal treatment&#xD;
      to active surveillance in 513 mans with PCa diagnosis. With a 24 month follow-up&#xD;
      progression-free ratios (28% x 58%) and positive control prostate biopsy ratios (14% x 49%)&#xD;
      were fairly superior in treatment group. This exiting novel data turns urological oncology&#xD;
      paths to the new era of minimally harmful therapy with targeted focused procedure. At our&#xD;
      knowledge there is no high evidence clinical trial comparing HIFU to active surveillance.&#xD;
&#xD;
      The objective of this study is to evaluate prospectively the initial experience with 50&#xD;
      patients submitted to HIFU therapy for low risk prostate cancer in Brazilian single center&#xD;
      considering the following aspects:&#xD;
&#xD;
      One year of treatment prostate biopsy positiveness; Biochemical recurrence free survival&#xD;
      using Phoenix and Stuttgart criteria in one year; Sexual function using IIEF-5 questionnaire&#xD;
      and the usage of 5-phosphodiesterase inhibitors (5-PDI); Urinary symptoms using EPIC and IPSS&#xD;
      questionnaires and free urinary flow; Quality of life based on SF-36 questionnaire&#xD;
      evaluation; Post procedure morbidity using Clavien-Dindo classification.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Prostate cancer (PCa) is the most prevalent non cutaneous cancer in occidental countries. In&#xD;
      Brazil incidence was about sixty thousand new cases in 2016 and occupied second place as all&#xD;
      cancer mortality, just behind lung cancer. Literature shows than younger patients tend to&#xD;
      have more aggressive tumors rising cancer specific mortality scores. Main risk factors are&#xD;
      age, life style (sedentary, high meat and fat intake) and family history (gene inheritance).&#xD;
&#xD;
      Screening programs suggested by urological and oncologic societies, mainly based on Prostate&#xD;
      Specific Antigen (PSA), changed natural history of this disease, overturning past late&#xD;
      diagnosis with advanced disease to early discover in present days, with localized highly&#xD;
      curable cancer by local therapy (surgery or radiation therapy) turning focus on morbidity&#xD;
      status based on the high long term cancer specific survival.&#xD;
&#xD;
      Besides vast advances in precocious tumors detection, challenges remain in the definition of&#xD;
      the biological status of the tumor, which is highly variable and full of prognostic&#xD;
      implications. PCa heterogeneity is demonstrated by the uncertain natural history, varying&#xD;
      from indolent lesion to aggressive metastatic and fast progression cancer resistant to&#xD;
      conventional therapies. In an actual treatment scenario, prognostic identification is the&#xD;
      cornerstone of daily practice treatment considering the natural history variability cited&#xD;
      before and the discrepancy of long term slow growth (studies estimate eight to sixteen years&#xD;
      of tumor growth to achieve metastatic disease) to high grade aggressive cancer.&#xD;
&#xD;
      Aiming to reduce PCa cancer specific mortality, PSA tests associated with digital rectal&#xD;
      examination are the actual standard of care in PCa screening. A randomized clinical trial&#xD;
      demonstrated reduction in the risk of PCa death up to 25% in patients maintaining regular&#xD;
      screening. Risk stratification after tumor diagnosis includes nomograms, most used is D'Amico&#xD;
      score stratifying low, intermediate and high risk cancer based on PSA value, digital rectal&#xD;
      examination, tumor histology and volume. Considering the risk, treatment may be localized,&#xD;
      systemic or active surveillance.&#xD;
&#xD;
      Three randomized trials compared active surveillance with local treatment, one showing&#xD;
      benefit in cancer specific survival with 40% reduction and other two demonstrating comparable&#xD;
      outcomes. Considering this studies results, one important detail was related to metastasis,&#xD;
      pointing that metastasis free survival was better for the treatment group compared to&#xD;
      surveillance. Based on this studies active surveillance was introduced in guidelines and&#xD;
      clinical practice with the benefits of minimizing morbidity and disadvantage of slightly&#xD;
      higher risk of metastasis and local complications.&#xD;
&#xD;
      Radical prostatectomy (RP) have high cure rates, overall survival of 99% and cancer specific&#xD;
      survival superior to 80%, however, deem to have quality of life changing implications that&#xD;
      are at least relevant in this highly curable scenario. Urinary incontinence ranging from&#xD;
      1-15% and erectile dysfunction compromising about 40% of the patients (highly variable&#xD;
      considering previous status, age, comorbidities, local and technical aspects) Radiation&#xD;
      therapy is implied with slightly higher local recurrence when compared to RP, lower&#xD;
      incontinence risk but can damage surrounding structures like bladder and rectum causing&#xD;
      bothersome and difficult to manage bleeding (radiation cystitis and radiation proctitis can&#xD;
      occur in 10 to 20% of patients). In intermediate or high risk groups radiation therapy alone&#xD;
      has inferior oncologic results and is associated with periodic androgen deprivation therapy&#xD;
      (ADT), aggregating other undesired effects (erectile dysfunction, osteopenia, muscular loss&#xD;
      and cardiovascular disease).&#xD;
&#xD;
      Considering all this background and taking in account the indolent evolution of low risk PCa&#xD;
      new therapies emerge with promising outcomes. High-Intensity Focused Ultrasound (HIFU) have&#xD;
      to be highlighted due to easy operation, good oncologic results and low complication profile.&#xD;
      The method is based on real-time imaging guided high intensity ultrasound (US) causing&#xD;
      overheat and cavitation in the focused tissue. Applied since 90's, mainly in German and&#xD;
      French groups, initially programmed to treat hole gland preserving only urinary sphincter and&#xD;
      bladder neck, showed recently some data on 1700 patients, 5 years biochemical recurrence free&#xD;
      survival of 80% and best results including morbidity profile in low risk, low prostate volume&#xD;
      and in the group with previous trans urethral prostate resection (TURP). This results are&#xD;
      very similar to other radical treatment options with median followup of 8 years, cancer&#xD;
      specific survival 98% and metastasis free survival of 95% If local recurrence was identified&#xD;
      another HIFU ablation or even radical treatment achieved good results in local control with&#xD;
      acceptable morbidity profile.&#xD;
&#xD;
      HIFU morbidity profile seems acceptable when compared to the other treatments available.&#xD;
      Urinary incontinence was mostly minor in 1-3%, sexual dysfunction compromised about 50% of&#xD;
      the cases, urethral or bladder neck stricture in 5%. To reach this results, cancer centers&#xD;
      associated TURP before HIFU ablation and optimized patient selection to reach the best of the&#xD;
      method.&#xD;
&#xD;
      In 2014 the US Food and Drug Administration (FDA) approved HIFU use in prostate tissue&#xD;
      ablation, hissing interest in this technology. Up to now 50 thousand patients undergone&#xD;
      prostate ablation with HIFU (half of them to treat PCa). Recently some centers concentrated&#xD;
      their efforts to establish focal treatment for PCa in detriment to hole gland. Focal&#xD;
      treatment seems a good alternative to active surveillance and for a specific group of&#xD;
      patients who are not candidates do radical therapy due to performance status, comorbidities&#xD;
      or personal preferences.&#xD;
&#xD;
      In recent reports about prostate cancer biology, the index lesion seems to be the main&#xD;
      therapy target due to aggressive comportment and higher dissemination potential, different&#xD;
      from the secondary lesions that have indolent growth. Considering this paradigm, treat the&#xD;
      index lesion seems to be a logical way to have good oncologic control with the best treatment&#xD;
      related morbidity status, and is properly possible due to advances in radiologic imaging&#xD;
      diagnosis using multi-parametric prostate magnetic resonance.&#xD;
&#xD;
      Focal treatment is a new entity in PCa therapy. One randomized trial compared focal treatment&#xD;
      to active surveillance in 513 mans with PCa diagnosis. With a 24 month follow-up&#xD;
      progression-free ratios (28% x 58%) and positive control prostate biopsy ratios (14% x 49%)&#xD;
      were fairly superior in treatment group. This exiting novel data turns urological oncology&#xD;
      paths to the new era of minimally harmful therapy with targeted focused procedure. At our&#xD;
      knowledge there is no high evidence clinical trial comparing HIFU to active surveillance.&#xD;
&#xD;
      OBJECTIVE To evaluate prospectively the initial experience with 50 patients submitted to HIFU&#xD;
      therapy for low risk prostate cancer in Brazilian single center.&#xD;
&#xD;
      The research team will evaluate:&#xD;
&#xD;
        1. One year of treatment prostate biopsy positiveness;&#xD;
&#xD;
        2. Biochemical recurrence free survival using Phoenix and Stuttgart criteria in one year;&#xD;
&#xD;
        3. Sexual function using IIEF-5 questionnaire and the usage of 5-phosphodiesterases&#xD;
           inhibitors (5-PDI);&#xD;
&#xD;
        4. Urinary symptoms using EPIC and IPSS questionnaires and free urinary flow;&#xD;
&#xD;
        5. Quality of life based on SF-36 questionnaire evaluation;&#xD;
&#xD;
        6. Post procedure morbidity using Clavien-Dindo classification.&#xD;
&#xD;
      METHODS Patients selection will involve males with recent diagnosis of usual acinar prostate&#xD;
      adenocarcinoma with Gleason score ranging from 6 to 7 (ISUP 1, 2 or 3). Maximum PSA level&#xD;
      cutoff will be 15 with no minimum level. Digital rectal examination demonstrating organ&#xD;
      confined cancer (clinical stage ≤T2c). There will be no limit on patients age and study&#xD;
      candidates may not have been submitted to any Cap treatment. Other exclusion criteria will be&#xD;
      rectal functional or anatomical abnormalities.&#xD;
&#xD;
      After patient entrance by study therm signature, there will be the first medical evaluation&#xD;
      with medical history, full physical examination including digital rectal examination and&#xD;
      pre-treatment questionnaires application (IIEF-5, EPIC, IPSS, SF-36). General blood samples,&#xD;
      free urinary flow and any other examination that will be considered necessary by the&#xD;
      assistant urologist will be collected in the first day of evaluation. Clinical and&#xD;
      demographic data will be collected: age, symptoms, post-treatment complications,&#xD;
      comorbidities, medications in use, previous surgery, alcohol, tobacco and other drugs usage,&#xD;
      weight, height, blood count, urea, creatinine, C reactive protein, PSA (total and free&#xD;
      portion), urine analysis and culture, urinary tract ultrasound, prostate ultrasound (US) with&#xD;
      estimated prostate weight, multi-parametric prostate MRI (when feasible) considering PIRADs&#xD;
      category, extra-prostatic extension, seminal vesicle compromising and lymph node status,&#xD;
      presence of median lobe of prostate, bone scan (if indicated), number of biopsies fragments,&#xD;
      positiveness of fragments, Gleason grade, tumor localization, percentage of tumor&#xD;
      compromising in the fragment, need of previous TURP, bladder catheter usage, free urinary&#xD;
      flow after TURP, pathology evaluation of TURP product, HIFU treatment time, HIFU treatment&#xD;
      protocol (hole gland, half-gland or focal treatment), in hospital stay, time of urethral&#xD;
      catheter usage, analgesics usage, opioids usage and post treatment questionnaires (IIEF-5,&#xD;
      EPIC, IPSS e SF-36).&#xD;
&#xD;
      TREATMENT DESCRIPTION Procedures will take place in single reference urological hospital in&#xD;
      Sao Paulo Brazil, with FocalOneR, Edap TMS, France as the device. Treatment will be planned&#xD;
      in accordance with biopsy laterality in half-gland protocols for unilateral disease and whole&#xD;
      gland ablation for bilateral cases. Neurovascular bundle preservation will occur on the&#xD;
      contralateral side of the disease. Urinary sphincter margin will be planned with 3 millimeter&#xD;
      distance to ensure sphincter preservation.&#xD;
&#xD;
      Every patient with prostate gland volume higher than 40 cc in pre-treatment US or MRI must&#xD;
      have an TURP before ablation. In symptomatic patients with prostate volume lower than 40 cc&#xD;
      assistant urologist clinical judgement will decide between doing or not pre-ablation TURP.&#xD;
&#xD;
      Rectal cleansing with enema is done up to 3 hours before procedure. Prophylactic antibiotic&#xD;
      of choice is second generation cephalosporin (Cefuroxime 1.5 g intravenous), used 30 minutes&#xD;
      before procedure.&#xD;
&#xD;
      Prostate cancer ablation will follow previous established treatment protocol from FocalOne:&#xD;
      general anesthesia, Foley bladder catheter 16 or 18 Fr is inserted just before treatment and&#xD;
      maintained up to 72 hours (Hole gland).&#xD;
&#xD;
      Post ablation medications includes antibiotics and analgesics if necessary. Patient discharge&#xD;
      can take place at same ablation day if procedure finish up to 1 PM, otherwise patient&#xD;
      discharge normally happen in first post-procedure day. Patients discharged with bladder&#xD;
      catheter are orientated to return in ambulatory to take it off up to the third day after&#xD;
      ablation.&#xD;
&#xD;
      FOLLOW UP First follow up medical visit occurs with 15 days after HIFU. Medical interview&#xD;
      will focus on complications and adverse events. Follow up will continue with medical visits&#xD;
      in 3, 6 and 12 months after procedure.&#xD;
&#xD;
      Evaluations in the follow up visits consist in clinical and physical examinations, digital&#xD;
      prostate examination, obtainment of blood samples (PSA). When reaching 12 months after&#xD;
      treatment patients will take another saturation prostate biopsy (20 fragments) for treatment&#xD;
      control. Questionnaires IIEF-5, EPIC, IPSS, SF-36 and free urinary flow will be done at all&#xD;
      medical visits (3, 6 e 12 months).&#xD;
&#xD;
        1. Post HIFU medical visits will occur at 3, 6 e 12 months;&#xD;
&#xD;
        2. First post ablation visit will occur at the 15th day;&#xD;
&#xD;
        3. Medical interview, physical examination with digital rectal prostate examination and&#xD;
           blood sample obtain to PSA analysis will be collected in each of the medical visit&#xD;
           except the PSA collection at 15th day one.&#xD;
&#xD;
        4. 12 months after treatment patients will take another saturation prostate biopsy (20&#xD;
           fragments) for treatment control;&#xD;
&#xD;
        5. Questionnaires IIEF-5, EPIC, IPSS, SF-36 and free urinary flow will be done at all&#xD;
           medical visits (3, 6 e 12 months);&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">May 31, 2018</start_date>
  <completion_date type="Anticipated">July 2019</completion_date>
  <primary_completion_date type="Actual">May 31, 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Prostate cancer biochemical recurrence free survival after prostate cancer focal therapy</measure>
    <time_frame>12 months</time_frame>
    <description>Biochemical recurrence free survival using Phoenix criteria in one year</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Prostate cancer pathological persistence after prostate cancer focal therapy</measure>
    <time_frame>12 months</time_frame>
    <description>One year post-HIFU treatment prostate biopsy positivity</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>IIEF-5 - Sexual function after prostate cancer focal therapy</measure>
    <time_frame>12 months</time_frame>
    <description>Sexual function using IIEF-5 questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>5-PDI - Sexual function after prostate cancer focal therapy</measure>
    <time_frame>12 months</time_frame>
    <description>Sexual function using evaluation of usage of 5-Phosphodiesterase inhibitors (5-PDI)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Free urinary flow - Urinary symptoms after prostate cancer focal therapy</measure>
    <time_frame>12 months</time_frame>
    <description>Urinary symptoms using free urinary flow measure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EPIC - Urinary symptoms after prostate cancer focal therapy</measure>
    <time_frame>12 months</time_frame>
    <description>Urinary symptoms using EPIC questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>IPSS - Urinary symptoms after prostate cancer focal therapy</measure>
    <time_frame>12 months</time_frame>
    <description>Urinary symptoms using IPSS questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life after prostate cancer focal therapy</measure>
    <time_frame>12 months</time_frame>
    <description>Quality of life based on SF-36 questionnaire evaluation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Morbidity after prostate cancer focal therapy</measure>
    <time_frame>12 months</time_frame>
    <description>Post procedure morbidity using Clavien-Dindo classification</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">130</enrollment>
  <condition>Prostate Cancer</condition>
  <condition>Prostate Adenocarcinoma</condition>
  <condition>Transrectal High Intensity Focused Ultrasound</condition>
  <arm_group>
    <arm_group_label>HIFU</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients with untreated recent diagnosed localized prostate cancer candidates of focal therapy.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>HIFU</intervention_name>
    <description>High intensity focused ultrasound prostate cancer therapy guided by biopsy specimens and multiparametric prostate magnetic resonance using Focal One, Edap TMS, France device.</description>
    <arm_group_label>HIFU</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  1. Patients with recent diagnosis of usual adenocarcinoma of prostate untreated and&#xD;
             with indication of specific treatment by the assisting urologist;&#xD;
&#xD;
          -  2. And low or intermediate prostate cancer in clinical staging;&#xD;
&#xD;
          -  3. And concordance with the clinical trial by signing the terms.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  1. Other types of prostate cancer not usual adenocarcinoma;&#xD;
&#xD;
          -  2. Or any previous treatment to prostate cancer;&#xD;
&#xD;
          -  3. Or any patient who presents with proctologic abnormalities;&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>30 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Hospital de Transplantes Euryclides de Jesus Zerbini</name>
      <address>
        <city>Sao Paulo</city>
        <zip>01401901</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
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    <citation>Wallis CJD, Saskin R, Choo R, Herschorn S, Kodama RT, Satkunasivam R, Shah PS, Danjoux C, Nam RK. Surgery Versus Radiotherapy for Clinically-localized Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol. 2016 Jul;70(1):21-30. doi: 10.1016/j.eururo.2015.11.010. Epub 2015 Dec 15.</citation>
    <PMID>26700655</PMID>
  </reference>
  <reference>
    <citation>Gelet A, Chapelon JY, Bouvier R, Souchon R, Pangaud C, Abdelrahim AF, Cathignol D, Dubernard JM. Treatment of prostate cancer with transrectal focused ultrasound: early clinical experience. Eur Urol. 1996;29(2):174-83.</citation>
    <PMID>8647143</PMID>
  </reference>
  <reference>
    <citation>Thuroff S, Chaussy C. Evolution and outcomes of 3 MHz high intensity focused ultrasound therapy for localized prostate cancer during 15 years. J Urol. 2013 Aug;190(2):702-10. doi: 10.1016/j.juro.2013.02.010. Epub 2013 Feb 13.</citation>
    <PMID>23415962</PMID>
  </reference>
  <reference>
    <citation>Crouzet S, Chapelon JY, Rouviere O, Mege-Lechevallier F, Colombel M, Tonoli-Catez H, Martin X, Gelet A. Whole-gland ablation of localized prostate cancer with high-intensity focused ultrasound: oncologic outcomes and morbidity in 1002 patients. Eur Urol. 2014 May;65(5):907-14. doi: 10.1016/j.eururo.2013.04.039. Epub 2013 Apr 30.</citation>
    <PMID>23669165</PMID>
  </reference>
  <reference>
    <citation>van Velthoven R, Aoun F, Marcelis Q, Albisinni S, Zanaty M, Lemort M, Peltier A, Limani K. A prospective clinical trial of HIFU hemiablation for clinically localized prostate cancer. Prostate Cancer Prostatic Dis. 2016 Mar;19(1):79-83. doi: 10.1038/pcan.2015.55. Epub 2015 Nov 24.</citation>
    <PMID>26597660</PMID>
  </reference>
  <reference>
    <citation>Feijoo ER, Sivaraman A, Barret E, Sanchez-Salas R, Galiano M, Rozet F, Prapotnich D, Cathala N, Mombet A, Cathelineau X. Focal High-intensity Focused Ultrasound Targeted Hemiablation for Unilateral Prostate Cancer: A Prospective Evaluation of Oncologic and Functional Outcomes. Eur Urol. 2016 Feb;69(2):214-20. doi: 10.1016/j.eururo.2015.06.018. Epub 2015 Jul 9.</citation>
    <PMID>26164416</PMID>
  </reference>
  <reference>
    <citation>Ahmed HU. The index lesion and the origin of prostate cancer. N Engl J Med. 2009 Oct 22;361(17):1704-6. doi: 10.1056/NEJMcibr0905562. No abstract available.</citation>
    <PMID>19846858</PMID>
  </reference>
  <reference>
    <citation>Azzouzi AR, Vincendeau S, Barret E, Cicco A, Kleinclauss F, van der Poel HG, Stief CG, Rassweiler J, Salomon G, Solsona E, Alcaraz A, Tammela TT, Rosario DJ, Gomez-Veiga F, Ahlgren G, Benzaghou F, Gaillac B, Amzal B, Debruyne FM, Fromont G, Gratzke C, Emberton M; PCM301 Study Group. Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk prostate cancer (CLIN1001 PCM301): an open-label, phase 3, randomised controlled trial. Lancet Oncol. 2017 Feb;18(2):181-191. doi: 10.1016/S1470-2045(16)30661-1. Epub 2016 Dec 20.</citation>
    <PMID>28007457</PMID>
  </reference>
  <reference>
    <citation>Rischmann P, Gelet A, Riche B, Villers A, Pasticier G, Bondil P, Jung JL, Bugel H, Petit J, Toledano H, Mallick S, Rouviere O, Rabilloud M, Tonoli-Catez H, Crouzet S. Focal High Intensity Focused Ultrasound of Unilateral Localized Prostate Cancer: A Prospective Multicentric Hemiablation Study of 111 Patients. Eur Urol. 2017 Feb;71(2):267-273. doi: 10.1016/j.eururo.2016.09.039. Epub 2016 Oct 6.</citation>
    <PMID>27720531</PMID>
  </reference>
  <reference>
    <citation>Ahmed HU, Hindley RG, Dickinson L, Freeman A, Kirkham AP, Sahu M, Scott R, Allen C, Van der Meulen J, Emberton M. Focal therapy for localised unifocal and multifocal prostate cancer: a prospective development study. Lancet Oncol. 2012 Jun;13(6):622-32. doi: 10.1016/S1470-2045(12)70121-3. Epub 2012 Apr 17.</citation>
    <PMID>22512844</PMID>
  </reference>
  <reference>
    <citation>Barret E, Ahallal Y, Sanchez-Salas R, Galiano M, Cosset JM, Validire P, Macek P, Durand M, Prapotnich D, Rozet F, Cathelineau X. Morbidity of focal therapy in the treatment of localized prostate cancer. Eur Urol. 2013 Apr;63(4):618-22. doi: 10.1016/j.eururo.2012.11.057. Epub 2012 Dec 13.</citation>
    <PMID>23265382</PMID>
  </reference>
  <verification_date>June 2019</verification_date>
  <study_first_submitted>August 9, 2017</study_first_submitted>
  <study_first_submitted_qc>August 16, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 21, 2017</study_first_posted>
  <last_update_submitted>June 26, 2019</last_update_submitted>
  <last_update_submitted_qc>June 26, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">June 27, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prostatic Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03255135
org study id: HIFU01
nct id: NCT03255135
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Prostate cancer (PCa) is the most prevalent non cutaneous cancer in occidental countries. In
      Brazil incidence was about sixty thousand new cases in 2016 and occupied second place as all
      cancer mortality, just behind lung cancer. Literature shows than younger patients tend to
      have more aggressive tumors rising cancer specific mortality scores. Main risk factors are
      age, life style (sedentary, high meat and fat intake) and family history (gene inheritance).

      Besides vast advances in precocious tumors detection, challenges remain in the definition of
      the biological status of the tumor, which is highly variable and full of prognostic
      implications. PCa heterogeneity is demonstrated by the uncertain natural history, varying
      from indolent lesion to aggressive metastatic and fast progression cancer resistant to
      conventional therapies. In an actual treatment scenario, prognostic identification is the
      cornerstone of daily practice treatment considering the natural history variability cited
      before and the discrepancy of long term slow growth (studies estimate eight to sixteen years
      of tumor growth to achieve metastatic disease) to high grade aggressive cancer.

      Considering all this background and taking in account the indolent evolution of low risk PCa
      new therapies emerge with promising outcomes. High-Intensity Focused Ultrasound (HIFU) have
      to be highlighted due to easy operation, good oncologic results and low complication profile.
      The method is based on real-time imaging guided high intensity ultrasound (US) causing
      overheat and cavitation in the focused tissue. Applied since 90's, mainly in German and
      French groups, initially programmed to treat hole gland preserving only urinary sphincter and
      bladder neck, showed recently some data on 1700 patients, 5 years biochemical recurrence free
      survival of 80% and best results including morbidity profile in low risk, low prostate volume
      and in the group with previous trans urethral prostate resection (TURP). This results are
      very similar to other radical treatment options with median follow up of 8 years, cancer
      specific survival 98% and metastasis free survival of 95% If local recurrence was identified
      another HIFU ablation or even radical treatment achieved good results in local control with
      acceptable morbidity profile.

      Focal treatment is a new entity in PCa therapy. One randomized trial compared focal treatment
      to active surveillance in 513 mans with PCa diagnosis. With a 24 month follow-up
      progression-free ratios (28% x 58%) and positive control prostate biopsy ratios (14% x 49%)
      were fairly superior in treatment group. This exiting novel data turns urological oncology
      paths to the new era of minimally harmful therapy with targeted focused procedure. At our
      knowledge there is no high evidence clinical trial comparing HIFU to active surveillance.

      The objective of this study is to evaluate prospectively the initial experience with 50
      patients submitted to HIFU therapy for low risk prostate cancer in Brazilian single center
      considering the following aspects:

      One year of treatment prostate biopsy positiveness; Biochemical recurrence free survival
      using Phoenix and Stuttgart criteria in one year; Sexual function using IIEF-5 questionnaire
      and the usage of 5-phosphodiesterase inhibitors (5-PDI); Urinary symptoms using EPIC and IPSS
      questionnaires and free urinary flow; Quality of life based on SF-36 questionnaire
      evaluation; Post procedure morbidity using Clavien-Dindo classification.
Prostate cancer (PCa) is the most prevalent non cutaneous cancer in occidental countries. In
      Brazil incidence was about sixty thousand new cases in 2016 and occupied second place as all
      cancer mortality, just behind lung cancer. Literature shows than younger patients tend to
      have more aggressive tumors rising cancer specific mortality scores. Main risk factors are
      age, life style (sedentary, high meat and fat intake) and family history (gene inheritance).

      Screening programs suggested by urological and oncologic societies, mainly based on Prostate
      Specific Antigen (PSA), changed natural history of this disease, overturning past late
      diagnosis with advanced disease to early discover in present days, with localized highly
      curable cancer by local therapy (surgery or radiation therapy) turning focus on morbidity
      status based on the high long term cancer specific survival.

      Besides vast advances in precocious tumors detection, challenges remain in the definition of
      the biological status of the tumor, which is highly variable and full of prognostic
      implications. PCa heterogeneity is demonstrated by the uncertain natural history, varying
      from indolent lesion to aggressive metastatic and fast progression cancer resistant to
      conventional therapies. In an actual treatment scenario, prognostic identification is the
      cornerstone of daily practice treatment considering the natural history variability cited
      before and the discrepancy of long term slow growth (studies estimate eight to sixteen years
      of tumor growth to achieve metastatic disease) to high grade aggressive cancer.

      Aiming to reduce PCa cancer specific mortality, PSA tests associated with digital rectal
      examination are the actual standard of care in PCa screening. A randomized clinical trial
      demonstrated reduction in the risk of PCa death up to 25% in patients maintaining regular
      screening. Risk stratification after tumor diagnosis includes nomograms, most used is D'Amico
      score stratifying low, intermediate and high risk cancer based on PSA value, digital rectal
      examination, tumor histology and volume. Considering the risk, treatment may be localized,
      systemic or active surveillance.

      Three randomized trials compared active surveillance with local treatment, one showing
      benefit in cancer specific survival with 40% reduction and other two demonstrating comparable
      outcomes. Considering this studies results, one important detail was related to metastasis,
      pointing that metastasis free survival was better for the treatment group compared to
      surveillance. Based on this studies active surveillance was introduced in guidelines and
      clinical practice with the benefits of minimizing morbidity and disadvantage of slightly
      higher risk of metastasis and local complications.

      Radical prostatectomy (RP) have high cure rates, overall survival of 99% and cancer specific
      survival superior to 80%, however, deem to have quality of life changing implications that
      are at least relevant in this highly curable scenario. Urinary incontinence ranging from
      1-15% and erectile dysfunction compromising about 40% of the patients (highly variable
      considering previous status, age, comorbidities, local and technical aspects) Radiation
      therapy is implied with slightly higher local recurrence when compared to RP, lower
      incontinence risk but can damage surrounding structures like bladder and rectum causing
      bothersome and difficult to manage bleeding (radiation cystitis and radiation proctitis can
      occur in 10 to 20% of patients). In intermediate or high risk groups radiation therapy alone
      has inferior oncologic results and is associated with periodic androgen deprivation therapy
      (ADT), aggregating other undesired effects (erectile dysfunction, osteopenia, muscular loss
      and cardiovascular disease).

      Considering all this background and taking in account the indolent evolution of low risk PCa
      new therapies emerge with promising outcomes. High-Intensity Focused Ultrasound (HIFU) have
      to be highlighted due to easy operation, good oncologic results and low complication profile.
      The method is based on real-time imaging guided high intensity ultrasound (US) causing
      overheat and cavitation in the focused tissue. Applied since 90's, mainly in German and
      French groups, initially programmed to treat hole gland preserving only urinary sphincter and
      bladder neck, showed recently some data on 1700 patients, 5 years biochemical recurrence free
      survival of 80% and best results including morbidity profile in low risk, low prostate volume
      and in the group with previous trans urethral prostate resection (TURP). This results are
      very similar to other radical treatment options with median followup of 8 years, cancer
      specific survival 98% and metastasis free survival of 95% If local recurrence was identified
      another HIFU ablation or even radical treatment achieved good results in local control with
      acceptable morbidity profile.

      HIFU morbidity profile seems acceptable when compared to the other treatments available.
      Urinary incontinence was mostly minor in 1-3%, sexual dysfunction compromised about 50% of
      the cases, urethral or bladder neck stricture in 5%. To reach this results, cancer centers
      associated TURP before HIFU ablation and optimized patient selection to reach the best of the
      method.

      In 2014 the US Food and Drug Administration (FDA) approved HIFU use in prostate tissue
      ablation, hissing interest in this technology. Up to now 50 thousand patients undergone
      prostate ablation with HIFU (half of them to treat PCa). Recently some centers concentrated
      their efforts to establish focal treatment for PCa in detriment to hole gland. Focal
      treatment seems a good alternative to active surveillance and for a specific group of
      patients who are not candidates do radical therapy due to performance status, comorbidities
      or personal preferences.

      In recent reports about prostate cancer biology, the index lesion seems to be the main
      therapy target due to aggressive comportment and higher dissemination potential, different
      from the secondary lesions that have indolent growth. Considering this paradigm, treat the
      index lesion seems to be a logical way to have good oncologic control with the best treatment
      related morbidity status, and is properly possible due to advances in radiologic imaging
      diagnosis using multi-parametric prostate magnetic resonance.

      Focal treatment is a new entity in PCa therapy. One randomized trial compared focal treatment
      to active surveillance in 513 mans with PCa diagnosis. With a 24 month follow-up
      progression-free ratios (28% x 58%) and positive control prostate biopsy ratios (14% x 49%)
      were fairly superior in treatment group. This exiting novel data turns urological oncology
      paths to the new era of minimally harmful therapy with targeted focused procedure. At our
      knowledge there is no high evidence clinical trial comparing HIFU to active surveillance.

      OBJECTIVE To evaluate prospectively the initial experience with 50 patients submitted to HIFU
      therapy for low risk prostate cancer in Brazilian single center.

      The research team will evaluate:

        1. One year of treatment prostate biopsy positiveness;

        2. Biochemical recurrence free survival using Phoenix and Stuttgart criteria in one year;

        3. Sexual function using IIEF-5 questionnaire and the usage of 5-phosphodiesterases
           inhibitors (5-PDI);

        4. Urinary symptoms using EPIC and IPSS questionnaires and free urinary flow;

        5. Quality of life based on SF-36 questionnaire evaluation;

        6. Post procedure morbidity using Clavien-Dindo classification.

      METHODS Patients selection will involve males with recent diagnosis of usual acinar prostate
      adenocarcinoma with Gleason score ranging from 6 to 7 (ISUP 1, 2 or 3). Maximum PSA level
      cutoff will be 15 with no minimum level. Digital rectal examination demonstrating organ
      confined cancer (clinical stage ≤T2c). There will be no limit on patients age and study
      candidates may not have been submitted to any Cap treatment. Other exclusion criteria will be
      rectal functional or anatomical abnormalities.

      After patient entrance by study therm signature, there will be the first medical evaluation
      with medical history, full physical examination including digital rectal examination and
      pre-treatment questionnaires application (IIEF-5, EPIC, IPSS, SF-36). General blood samples,
      free urinary flow and any other examination that will be considered necessary by the
      assistant urologist will be collected in the first day of evaluation. Clinical and
      demographic data will be collected: age, symptoms, post-treatment complications,
      comorbidities, medications in use, previous surgery, alcohol, tobacco and other drugs usage,
      weight, height, blood count, urea, creatinine, C reactive protein, PSA (total and free
      portion), urine analysis and culture, urinary tract ultrasound, prostate ultrasound (US) with
      estimated prostate weight, multi-parametric prostate MRI (when feasible) considering PIRADs
      category, extra-prostatic extension, seminal vesicle compromising and lymph node status,
      presence of median lobe of prostate, bone scan (if indicated), number of biopsies fragments,
      positiveness of fragments, Gleason grade, tumor localization, percentage of tumor
      compromising in the fragment, need of previous TURP, bladder catheter usage, free urinary
      flow after TURP, pathology evaluation of TURP product, HIFU treatment time, HIFU treatment
      protocol (hole gland, half-gland or focal treatment), in hospital stay, time of urethral
      catheter usage, analgesics usage, opioids usage and post treatment questionnaires (IIEF-5,
      EPIC, IPSS e SF-36).

      TREATMENT DESCRIPTION Procedures will take place in single reference urological hospital in
      Sao Paulo Brazil, with FocalOneR, Edap TMS, France as the device. Treatment will be planned
      in accordance with biopsy laterality in half-gland protocols for unilateral disease and whole
      gland ablation for bilateral cases. Neurovascular bundle preservation will occur on the
      contralateral side of the disease. Urinary sphincter margin will be planned with 3 millimeter
      distance to ensure sphincter preservation.

      Every patient with prostate gland volume higher than 40 cc in pre-treatment US or MRI must
      have an TURP before ablation. In symptomatic patients with prostate volume lower than 40 cc
      assistant urologist clinical judgement will decide between doing or not pre-ablation TURP.

      Rectal cleansing with enema is done up to 3 hours before procedure. Prophylactic antibiotic
      of choice is second generation cephalosporin (Cefuroxime 1.5 g intravenous), used 30 minutes
      before procedure.

      Prostate cancer ablation will follow previous established treatment protocol from FocalOne:
      general anesthesia, Foley bladder catheter 16 or 18 Fr is inserted just before treatment and
      maintained up to 72 hours (Hole gland).

      Post ablation medications includes antibiotics and analgesics if necessary. Patient discharge
      can take place at same ablation day if procedure finish up to 1 PM, otherwise patient
      discharge normally happen in first post-procedure day. Patients discharged with bladder
      catheter are orientated to return in ambulatory to take it off up to the third day after
      ablation.

      FOLLOW UP First follow up medical visit occurs with 15 days after HIFU. Medical interview
      will focus on complications and adverse events. Follow up will continue with medical visits
      in 3, 6 and 12 months after procedure.

      Evaluations in the follow up visits consist in clinical and physical examinations, digital
      prostate examination, obtainment of blood samples (PSA). When reaching 12 months after
      treatment patients will take another saturation prostate biopsy (20 fragments) for treatment
      control. Questionnaires IIEF-5, EPIC, IPSS, SF-36 and free urinary flow will be done at all
      medical visits (3, 6 e 12 months).

        1. Post HIFU medical visits will occur at 3, 6 e 12 months;

        2. First post ablation visit will occur at the 15th day;

        3. Medical interview, physical examination with digital rectal prostate examination and
           blood sample obtain to PSA analysis will be collected in each of the medical visit
           except the PSA collection at 15th day one.

        4. 12 months after treatment patients will take another saturation prostate biopsy (20
           fragments) for treatment control;

        5. Questionnaires IIEF-5, EPIC, IPSS, SF-36 and free urinary flow will be done at all
           medical visits (3, 6 e 12 months);
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Prostate cancer biochemical recurrence free survival after prostate cancer focal therapy
time frame: 12 months
description: Biochemical recurrence free survival using Phoenix criteria in one year
measure: Prostate cancer pathological persistence after prostate cancer focal therapy
time frame: 12 months
description: One year post-HIFU treatment prostate biopsy positivity
measure: IIEF-5 - Sexual function after prostate cancer focal therapy
time frame: 12 months
description: Sexual function using IIEF-5 questionnaire
measure: 5-PDI - Sexual function after prostate cancer focal therapy
time frame: 12 months
description: Sexual function using evaluation of usage of 5-Phosphodiesterase inhibitors (5-PDI)
measure: Free urinary flow - Urinary symptoms after prostate cancer focal therapy
time frame: 12 months
description: Urinary symptoms using free urinary flow measure
measure: EPIC - Urinary symptoms after prostate cancer focal therapy
time frame: 12 months
description: Urinary symptoms using EPIC questionnaire
measure: IPSS - Urinary symptoms after prostate cancer focal therapy
time frame: 12 months
description: Urinary symptoms using IPSS questionnaire
measure: Quality of life after prostate cancer focal therapy
time frame: 12 months
description: Quality of life based on SF-36 questionnaire evaluation
measure: Morbidity after prostate cancer focal therapy
time frame: 12 months
description: Post procedure morbidity using Clavien-Dindo classification
arm group label: HIFU
arm group type: Experimental
description: Patients with untreated recent diagnosed localized prostate cancer candidates of focal therapy.
intervention type: Device
intervention name: HIFU
description: High intensity focused ultrasound prostate cancer therapy guided by biopsy specimens and multiparametric prostate magnetic resonance using Focal One, Edap TMS, France device.
arm group label: HIFU
criteria: 
gender: Male
minimum age: 30 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: Brazil
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citation: Wallis CJD, Saskin R, Choo R, Herschorn S, Kodama RT, Satkunasivam R, Shah PS, Danjoux C, Nam RK. Surgery Versus Radiotherapy for Clinically-localized Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol. 2016 Jul;70(1):21-30. doi: 10.1016/j.eururo.2015.11.010. Epub 2015 Dec 15.
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citation: Gelet A, Chapelon JY, Bouvier R, Souchon R, Pangaud C, Abdelrahim AF, Cathignol D, Dubernard JM. Treatment of prostate cancer with transrectal focused ultrasound: early clinical experience. Eur Urol. 1996;29(2):174-83.
PMID: 8647143
citation: Thuroff S, Chaussy C. Evolution and outcomes of 3 MHz high intensity focused ultrasound therapy for localized prostate cancer during 15 years. J Urol. 2013 Aug;190(2):702-10. doi: 10.1016/j.juro.2013.02.010. Epub 2013 Feb 13.
PMID: 23415962
citation: Crouzet S, Chapelon JY, Rouviere O, Mege-Lechevallier F, Colombel M, Tonoli-Catez H, Martin X, Gelet A. Whole-gland ablation of localized prostate cancer with high-intensity focused ultrasound: oncologic outcomes and morbidity in 1002 patients. Eur Urol. 2014 May;65(5):907-14. doi: 10.1016/j.eururo.2013.04.039. Epub 2013 Apr 30.
PMID: 23669165
citation: van Velthoven R, Aoun F, Marcelis Q, Albisinni S, Zanaty M, Lemort M, Peltier A, Limani K. A prospective clinical trial of HIFU hemiablation for clinically localized prostate cancer. Prostate Cancer Prostatic Dis. 2016 Mar;19(1):79-83. doi: 10.1038/pcan.2015.55. Epub 2015 Nov 24.
PMID: 26597660
citation: Feijoo ER, Sivaraman A, Barret E, Sanchez-Salas R, Galiano M, Rozet F, Prapotnich D, Cathala N, Mombet A, Cathelineau X. Focal High-intensity Focused Ultrasound Targeted Hemiablation for Unilateral Prostate Cancer: A Prospective Evaluation of Oncologic and Functional Outcomes. Eur Urol. 2016 Feb;69(2):214-20. doi: 10.1016/j.eururo.2015.06.018. Epub 2015 Jul 9.
PMID: 26164416
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PMID: 23265382
responsible party type: Sponsor
mesh term: Prostatic Neoplasms
sharing ipd: No