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Hemi-Ablative Prostate Brachytherapy (HAPpy)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02632669
Recruitment Status : Active, not recruiting
First Posted : December 17, 2015
Last Update Posted : April 11, 2018
Sponsor:
Information provided by (Responsible Party):
Stephen Langley, Royal Surrey County Hospital NHS Foundation Trust

Tracking Information
First Submitted Date  ICMJE November 16, 2015
First Posted Date  ICMJE December 17, 2015
Last Update Posted Date April 11, 2018
Study Start Date  ICMJE November 2013
Estimated Primary Completion Date April 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 17, 2015)
  • Treatment related Urinary toxicity (symptoms) as recorded by the IPSS questionnaire score. [ Time Frame: 2 years ]
    The International Prostate Symptom Score (IPSS) validated questionnaire will be used to score urinary toxicity (symptoms) after hemigland focal brachytherapy. Scores (mild = 0 to 7; moderate = 8 to 19; severe = 20 to 35) will be obtained pre-treatment and the outcomes reported as the change in score at 6 weeks, 3, 6, 9, 12, 18 and 24 months after treatment.
  • Treatment related Quality of Life (QoL) due to urinary symptoms as recorded by the Quality of Life (QoL) component of the IPSS questionnaire score. [ Time Frame: 2 years ]
    The QoL component of the IPSS questionnaire will be used to score QoL due to urinary symptoms that may arise after hemigland focal brachytherapy. Scores (good = 0 to 2 ; acceptable = 3 to 4 ; poor = 5 to 6) will be obtained pre-treatment and the outcomes reported as the change in score at 6 weeks, 3, 6, 9, 12, 18 and 24 months after treatment.
  • Treatment related bowel toxicity (symptoms) as recorded by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) questionnaire (30 PR 25) score. [ Time Frame: 2 years ]
    The EORTC QoL 30 PR 25 questionnaire will be used to score bowel toxicity (symptoms) after hemigland focal brachytherapy. Scores (normal bowel function = 4; mild bowel toxicity = 5 to 8 ; moderate toxicity = 9 to 12 ; severe toxicity = 13 to 16) will be obtained pre-treatment and the outcomes reported as the change in score at 6 weeks, 3, 6, 9, 12, 18 and 24 months after treatment.
  • Treatment related adverse events on Erectile function as recorded by the International Index of Erectile Function 5 (IIEF 5) questionnaire score. [ Time Frame: 2 years ]
    The IIEF 5 validated questionnaire will be used to score erectile function after hemigland focal brachytherapy. Scores (no erectile dysfunction (ED) = 22 to 25; mild ED = 17 to 21; mild to moderate ED = 12 to 16; moderate ED = 8 to 11; severe ED = 5 to 7) will be obtained pre-treatment and the outcomes reported as the change in score at 6 weeks, 3, 6, 9,12,18 and 24 months after treatment.
Original Primary Outcome Measures  ICMJE
 (submitted: December 13, 2015)
To assess the effect of hemigland focal brachytherapy on urinary and bowel toxicity, erectile function and urinary quality of life by means of self - reported patient symptom scores. [ Time Frame: 2 years ]
Urinary toxicity assessment by International Prostate Symptom Score (IPSS). Scores: mild = 0 - 7; moderate = 8 - 19; severe = 20 - 35 Bowel toxicity by European Organisation for Research and Treatment of Cancer Quality of Life (QOL) 30 PR 25 subscale for bowel symptoms. Scores:normal bowel function =4; mild bowel toxicity = 5 - 8 ; moderate toxicity = 9 - 12 ; severe toxicity = 13 - 16. Erectile function by International Index of Erectile Function 5 (IIEF). Scores: no erectile dysfunction (ED)= 22-25; mild ED 17-21; mild to moderate ED 12-16; moderate ED 8-11; severe ED 5-7. Quality of life secondary to urinary symptoms assessment by QOL component of IPSS questionnaire. Scores: 0 - 2 good ; 3 - 4 acceptable; 5 - 6 poor Scores obtained at baseline and 6 weeks, 3, 6, 9,12,18, 24 months after treatment. Outcomes will be reported as change in score from baseline to the various time points.
Change History Complete list of historical versions of study NCT02632669 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 13, 2015)
To evaluate tumor control of hemigland focal brachytherapy [ Time Frame: 2 years ]
The absence of clinically significant cancer in either treated or untreated prostate hemigland will be determined by Gleason score of transperineal template biopsy cores together with PI-RADS score of MRI imaging (T2, DWI and DCE) at two years after treatment.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Hemi-Ablative Prostate Brachytherapy
Official Title  ICMJE A Prospective Stage 2S Clinical Trial Evaluating Hemi-Ablative Low Dose Rate (LDR) Brachytherapy for Localised Prostate Cancer
Brief Summary

This clinical study will evaluate side effects, quality of life and cancer control in patients with prostate cancer diagnosed on only one side of the prostate gland.

The diagnosis of unilateral prostate cancer will be made by means of a prostate transperineal template biopsy (TTB) and multiparametric magnetic resonance imaging (mpMRI).

Patients will be treated with low dose rate brachytherapy, using permanent iodine seed implants.Treatment will be limited to the side of the gland where the cancer has been diagnosed and is therefore called "focal" brachytherapy.

Prostate brachytherapy is usually applied to the whole prostate gland. After whole gland prostate brachytherapy urinary, bowel and sexual function may be affected. In this focal approach, the side effects will be evaluated by means of patient questionnaires.These will be repeated at various intervals after treatment.The results will be compared to the same questionnaires responded by patients who have undergone whole gland brachytherapy.Therefore an assessment can be made whether focal therapy produces fewer side effects than whole gland brachytherapy.The observation period will last for two years after treatment. A biopsy and mpMRI will be repeated after two years to evaluate prostate cancer control.

Detailed Description

This is a pilot Stage IIS study to evaluate the feasibility of performing a larger multicentre trial.The HAPpy study is a prospective development study offering hemi ablative LDR brachytherapy to 34 men with histologically proven low or intermediate risk localised prostate adenocarcinoma which affects a single lobe of the prostate.The data obtained from these 34 patients will be compared to matched patients from a retrospective cohort of whole gland brachytherapy patients treated in the same institution.Precise mapping and characterisation of the disease will be established using mp-MRI (T2-weighted and DCE(gadolinium)) imaging and transperineal template biopsy (TTB). Only the lobes with disease (left or right half of the gland) will be treated provided that the contralateral side is free of disease. Patients will be followed for two years post treatment at which time a further mp-MRI and TTB will confirm disease control outcomes.

Focal therapy for prostate cancer is a new idea and is considered an experimental treatment which needs to be evaluated within carefully conducted clinical trials . Rather than investigating focal therapy in a strict sense where only known areas of disease are treated, a more conservative approach needs to be taken until more information can be obtained regarding the outcomes of changing treatment techniques. Hemi-ablative focal therapy is considered to be a low-risk treatment and investigations into the performance of the technique should provide a pathway for future investigations of less conservative methodologies. Hemi-ablative focal therapy treats half of the prostate gland with a treatment margin, effectively treating at least 50% of the whole gland with a prescription dose. In theory, this should lessen the side effects associated with radical treatment while still maintaining disease control.This type of treatment is only suitable for patients with unilateral disease.

An international group of experts was established to form a consensus on how to design and conduct an LDR focal brachytherapy program for clinical trials. The group's findings were published by Langley et al and a dosimetric modelling study by Al Qaisieh et al.

Focal hemi gland brachytherapy will be delivered by means of an adaptation of same real-time planning technique (denominated 4D Brachytherapy) used to deliver whole gland LDR prostate brachytherapy. Stranded iodine 125 sources are implanted on the periphery of the prostate gland and loose iodine 125 sources are implanted within the central volume of the gland. Because all planning and dosimetry are done in real-time, radiotherapy physics will be able to adhere to the strict planning protocols required for this study.

Treatment planning: For standard whole-gland treatment, the whole prostate gland is delineated to form the Planning Target Volume (PTV) and the V100 is planned such that it covers the entire PTV plus a 0.5cm margin. For hemi-ablative focal treatments, the prostate will be divided into half and a new HTV (called the HemiTreatment Volume) is outlined on the side of the prostate determined to have clinically significant disease. A treatment margin of 0.5cm is considered around the HTV, which is similar when planning whole-gland treatment. In this way, >95% of the HTV is aimed to receive 100% of the prescription dose (V100). The V150 is situated in a semi-horseshoe shape in order to spare the urethra from high doses of radiation.

Dose parameters to critical organs are as follows:-

HEMI PROSTATE:

Prescription Dose 145Gy V100 = >95% V150 = 50-60% D90 = 140 - 160 Gy

URETHRA:

V150 <15%

RECTUM:

D0.1cc <200 Gy

The trial design follows recommendations published by the Balliol Collaboration under the Idea, Development, Exploration, Assessment, Long-termfollow-up (IDEAL) model for a surgical study.

Data Collection and Statistics

  1. Sample Size- Pilot Study There are no published results available and this technique has not been trialled to determine its effectiveness in disease control and quality of life outcomes. As such, a preliminary study is necessary to determine efficacy and feasibility before a large, multi-centre trial can be performed where a significant number of patients can be recruited for appropriate statistical analysis.

    The trial site currently treats ~300 patients per year for whole-gland brachytherapy. Of these 300 patients, ~25% present with unilateral disease that is low and intermediate risk. Recruitment will be over 18 months, in which time 100 patients should be eligible for the HAPpy trial. We anticipate a 25% drop-out rate after mp- MRI and TPM biopsy results and a further 25% drop-out due to refusal to participate. This means that ~50 patients should be available for recruitment into the study over an 18 month period. In order to assess a decrease in side-effects (based on quality of life (QoL)) data of at least 10%, 34 patients will be required for the study. This is comparing two independent groups (prospective hemi group versus retrospective whole-gland group) when using α = 5%, β = 10%, and σ = 20%.

  2. Data collection The main research co-ordinator is a qualified and experienced data manager. Data will be collected in both paper and electronic form and the data will be stored in one place and backed up twice on two different servers. Data will be held according to the Data Protection Act 1998 and pseudo anonymised as necessary. Each participant will be given a study number and this will be used on all of their study records. The patient number will be known to the chief investigator, the research co-ordinator, and the research radiographer or nurse assigned to the study. Data will be kept in a secure manner in the research offices with access to named individuals from the study group only. The paper records will be kept for a minimum of 10 years after the end of the study. A research radiographer or nurse will be appointed at the time of trial commencement to ensure that the Quality of Life (QOL) questionnaires are completed at each follow-up visit as required by the trial protocol. The research radiographer or nurse is also responsible for ensuring that each patient in the trial has appropriate appointments set up for each treatment, scanning (mp-MRI, biopsy), and follow-up visit and the necessary information is collected at each visit under the protocol. All clinic visit information including questionnaires, scans, biopsy results, and blood results will be kept in study records.
  3. Analysis Thirty-four patients will be examined in the HAPpy trial and with this small sample number, non-parametric analysis of the data will be the most suitable. Patients will be paired or matched according to their tumour staging and pathology, age, and baseline scores. The Mann-Whitney U test, the Wilcoxon test, as well as tests for normality (if appropriate) of the data will be performed to determine if there are differences in the trial groups. Analysis of variance will be performed if the data is appropriate to use in this manner.

    Data to be collected:- IPSS + QoL questionnaire = Numerical scores, time-points IIEFF-5 QoL questionnaire = Numerical scores, time-points EORTC QoL 30, PR25 bowel symptoms questionnaire = Numerical scores, time-points Dosimetry Values for PTV and HTV = Numerical V100, V150, D90 = Numerical Dose to the Urethra (V150) = Numerical Dose to the Rectum (D0.1cc) = Numerical Pathology review of biopsies (all) Standard reporting, qualitative, ranked mm of core invaded = Numerical Biopsy % core invaded = Numerical PSA = Numerical, time-points EN2 = Numerical, time-points Gleason Score= Numerical Staging = Standard reporting, qualitative, ranked

    Outcomes will be reported as estimates with 95% confidence intervals using appropriate methods based on the type of data. For patient reported outcomes with available baseline measurements, a comparison will be made with baseline values using paired analyses. Logistic regression will be used to investigate associations with potential risk factors for histological failure, considering PSA and EN2, Gleason score, cancer core length involvement (mm and %), number and % of positive biopsies for any cancer on TTB, stage and risk group. Sensitivity and specificity (with 95% confidence intervals) will be estimated in considering the use of standard PSA kinetics and thresholds for identifying clinically significant cancer. Scores from the quality of life questionnaires will be used in multivariable cross-sectional and longitudinal regression analysis comparing the treatment groups.

    Dosimetric evaluation to the PTV, HTV, and structures (urethra, rectum,bladder) will be performed (ultrasound real-time planning and post-operative CT). The dosimetry will be correlated with QoL information and disease control outcomes.

    Results from the TTB will be compared with the mp-MRI scans to evaluate the efficacy of using mp-MRI for diagnosis of disease. Disease modelling in three dimensions may be performed if a suitable physicist can be found to perform such an analysis.

    EN2 and PSA evaluation over time will be examined using regression analysis and compared between the two trial arms.

    Biopsy and mp-MRI results at 2-years (disease control outcomes) will be compared with pre-treatment biopsy and mp-MRI data and correlated with QoL information and dosimetry.

    Thirty-four patients will be examined in the HAPpy trial and with this small sample number, non-parametric analysis of the data will be the most suitable. Patients will be paired or matched according to their tumour staging and pathology, age, and baseline scores. The Mann-Whitney U test, the Wilcoxon test, as well as tests for normality (if appropriate) of the data will be performed on the data to determine if there are differences in the trial groups. Analysis of variance will be performed if the data is appropriate to use in this manner.

  4. Reporting of Results The data will be analysed and submitted for peer reviewed journals for publication as full manuscripts. Abstracts to conferences will also be submitted for poster or oral presentation. An interim analysis at 12 months using histological and imaging data will be performed once sufficient data are available.

Data collection and reporting of results will follow the guidelines outlined in CONSORT and STROBE for clinical trials.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Prostatic Neoplasms
  • Cancer of the Prostate
Intervention  ICMJE Radiation: Hemi gland focal LDR brachytherapy
The treatment is limited to the hemigland that has been diagnosed with unilateral low to intermediate risk prostate cancer by means of pre - treatment staging with mpMRI and transperineal template biopsy. The affected hemigland will be treated with iodine 125 to a prescription dose of 145Gy. Patients will be assessed at baseline and subsequently at 6 weeks,3,6,9,12,18,24 months after treatment with PSA and EN2 measurements and validated questionnaires relating to erectile, urinary, and bowel function and general health related quality of life. mpMRI and transperineal template biopsy will be performed 24 months after treatment.
Study Arms  ICMJE Experimental: Hemi gland focal LDR brachytherapy
Hemi gland focal LDR brachytherapy using permanent iodine 125 seed implantation
Intervention: Radiation: Hemi gland focal LDR brachytherapy
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: April 10, 2018)
31
Original Estimated Enrollment  ICMJE
 (submitted: December 13, 2015)
34
Estimated Study Completion Date  ICMJE June 2018
Estimated Primary Completion Date April 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. TRUS biopsy (if taken):

    unilateral disease only

  2. Template biopsy (TTB):

    unilateral disease only, AND Gleason < 7 (either 3+4 or 4+3)

  3. mp-MRI results: Disease must present as unilateral (left or right) only
  4. Stage T1-T2bN0M0 disease, as determined by local guidelines *
  5. Serum PSA < 15
  6. Prostate volume < 50cc
  7. Eligible for brachytherapy as outlined in local guidelines*
  8. Life expectancy > 10 years

Exclusion Criteria:

  1. Men who have had previous radiation therapy
  2. Men who have had androgen suppression/hormone treatment within the previous 12 months for their prostate cancer
  3. Men with evidence of metastatic disease or nodal disease outside the prostate on bone scan or cross-sectional imaging.

    • https://www.rcr.ac.uk/quality-assurance-practice-guidelines-transperineal-ldr-permanent-seed-brachytherapy-prostate-cancer
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Gender Based Eligibility: Yes
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02632669
Other Study ID Numbers  ICMJE R&D12oncn0015
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Stephen Langley, Royal Surrey County Hospital NHS Foundation Trust
Study Sponsor  ICMJE Royal Surrey County Hospital NHS Foundation Trust
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Stephen Langley, MD Royal Surrey NHS Foundation Trust
PRS Account Royal Surrey County Hospital NHS Foundation Trust
Verification Date April 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP