This study will be a randomized, two-arm trial in which intermediate and high-risk prostate cancer patients are treated with both HDR brachytherapy and EBRT. In Arm A, patients will receive HDR brachytherapy before EBRT. In Arm B (control arm), patients will receive EBRT before HDR brachytherapy. The assessment of the acute and late toxicities at various time points will be carried out. The treatment should start within 3 months from the randomization date. This trial has been registered with the International Standard Randomized Controlled Trial Number (ISRCTN) registry (ISRCTN: 15835424).
Toxicity will be assessed using the following tools:
1. International Prostate Symptom Score (IPSS)
2. International Index of Erectile Function Scale (IIEFS)
3. Functional Assessment of Cancer Therapy-Prostate (FACT-P), version 4
4. National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4, grading system
The THEPCA study scheme design is shown in
THEPCA study scheme design.
A total of 50 patients will be recruited to the whole study, which includes both arms of the study for evaluation of the outcomes. It is estimated that the dropout rate due to screen failures will be approximately 10%. Inclusion and exclusion criteria for the study are shown in
Inclusion Criteria
18 years of age or older
Histologically diagnosed prostate cancer (stages T1b-T3bN0M0)
Any Gleason score
Any PSA level
Patient must be able to provide consent and fill in the questionnaires
Exclusion Criteria
Previous transurethral resection of the prostate (TURP)/holmium laser enucleation of the prostate (HoLEP) laser prostatectomy
Any metastatic disease
An IPSS greater than 20
Pubic arch interference
Lithotomy position
Anesthesia is not possible
Rectal fistula
Prior pelvic radiotherapy
Patients will undergo the following procedures as per the standard of care, the results of which will be communicated to the investigator for their review prior to approaching the potential participant: tumor staging (CT/MRI/bone scans), histological confirmation of diagnosis (Gleason score), and PSA measurement.
It is the responsibility of the investigator, or an appropriately trained person (ie, trained in Good Clinical Practice [GCP]) delegated by the investigator as documented in the site delegation log, to obtain written informed consent from each participant prior to any participation-/study-specific procedures. This will follow adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study.
The participant will be given ample time to consider giving their informed consent for the study—for this study, 24 hours will be given during which time the consenting physician will be reachable by phone to answer any questions. The date that the Participant Information Sheet (PIS) is given to the participant will be documented within the patient’s notes to ensure that sufficient time was given.
If, for some reason, the consenting physician is not accessible by phone and the participant wishes to speak with them, a second consent visit should be arranged.
The investigator, or other qualified person, will explain to the potential participant that they are free to refuse involvement with any part of the study, or alternatively may withdraw their consent at any point during the study for any reason.
If there is any further safety information which may result in significant changes in the risk/benefit analysis, the PIS and the Informed Consent Form (ICF) will be reviewed and updated accordingly. All participants that are actively enrolled in the study will be informed of the updated information and given revised copies of the PIS and ICF in order to confirm their wish to continue in the study.
Randomization will be carried out by the clinical trials data manager within the Anglia Ruskin Clinical Trials Unit (ARCTU) at Anglia Ruskin University (ARU). ARCTU uses the Trans European Network ALEA (TENALEA) randomization service provided by the Trans European Network for Clinical Trial Services. This is an Internet-based randomization system, which will be set up for the study by ARCTU in accordance with the protocol. It will be a simple 1:1 ratio randomization, which will only be possible if a participant meets the inclusion criteria and not the exclusion criteria. The system stores the predetermined sequence of randomization—this list is not visible to the investigator or to the Anglia Ruskin Clinical Trials Unit. Once a patient has consented to take part in the trial, they will be randomly allocated to either Arm A or Arm B. The research nurse or investigator will log onto the Web browser application and enter the patient’s eligibility and stratification factors into the system. The study arm allocation is then returned to the investigator and to selected members of ARCTU and the study team. Please refer to the study scheme diagram in
The following baseline procedures will be performed: physical examination, measurement of vital signs, and assessment of QoL baseline (IPSS, IIEFS, FACT-P, CTCAE questionnaires), hematology, biochemistry, concomitant treatment (eg, androgen deprivation therapy [ADT]), and PSA.
The brachytherapy procedure will be carried out at the surgical theaters in Southend University Hospital. The steps are as follows:
1. Patients will undergo prostate implantation under general or spinal anesthetic using a transrectal ultrasound-guided transperineal technique.
2. Imaging according to local practice using ultrasound, CT, and/or MRI will be undertaken.
3. The clinical target volume for prostate (CTVp) is defined by the prostate capsule and is extended to include any extra capsular or seminal vesicle disease. A volumetric expansion of 3 mm constrained to the rectum posteriorly is then added—this defines the planning target volume (PTV).
4. Catheter reconstruction and dwell time definition is then undertaken to provide a treatment plan for approval by the treating clinician.
5. Treatment is delivered once an optimized plan has been approved.
6. After completion of treatment in the brachytherapy room, the implant catheters and urinary catheter are removed—no anesthesia is required for this procedure.
7. The patient will return to the ward and may be discharged home later the same day or the following day.
A dose of 15 Gy will be given in a single treatment exposure defined at 100% isodose, which is the minimum tumor isodose to cover the PTV. PTV recommendations are as follows: the minimum dose received by 90% of PTV (D90) should be ≥15 Gy, and the volume of the target area receiving 100% of the prescribed dose (V100) should be ≥95%. See
Organs at risk-tolerance doses.
| Organ | Risk-tolerance dose |
| Rectum D2cca | 12 Gy |
| Rectum V100b | 0 cc |
| Urethra D10c | <17.5 Gy |
| Urethra D30d | <16.5 Gy |
| Urethra V150e | 0 cc |
aDose to 2 cm3(D2cc).
bVolume of target area receiving 100% of prescribed dose (V100).
cDose covering 10% (D10) of the urethral volume.
dDose covering 30% (D30) of the urethral volume.
eVolume of target area receiving 150% of prescribed dose (V150).
EBRT will be given to prostate and seminal vesicles only, using either intensity-modulated radiotherapy or volumetric-modulated arc radiotherapy (VMAT) to a dose of 46 Gy in 23 fractions over 4½ weeks. The dose-volume histogram (DVH) would be according to the local radiotherapy protocol. The gap between BT and EBRT, irrespective of their sequence, should not exceed 3 weeks. Therefore, the total radiotherapy treatment time should be up to 7½ weeks.
Patients will receive neoadjuvant and adjuvant antiandrogen therapy from 6 months to 3 years according to the risk stratification of the disease as per the standard of care.
Schedule of assessments during the study.
| Steps and |
Pretreatment time points | Treatment time points | Posttreatment time pointsa | |||||
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Screeningband consent | Baseline | Start of second treatmentc | 6 weeks | 3 months | 6 months | 9 months | 12 months |
| Informed consent | * |
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| Physical examination |
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* | * | * | * | * | * | * |
| Vital signs |
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* | * | * | * | * | * | * |
| QoL, IPSS, IIEFS, FACT-P, CTCAEd |
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* |
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* | * |
| Hematology |
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* |
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* |
| Biochemistry |
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* |
| Concomitant treatment (eg, ADTd) |
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* | * | * | * | * | * | * |
| Tumor staging | * |
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| Histological confirmation of diagnosis | * |
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| PSAd | * | * |
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* | * | * | * |
| RTdand brachytherapy dose |
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* |
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aassessments performed after complete treatment
bscreening procedures carried out as per standard of care
cstart day of second treatment modality
dQuality of life (QoL), International Prostate Symptom Score (IPSS), International Index of Erectile Function Scale (IIEFS), Functional Assessment of Cancer Therapy-Prostate (FACT-P), Common Terminology Criteria for Adverse Events (CTCAE), androgen deprivation therapy (ADT), prostate-specific antigen (PSA), radiotherapy (RT).
The definition of the end of the study is the point at which the last patient recruited has had the last visit at the end of the 1-year follow-up session.
A patient may withdraw, or be withdrawn, from trial treatment for the following reasons:
1. If the patient has to undergo urinary catheterization for relieving blockage symptoms while undergoing EBRT and should not proceed further with HDR.
2. Any other unforeseen toxicity developed during RT treatment, and as a consequence the patient is unable to finish the protocol treatment.
The withdrawn patients will be followed as per protocol up to the end of year 1 from the time of completed treatment. With ongoing consent, patients should remain in the trial and be followed up according to the protocol visit schedule.
Patients may withdraw their consent to participate in the trial at any time. If the patient explicitly states their wish not to contribute further data to the study, the investigator should inform the coordinating center in writing and the withdrawal of consent should be documented by the investigator in the patient’s case report form (CRF). However, data up to the time of consent withdrawal will be included in the data reported for the study.
Although the participant is not obliged to give the reason for withdrawing their consent, this information will help ascertain any trends related to trial procedures and may influence the protocol development in future projects.
All laboratory tests will be taken as per the standard of care within the local pathology department at Southend University Hospital National Health Service (NHS) Foundation Trust. Tests include full blood count (FBC), liver function tests (LFTs), urea, electrolytes, and PSA.
The samples will be collected by the trial nurse, labelled and logged in the CRFs, processed according to the local standard operating procedures (SOPs), and the results will be recorded in the CRFs.
An adverse event (AE) is any untoward medical occurrence in a participant to whom a medicinal product has been administered, including occurrences which are not necessarily caused by, or related to, that product. An AE can, therefore, be any unfavorable and unintended sign, including an abnormal laboratory finding, symptom, or disease temporarily associated with study activities.
A serious adverse event (SAE) fulfils at least one of the following criteria: (1) is fatal—results in death (NOTE: death is an outcome, not an event), (2) is life-threatening, (3) requires inpatient hospitalization or prolongation of existing hospitalization, (4) results in persistent or significant disability/incapacity, (5) is a congenital anomaly/birth defect, or (6) is otherwise considered medically significant by the investigator.
The chief investigator (CI) or principal investigator (PI) responsible for the care of the participant, or in his absence an authorized medic within the research team, is responsible for assessing whether an event is serious according to the definitions given above.
The investigator must assess the causality of all serious adverse events in relation to the trial treatment according to the definitions given above.
The investigator must assess the expectedness of all SAEs according to the definitions given above. If the SAE is unexpected and related, then it needs immediate reporting.
The investigator must assess the severity of the event according to the following terms and assessments. The intensity of an event should not be confused with the term “serious” which is a regulatory definition based on participant/event outcome criteria.
1. Mild: intensity of an event is mild if some discomfort is noted, but without disruption of daily life.
2. Moderate: intensity of an event is moderate if discomfort is enough to affect/reduce normal activity.
3. Severe: intensity of an event is severe if it causes a complete inability to perform daily activities and lead a normal life.
If the AE is not defined as
Serious adverse events that are considered to be
The CI may take urgent safety measures to ensure the safety and protection of the clinical trial participants from any immediate hazard to their health and safety, in accordance with Regulation 30 of The Medicines for Human Use (Clinical Trials) Regulations 2004: SI 2004/1031. The measures should be taken immediately. In this instance, the approval from the licensing authority prior to implementing these safety measures is not required. However, it is the responsibility of the CI to inform the sponsor and main research ethics committee—via telephone—of this event immediately.
The CI has an obligation to inform the main ethics committee
The CI will send the Annual Safety Report (ASR) to the main REC using the National Research Ethics Service (NRES) template—the anniversary date is the date on the multicenter research ethics committee (MREC) “favorable opinion” letter—and to the sponsor.
The CI has the overall pharmacovigilance oversight responsibility. The CI has a duty to ensure that pharmacovigilance monitoring and reporting is conducted in accordance with the sponsor’s requirements.
Percentages will be compared using Fisher’s exact test. This analysis will be carried out after the end of the follow-up at 12 months.
For the IPSS and IIEFS scale scores, the two means at each of the follow-up assessments will be compared using a two-sided permutation
As the primary endpoint is concerned with adverse events, this will be a central concern of the primary endpoint analysis as described above—the analyses will be carried out after the end of the follow-up at 12 months.
In this feasibility study, the sample size has not been determined according to statistical principles, but is the number judged to be suitable for evaluating the suitability of the processes and procedures of running the study, and for assessing the patient experience and adherence in the study. To this end, two samples of 25 patients—50 overall—will be randomized to the two treatments.
Although the sample size will be small, there will nevertheless be attempts to analyze the data in the same way as would be the case for a main study. However, this might not always be possible depending on the pattern of the outcomes and missing values. For descriptive statistical summaries, continuous data will be summarized using means, medians, standard deviations, interquartile ranges, and ranges. Categorical data will be summarized using counts and percentages. All statistical significance testing will be at the 5% significance level. For the IPSS and IIEFS scale scores, the two means at each of the follow-up assessments will be compared using a two-sided permutation
For categorical data based on adverse events, percentages will be compared using Fisher’s exact test. In this small study it will be possible to carry out the full combinatorial calculations for Fisher’s exact test, whereas in a main study, 10,000 random permutations will be obtained in a Monte Carlo approach. For differences between percentages, the 95% confidence limits will be obtained using Newcombe’s Hybrid Score Interval method. For the secondary analysis, prostate-specific antigen relapse-free survival will be estimated using the Kaplan-Meier method, with a test for the difference between the survival curves using the log-rank test—the
The investigator has the responsibility to ensure that participant anonymity is protected and maintained. He/she must also ensure that participant identities are protected from any unauthorized parties. Information with regard to study participants will be kept confidential and managed in accordance with the Data Protection Act, NHS Caldicott Guardian, The Research Governance Framework for Health and Social Care and Research Ethics Committee Approval.
The list of study documents is shown in
A signed protocol and any subsequent amendments
Current/superseded Participant Information Sheets (as applicable)
Current/superseded Informed Consent Forms (as applicable)
Indemnity documentation from sponsor
Conditions of sponsorship from sponsor
Conditional/final research and development (R&D) approval
Signed site agreement
Ethics submissions/approvals/correspondence
CVs of CI and site staff
Laboratory accreditation letter, certification, and normal ranges for all laboratories to be utilized in the study
Delegation log
Staff training log
Site signature log
Participant identification log
Screening log
Enrolment log
Monitoring visit log
Protocol training log
Correspondence relating to the trial
Communication plan between the CI/PI and members of the study team
SAE reporting plan for the study
Project data collection will be managed by the Clinical Trials Unit data manager who will oversee recruitment and collection of data. The responsibility for data entry rests with the research nurse who is supported by the investigator. The ARCTU uses an online data management system called MACRO to design and manage electronic case report forms (eCRFs). The ARCTU will work together with the Southend study team to design and validate the data collection tools so that they are appropriate for this study. Once a patient is enrolled in the study, the research team can access these forms remotely through the Internet portal and study data will be entered and captured for the study.
All data will be in anonymized form—patients will be identifiable only by study number. Data will be remotely monitored by the ARCTU and discussed at data monitoring committee meetings. Any inconsistencies, validation errors, or inaccuracies will be reported to the lead investigator regularly. Once data collection is complete and the data has been validated, a data lock will be performed and analysis can begin.
During the course of the research, all records are the responsibility of the chief investigator and must be kept in secure conditions. When the research trial is complete, it is a requirement of the Research Governance Framework and Trust Policy that the records be kept for a further 20 years.
The CI will ensure that the trial is conducted in compliance with the principles of the Declaration of Helsinki (1996), and in accordance with all applicable regulatory requirements, including, but not limited to, the Research Governance Framework, Trust and Research Office policies and procedures and any subsequent amendments.
This protocol and any subsequent amendments, along with any accompanying material provided to the participant in addition to any advertising material, will be submitted by the investigator to an independent research ethics committee. Written approval from the committee must be obtained and subsequently submitted to the Trust’s Research and Development Office to obtain final R&D approval.
The ARCTU will ensure that the project is carried out in accordance with the Research Governance Framework. All research team members will have GCP training before the research commences to ensure every aspect from trial design to dissemination is carried out in line with these principles. GCP is an international quality standard that is provided by the International Conference on Harmonisation (ICH), an international body that defines standards, which governments can transpose into regulations for clinical trials involving human subjects.
The definition for
The THEPCA study may receive an audit by any of methods listed below:
1. A project may be identified via the risk assessment process.
2. An individual investigator or department may request an audit.
3. A project may be identified via an allegation of research misconduct or fraud, or a suspected breach of regulations.
4. Projects may be selected at random. The Department of Health states that Trusts should be auditing a minimum of 10% of all research projects.
5. Projects may be randomly selected for audit by an external organization. Internal audits will be conducted by a sponsor’s representative.
Noncompliance, as described in the ICH GCP Guideline, can be defined as “a noted systematic lack of both the CI and the study staff adhering to SOPs/protocol/ICH-GCP, which leads to prolonged collection of deviations, breaches or suspected fraud.”
Noncompliance events may be captured from a variety of different sources including monitoring visits, CRFs, communications, and updates. The sponsor will maintain a log of the noncompliance events to ascertain if there are any trends developing which need to be escalated. The sponsor will assess the noncompliance events and implement a time frame of actions in which they need to be dealt with. Each action will be given a different time frame dependent on the severity. If the noncompliance events are not dealt with accordingly, the sponsor will agree on an appropriate action, including an on-site audit.
A Trial Management Group (TMG) has been formed comprising the chief investigator, other lead investigators—clinical and nonclinical—and members of the data centers. The TMG will be responsible for the day-to-day running and management of the trial and will meet at least three times a year by teleconference.
The Trial Steering Committee (TSC) has membership from TMG plus independent members, including the chair. The role of the TSC is to provide overall supervision for the trial and provide advice through its independent chairman. The ultimate decision for the continuation of the trial lies with the TSC.
The Independent Data Monitoring Committee (IDMC) is the only group who sees the confidential, accumulating data from the trial. Reports to the IDMC will be produced by the Clinical Trials Unit (CTU) statisticians. The IDMC will meet within 6 months of the trial opening, with the frequency of meetings dictated by the IDMC.
The Radiotherapy Quality Assurance Subgroup developed the RT quality assurance (QA) plan and issued guidance on delivering RT in this trial.