New Treatment Modalities for Localized Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effectiveness of four of the nowadays most established primary treatments for patients with clinically localized prostate cancer (active surveillance, robot-assisted radical prostatectomy, intensity-modulated radiotherapy, and real-time brachytherapy) at short-, mid- and long-term follow-up. The primary aim is assessing the impact of treatments' side effects on patient's quality of life. As secondary objectives, biochemical disease-free survival, overall survival, and prostate cancer-specific survival will also be assessed.

Detailed Description
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Primary Objective: To compare the impact of active surveillance, robot-assisted radical prostatectomy, intensity-modulated radiotherapy, and real-time brachytherapy in patients with localized prostate cancer, in Patient-Reported Outcome Measures, considering side effects and physical and mental health at short-, mid- and long-term follow-up. Secondary Objectives: To assess biochemical disease-free survival by treatment and risk group, at mid- and long-term follow-up. To assess overall survival by treatment and risk group, at mid- and long-term follow-up. To assess prostate cancer-specific survival by treatment and risk group, at mid- and long-term follow-up. To assess perceived general health and cancer-specific quality of life by treatment and risk group, at short-, mid- and long-term follow-up. To assess benefits and risks of the new treatment modalities for localized prostate cancer, compared with the traditional ones (open radical prostatectomy, external-beam radiotherapy and intersticial pre-planned brachytherapy). To assess utilities with direct and indirect methods. Outline: This is a prospective observational study of a cohort with clinically localized prostate cancer treated with either active surveillance, robot-assisted radical prostatectomy, intensity-modulated radiotherapy, or real-time brachytherapy. Participants are consecutively recruited in 18 Spanish hospital departments (located in six autonomous communities). Patients eligible for inclusion were: age 50-75, tumor stage T1c or T2a, N0 and M0; Gleason ≤ 6 (or 3+4 if T1c); Prostate Specific Antigen (PSA) ≤ 10 ng/mL; and to be treated with active surveillance, robot-assisted radical prostatectomy, intensity-modulated radiotherapy, or real-time brachytherapy. Patients were excluded when body mass index was >33, they had undergone neoadjuvant hormonal treatment, previous pelvic treatments, and/or had presence of serious comorbidities. The decision regarding treatment is made jointly by patients and health professionals. Demographic and clinical characteristics at baseline are recorded at clinical sites and include age, PSA, Gleason score, prostate volume, risk group and use of adjuvant hormonal treatment. According to the national health guidelines, participants will be visited every 6-12 months after treatment, and at least annualy thereafter. Quality of Life questionnaires are administered centrally by telephone interview before treatment and during follow-up at 1, 3, 6, and 12 months after treatment the first year, and annually thereafter. Quality of Life evaluations are gathered using computer-assisted telephone administration and include: (1) the Expanded Prostate cancer Index Composite (EPIC), specifically designed to measure the impact of the different treatments; (2) 36-item Short-Form Health Survey version 2 (SF-36v2); (3) the EuroQol-5 Dimension (EQ-5D-5L); and (4) the Patient-Oriented Prostate Utility Scale (PORPUS). The sample size calculated to detect small differences between groups (0.3 SD) on the EPIC or SF-36v2 scores was of 90 patients per treatment group, given a statistical power of at least 80% at a significance level of 5%, and loss to follow-up of 10%.

Official Title
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Comparative Effectiveness of New Treatment Modalities for Localized Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Procedure: Active Surveillance
* Procedure: Robot-Assisted Radical Prostatectomy
* Radiation: Intensity-Modulated Radiotherapy
* Radiation: Real-time brachytherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 50 and 75 years. Clinical stage T1 or T2, N0/Nx and M0/Mx. Gleason ≤6 or 7 (if 3+4 with T1c). Prostate-Specific Antigen (PSA) ≤ 10 . To be treated with active surveillance, robot-assisted radical prostatectomy, intensity-modulated radiotherapy or real-time brachytherapy Exclusion Criteria: Body mass index > 33. Neoadjuvant hormonal treatment. Previous pelvic treatments. Presence of serious comorbidities.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| New Treatment Modalities Cohort<br>A consecutive sample of clinically localized prostate cancer patients treated with active surveillance, robot-assisted radical prostatectomy, intensity-modulated radiotherapy, or real-time brachytherapy in 18 Spanish hospitals. | Procedure: Active Surveillance<br>* It consists on monitoring the cancer with regular tests including PSA, blood test and digital rectal examination every 6 months, a magnetic resonance imaging and prostate biopsy at the first year, and based on clinical decision thereafter. If there was a change on the results, the patient is considered for treatment.<br>Procedure: Robot-Assisted Radical Prostatectomy<br>* It consists on the removal of the prostate gland and seminal vesicles with neurovascular preservation whenever anatomically and oncologically possible, with the Da Vinci procedure. Access is made through 5 or 6 small incisions, less than 1 cm. An extended pelvic lymph node dissection is performed when the risk estimation of node involvement is above the 5%. After surgery, the patient will be hospitalized for about 3 days and will probably resume his work activity between 3 and 5 weeks.<br>Radiation: Intensity-Modulated Radiotherapy<br>* Patients in this group undergo volumetric modulated arc therapy under daily image-guided radiation therapy in the supine position. Radiation is delivered in 2-3 Gy daily fractions, 5 days per week, with a prescription dose of 60-70 Gy to the prostate.<br>Radiation: Real-time brachytherapy<br>* Patients in this group receive I125 permanent seeds (low dose rate). The images are obtained with a transrectal ultrasound probe and are transferred to a planning system for calculating the number and position of the seeds. The prescrption dose is 145 Gy to the reference isodose (100%).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Impact of treatments' side effects on patients' quality of life measured in terms of change in the score of the Expanded Prostate Cancer Index Composite (EPIC) from baseline to 1, 3, 6, 12, 24, 60, 84, 120, 180, and 240 months after treatment. | The Expanded Prostate Cancer Index Composite-26 (EPIC-26) is a prostate cancer-specific questionnaire that measures urinary, sexual, bowel, and hormonal domains, ranging from 0 to 100. Response options for each EPIC item are on a 4-, 5-, or 6-level Likert scale. Items are grouped in summary scores for sexual, bowel, and hormonal domains, and in 2 scores for the urinary domain (incontinence and irritative/obstructive symptoms), which are transformed linearly to a scale from 0 to 100, where higher scores indicate better outcomes. | Baseline to 1, 3, 6, 12, 24, 60, 84, 120, 180, and 240 months after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biochemical disease-free survival | Number of participants who are free of biochemical relapse after a specified duration of time. Biochemical relapse is measured by PSA levels. For patients treated with radical prostatectomy, biochemical relapse criteria of the American Urological Association is applied, and for patients treated with external radiotherapy or brachytherapy, criteria of the American Society for Therapeutic Radiology and Oncology is followed. | 5, 7, 10, 15, and 20 years after treatment | 
| Overall survival | Number of participants who are alive after a specified duration of time. Vital status and data of death from any cause recorded by linkage with the National Institute of Statistics. | 5, 7, 10, 15, and 20 years after treatment | 
| Prostate cancer-specific survival | Number of participants who are not dead due to prostate cancer after a specified duration of time. Death due to prostate cancer according to the cause of death registered in the the National Institute of Statistics. | 5, 7, 10, 15, and 20 years after treatment | 
| Perceived general health measured with the 36-item Short-Form Health Survey version 2 (SF-36v2) | The 36-Item Short-Form Health Survey version 2 (SF-36v2) contains 36 items covering eight dimensions: physical functioning, role limitations due to physical health problems, bodily pain, general health, vitality, social functioning, role limitations due to emotional problems and mental health. For each dimension, a score ranges from 0-100 (higher score indicate better health).Physical and mental component summaries are constructed, using recommended scoring algorithms. Summary scores are standardized to have a mean of 50 and standard deviation of 10 in the US general population. | Baseline to 1, 3, 6, 12, 24, 60, 84, 120, 180, and 240 months after treatment | 
| Quality-Adjusted Life Years measured with the EuroQol-5 Dimensions | The EuroQol-5 Dimensions (EQ-5D-5L) is a generic econometric instrument that contains five dimensions of health (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) with five levels of severity in each dimension. From the possible combinations of scales and severity levels (3125 health states), a utility index is obtained, which ranges from 1 (perfect health) to negative values, 0 being the value attributed to death. | Baseline to 1, 3, 6, 12, 24, 60, 84, 120, 180, and 240 months after treatment | 
| Disease-specific Quality-Adjusted Life Years measured with the Patient-Oriented Prostate Utility Scale | The Patient-Oriented Prostate Utility Scale (POPRUS) is a 10-attribute health state classification system that includes 5 broad items of health-related quality of life (pain, energy, social support, communication with doctor, and emotional well-being) and 5 prostate cancer-specific items (urinary frequency and incontinence, sexual function and desire, and bowel function. A multiattribute utility function is constructed using the patient-weighted utilities elicited with standard gamble. This utility index (PORPUS-U) ranges from 1 (perfect health) to 0 (dead). | Baseline to 1, 3, 6, 12, 24, 60, 84, 120, 180, and 240 months after treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostatic neoplasms, Active Surveillance, Robot-assisted radical prostatectomy, Intensity-Modulated Radiotherapy, Real-time brachytherapy, Health-related quality of life, Patient-Reported Outcomes, PRO, Impact, Comparative effectiveness research