Conformal Radiotherapy (CRT) Alone Versus CRT Combined With HDR BT or Stereotactic Body Radiotherapy for Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to compare the outcomes of conventionally fractionated conformal radiotherapy with CF-CRT combined with either high-dose-rate brachytherapy or stereotactic body radiotherapy for intermediate or high-risk prostate cancer patients.

Detailed Description
-----------------
Prostate cancer is considered as a disease with relatively slow natural course and good clinical prognosis. Such description, however, does not well refer to intermediate and high-risk cases where long-term rate of biochemical progression remains not satisfactory, and the available treatment modalities entail a considerable morbidity. Over the last decade several competitive therapeutic approaches have evolved in curative treatment for intermediate and high-risk prostate cancer. The use of intensity-modulated radiation therapy (IMRT) made possible to escalate the total dose to the prostate without excessive toxicity. Based on assumption of low value of low α/β value for adenocarcinoma of prostate, there is a potential of escalating the biological dose to the tumor with higher dose per fraction. High-dose-rate brachytherapy (HDR-BT) is one of the options, with the ability to conform radiation dose to the prostate with sharp dose gradient adjacent to critical organs. An increasing number of studies suggest its usefulness as a boost in intermediate and high risk disease. The randomized trial conducted in UK compared external beam radiotherapy (EBRT) alone with EBRT and HDR brachytherapy as a boost. Combining EBRT with HDR BT - boost resulted in significantly higher relapse-free-survival (RFS) with comparable incidence of severe late toxicity. However, the total dose used in EBRT alone - arm and radiotherapy technique may be considered suboptimal according to current standards. Stereotactic body radiotherapy (SBRT) may be an interesting alternative to HDR brachytherapy, not requiring implantation of multiple catheters and anesthesia. SBRT boost for advanced localized prostate cancer has the potential to reduce toxicity while escalating the dose. First results of trials combining conventional irradiation with hypofractionated stereotactic boost and institutional pilot results gave promising outcome. The comparison of these modalities of radiation therapy for prostate cancer will be performed in the current phase III trial study.

Official Title
-----------------
Phase III Clinical Trial on Conventionally Fractionated Conformal Radiotherapy (CF-CRT) Versus CF-CRT Combined With High-dose-rate Brachytherapy or Stereotactic Body Radiotherapy for Intermediate and High-risk Prostate Cancer.

Conditions
-----------------
Prostate Cancer

Intervention / Treatment
-----------------
* Radiation: CF-CRT combined with BT or SBRT boost.
* Radiation: CF-CRT alone
* Drug: Hormonal treatment (neoadjuvant androgen deprivation)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pathologically proven adenocarcinoma of the prostate Clinical stage T1-T3a (Intermediate or high risk features according to NCCN criteria) No evidence of nodal or distant spread as determined by chest X-ray, bone scan and abdominal ultrasound or CT-scan or other investigations such as Positron Emission Tomography [PET] scan if required No evidence of bulky spread beyond the capsule of the prostate, no seminal vesicle involvement assessed by TRUS or MRI of pelvis. Good performance status (ZUBROD <2, Karnofsky index >=80%). No contradictions for spinal anesthesia. No contradictions for hormonal treatment (androgen deprivation). Adequate bone marrow, renal and liver function. Life expectancy in excess of 5 years. No prior malignancy, except basal or squamous cell skin cancer. Informed consent for participation in the study (confirmed by the signature together with the standard medical consent form for radiotherapy within the pelvis) Exclusion Criteria: Different histology than adenocarcinoma. Previous or concurrent malignancy, with the exception of basal cell carcinoma of the skin. Locally advanced disease: bulky T3a and/or T3b. Presence of metastatic disease (nodal and/or distant). PSA >100ng/ml Any previous therapy other than hormonal treatment. Concurrent uncontrolled medical conditions. Medical or psychiatric conditions that compromise the patient's ability to give informed consent. Withdrawal of informed consent. -

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CF-CRT combined with BT or SBRT boost<br>Conventionally fractionated CRT (IMRT or Rapid Arc) to the TD of 50 Gy, 2.0 Gy d fx, 5 days a week over the period of 5 weeks AND two 10 Gy fractions of real- time HDR brachytherapy OR CRT combined with two stereotactic body radiotherapy boosts of 10 Gy per fraction delivered with dynamic SBRT technique (IMRT or Rapid Arc). The choice between two ways of delivering radiation dose to the boost volume will be based solely on clinical criteria, decision made by interdisciplinary team, according to the institutional protocol (in non-randomized fashion). Hormonal treatment: three months of neoadjuvant androgen deprivation (MAB -maximal androgen blockade) in all patients. Long-term (3 years) of adjuvant hormonotherapy (LHRH agonists only) in high risk patients. | Radiation: CF-CRT combined with BT or SBRT boost.<br>* CF-CRT to the prostate and SV (IM risk group) or to the prostate, SV and LN (high risk group) to the TD of 50 Gy, 2.0 Gy d fx, 5 days a week over the period of 5 weeks AND A. Two 10 Gy fractions of HDR BT 1-7 d. before external beam radiotherapy and one 1-7 d. after external beam radiotherapy OR B. Two stereotactic body radiotherapy (SBRT) fractions of 10 Gy to the prostate (CTV boost) delivered with dynamic SBRT technique (IMRT or Rapid Arc). First and second fraction of SBRT boost is scheduled 1-7 d. before and 1-7 d. after the start of conventionally fractionated radiotherapy, respectively.<br>Drug: Hormonal treatment (neoadjuvant androgen deprivation)<br>* Hormonal treatment: three months of neoadjuvant androgen deprivation (MAB -maximal androgen blockade) in all patients. Long-term (3 years) of adjuvant hormonotherapy (LHRH agonists only) in high risk patients.<br>|
| Active Comparator: CF-CRT alone<br>Conventionally fractionated external beam conformal radiotherapy (IMRT or Rapid Arc) to the prostate and seminal vesicles (intermediate risk group) or to the prostate, SV and pelvic lymph nodes (high risk group) to the total dose of 50 Gy in 2.0 Gy per fraction, 5 days a week over the period of 5 weeks, followed by a boost to the prostate (26 or 28 Gy in 2.0 Gy per fraction 5 days a week over the period of 2.5 weeks) to the total dose of 76 or 78 Gy (intermediate or high risk group of patients, respectively). Hormonal treatment: three months of neoadjuvant androgen deprivation (MAB -maximal androgen blockade) in all patients. Long-term (3 years) of adjuvant hormonotherapy (LHRH agonists only) in high risk patients. | Radiation: CF-CRT alone<br>* Conventionally fractionated EB-CRT (IMRT or Rapid Arc) to the TD of 50 Gy, followed by a boost to the prostate (26 or 28 Gy in 2.0 Gy per fraction 5 days a week over the period of 2.5 weeks) to the total dose of 76 or 78 Gy (intermediate or high risk group of patients, respectively).of 50 Gy in 2.0 Gy per fraction, 5 days a week over the period of 5 weeks, followed by a boost to the prostate (26 or 28 Gy in 2.0 Gy per fraction 5 days a week over the period of 2.5 weeks) to the total dose of 76 or 78 Gy (intermediate or high risk group of patients, respectively).<br>Drug: Hormonal treatment (neoadjuvant androgen deprivation)<br>* Hormonal treatment: three months of neoadjuvant androgen deprivation (MAB -maximal androgen blockade) in all patients. Long-term (3 years) of adjuvant hormonotherapy (LHRH agonists only) in high risk patients.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Freedom from biochemical failure (FFBF) | according to Phoenix definition (rise of PSA level of 2 ng/ml over the absolute nadir) | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Freedom from local relapse |  | 3 years | 
| Freedom from loco-regional relapse |  | 3 years | 
| Freedom from distant metastases |  | 3 years | 
| Time of occurrence, incidence and severity of acute normal tissue reactions as measured according to CTCAE v4.0 and RTOG/EORTC scoring system |  | 3 months | 
| Time of occurrence, incidence and severity late normal tissue reactions as measured according to CTCAE v4.0 and RTOG/EORTC scoring system |  | 3 years | 
| Overall survival |  | 5 years | 
| Progression-free survival |  | 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
randomized trial, prostate cancer,, high-dose-rate brachytherapy boost,, stereotactic body radiotherapy boost,, conformal radiotherapy,