FLAME: Investigate the Benefit of a Focal Lesion Ablative Microboost in Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
Rationale: Dose escalation in external-beam irradiation has proven to benefit outcome in local prostate cancer. Randomized trials were performed up to doses of 78 Gy in 2 Gy fractions. Nevertheless, the five-year biochemical relapse rate still was approximately 35% in the high-dose arm. Therefore further dose escalation seems to be required. A feasibility study up to appr. 85 Gy on the entire prostate has already been performed and showed acceptable toxicity when combined with adequate position verification. Higher doses to the entire prostate are expected to increase severe toxicity. As local recurrences only occur at the site of the primary macroscopic tumour area the next step in increasing the dose should be an ablative boost to the macroscopic tumour alone, while electively irradiating the rest of the prostate to the current gold standard dose. Feasibility of this approach has been shown for an ablative dose of 95 Gy to the macroscopic tumour within the prostate.

Detailed Description
-----------------
Objective: Primary study objective: To demonstrate the superiority of the ablative microboost dose schedule regarding 5-year biochemical no evidence of disease rate compared to the current standard of care. Secondary study objectives: Establish and compare the rates of treatment-related toxicity, quality of life and disease-free survival. Study design: Single blind prospective randomized controlled phase III trial. Study population: Patients with intermediate or high risk adenocarcinoma of the prostate. Intermediate or high risk is defined according to the Ash et al. 2000 criteria as: One (intermediate-risk) or more (high-risk) factors: T2, or Gleasonscore=7, or iPSA 10-20 ng/mL One or more (high-risk) factors: T3, or Gleasonscore >7, or iPSA >20 ng/mL Intervention: The standard arm receives the current gold standard, namely 77Gy to the prostate in 35 fractions of 2.2 Gy, 5 times per week. In the experimental arm patients receive in addition to the current gold standard of 77 Gy to the prostate an integrated boost to the macroscopically visible tumour to reach a total dose of 95 Gy in 35 fractions of 2.7 Gy, 5 times per week. Main study endpoint: To decrease the five-year biochemical relapse rate with at least 10%. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Patients will have to fill in a quality of life questionnaire before and after the radiotherapy treatments. The risk associated with the increased dose to the macroscopic tumour is an increase of toxicity and a reduction of quality of life.

Official Title
-----------------
FLAME: Single Blind Randomized Phase III Trial to Investigate the Benefit of a Focal Lesion Ablative Microboost in Prostate Cancer

Conditions
-----------------
MRI, Prostate Cancer, Radiotherapy

Intervention / Treatment
-----------------
* Radiation: FLAME boost
* Radiation: standard arm


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Prostate cancer patients scheduled for external beam radiotherapy using IMRT and fiducial marker-based position verification Intermediate and high risk prostate cancer, defined by Ash et al. 2000, namely: One or more factors: T2, or Gleasonscore >7, or iPSA > 10 ng/mL WHO score 0-2 Exclusion Criteria: Low risk prostate cancer, defined by Ash et al. 2000 World Heath Organisation (WHO) score >2 International Prostate Symptom Score (IPSS) >20 If for any patient related reason an MRI cannot be performed If anticoagulation cannot be stopped temporarily regarding the implant of fiducial markers Previous prostatectomy (except from Trans Urethral Prostatectomy (TURP)) TURP within 3 months from start treatment Previous pelvic irradiation

Ages Eligible for Study
-----------------
Minimum Age: 18 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: standard arm<br>The standard arm receives the current gold standard, namely 77Gy to the prostate in 35 fractions of 2.2 Gy, 5 times per week. | Radiation: standard arm<br>* The standard arm receives the current gold standard, namely 77Gy to the prostate in 35 fractions of 2.2 Gy, 5 times per week.<br>* Other names: normal dose;|
| Experimental: FLAME boost<br>In the experimental arm patients receive in addition to the current gold standard of 77 Gy to the prostate an integrated boost to the macroscopically visible tumour to reach a total dose of 95 Gy in 35 fractions of 2.7 Gy, 5 times per week. | Radiation: FLAME boost<br>* In the experimental arm patients receive in addition to the current gold standard of 77 Gy to the prostate an integrated boost to the macroscopically visible tumour to reach a total dose of 95 Gy in 35 fractions of 2.7 Gy, 5 times per week.<br>* Other names: FLAME;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To demonstrate the superiority of the ablative microboost dose schedule regarding 5-year biochemical no evidence of disease rate compared to the current standard of care. | PSA relapse is defined by the Phoenix definition (2005) as nadir +2ng/ml. | Every six months for 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Establish and compare the rates of treatment-related toxicity. | Toxicity is scored by Common Toxicity Criteria (CTC). Every grade>2 is considered severe toxicity. | Every six months until 10 years | 
| quality of life | Quality of life is measured by: SF-36, EORTC-C30 and EORTC-PR25. | every six months until 10 year | 
| Disease specific survival | Death with metastases is considered a death caused by the disease. | every 6 montths until 10 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
prostate cancer, external beam radiotherapy, dose escalation, dose painting, 95Gy in 35 fractions, MRI, FLAME