Standard Moderately Hypofractionated RT vs. Ultra-hypofractionated Focal Lesion Ablative Microboost in Prostate Cancer

Study Overview
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Brief Summary
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EBRT is one of the standard treatment options for patients with localized PCA. Based on the outcome of randomized trials, moderately hypofractionated RT(19-25 fractions of 2.5-3.4Gy) is considered equivalent to conventional fractionated schemes with 35-39 fractions of 2Gy. A schedule of 20 fractions to a dose of 60-62Gy is adopted as standard of care for all risk-groups. Driven by the success of moderate hypofractionation, there is a strong trend towards extreme hypofractionation, also called SBRT, reducing the number of fractions even further. The schedule mostly used is 5 fractions of 7-7.25Gy. Its effectiveness, equivalence to standard EBRT schedules, has been demonstrated for low and favourable intermediate risk (IM) patients. For unfavourable IM (here defined as IM with ISUP grade 3) and high-risk (HR) PCA the outcome of EBRT can be further improved by dose escalation. Because of dose-limiting toxicity, the maximal dose of EBRT for conventionally fractionated schemes was approximately 80Gy. Initially hypofractionation was considered as a potential way to escalate the biologically effective dose (BED) above 80Gy, however, this proved not to be the case. With hypofractionation, a saturation in dose effect seems to be present at a BED of 80Gy. Recently, the multi-centre phase III FLAME trial broke the '80Gy barrier' and showed that in mainly HR PCA patients, treated with a conventional fractionation schedule, focal boosting of the intraprostatic lesion to a total dose of 95Gy improves biochemical disease-free survival (bDFS). However, given the advantages of hypofractionation in terms of patient comfort and costs, the FLAME schedule is not ideal as the standard treatment. For unfavourable IM and HR PCA patients the value of SBRT has not yet been established. The FLAME trial showed that higher than standard BED is a prerequisite for optimal bDFS. Furthermore, post SBRT biopsies results suggest a dose response relationship with better outcome of dose levels above 40Gy. Therefore, probably a higher than standard dose SBRT is necessary for these patients. A recent meta-analysis suggests diminishing results from increased fraction sizes in SBRT. So, the question remains whether dose escalation in SBRT will indeed improve treatment outcome. With standard SBRT to the whole prostate, dose escalation is limited to 40Gy because of unacceptable toxicity. In line with FLAME, we conducted the Hypo-FLAME trial investigating focal dose escalation in SBRT. In the phase II Hypo-FLAME trial, 100 patients with IM or HR PCA were treated with SBRT 35Gy in 5 weekly fractions to the whole prostate with a focal boost up to 50Gy. The acute toxicity rates, the primary endpoint, were low and similar to standard SBRT indicating this schedule can be safely applied. Given this was a phase II trial, no conclusions on oncological outcome can be drawn. Shortening of the overall treatment time (OTT) has been suggested to play a role in SBRT efficacy and 5 fractions delivered every other day this is internationally accepted as standard. We therefore initiated the phase II Hypo-FLAME 2.0 trial, investigating the feasibility of a reduction in the OTT of the Hypo-FLAME schedule from 29 to 15 days with acute toxicity as primary endpoint. The accrual of this trial is completed and a first analysis of the primary endpoint shows low toxicity figures, well in the range of what was expected. We expect to submit the analysis for publication by the end of 2022. At present, it is unknown what the oncological efficacy of the Hypo-FLAME schedule is compared to the standard of care in unfavourable IM and HR prostate cancer. Therefore, we will conduct a Phase III multi-centre randomized trial, in which 484 patients with unfavourable IM or HR PCA will be randomized between: Standard treatment; moderately hypofractionated radiotherapy 62 Gy in 20 fractions of 3.1Gy Experimental treatment; SBRT 5x7Gy with an iso-toxic integrated focal boost up to 50 Gy (Hypo-FLAME).

Detailed Description
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Objective of the study: To demonstrate superiority of whole gland SBRT with a simultaneous integrated focal boost 35/50 Gy in 5 fractions (Hypo-FLAME) regarding 5-year bDFS compared to the current standard moderately hypofractionated schedule of 62 Gy in 20 fractions of 3.1 Gy. bDFS will be assessed, using the Phoenix consensus definition.

Official Title
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Standard Moderately Hypofractionated Radiotherapy vs. Ultra-hypofractionated Focal Lesion Ablative Microboost in Prostate Cancer, Hypo-FLAME 3.0

Conditions
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Prostate Cancer

Intervention / Treatment
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* Radiation: Radiotherapy standard
* Radiation: Radiotherapy Hypo-FLAME


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men ≥ 18 years with histologically confirmed prostate adenocarcinoma No evidence of lymph node or distant metastases N0M0. MRI visible tumor on mpMRI (PI-RADS v2 ≥ 4). Intermediate- or high-risk PCa, defined as at least one of the following risk criteria (note; both the clinical T-stage and imaging T stage are noted in the CRF): clinical stage cT2c-T3a (UICC TNM 8th edition) Imaging stage T2c, T3a or T3b with less than 5 mm invasion in the seminal vesicles (as defined on mp MRI) ≥ Gleason score 4+3, (ISUP Grade groups 3,4 or 5) PSA ≥ 20 ng/mL World Health Organization (WHO) performance score ≤ 2 International prostate symptoms score (IPSS score) < 15 PSA ≤ 30 ng/mL Prostate volume ≤ 90 cc on MRI Ability to give written informed consent and willingness to return for follow-up Exclusion Criteria: Prior pelvic radiotherapy TURP (transurethral prostate resection) within 6 months from start treatment On-line image guidance based on either fiducial markers or high-quality CBCT or MRI according to local guidelines not feasible. For example: Unsafe to have gold fiducial marker implantation, if gold fiducial markers are used for image guidance. Distorted images on MR because of hip protheses prohibit accurate MR image guidance, if MR is used for image guidance. Contraindications to MRI according to local hospital guidelines.

Ages Eligible for Study
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Minimum Age: 18 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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase III multi-centre randomized trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard treatment<br>moderately hypofractionated radiotherapy 62 Gy in 20 fractions of 3.1 Gy | Radiation: Radiotherapy standard<br>* Standard moderately hypofractionated radiotherapy in prostate cancer<br>|
| Experimental: Experimental treatment<br>SBRT 5x7Gy with an iso-toxic integrated focal boost up to 50 Gy (Hypo-FLAME) in 15 days (2 fractions per week) | Radiation: Radiotherapy Hypo-FLAME<br>* Ultra-hypofractionated focal lesion ablative microboost in prostate cancer<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-year bDFS | To demonstrate superiority of whole gland SBRT with a simultaneous integrated focal boost 35/50 Gy in 5 fractions (Hypo-FLAME) regarding 5-year bDFS compared to the current standard moderately hypofractionated schedule of 62 Gy in 20 fractions of 3.1 Gy. bDFS will be assessed, using the Phoenix consensus definition. | 5 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute toxicity | Toxicity will be assessed by the gastrointestinal (GI) and genitourinary (GU) Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). Acute toxicity is defined as toxicity occurring within 90 days after the first radiation treatment. Late toxicity is defined as toxicity occurring after at least 90 days after the first radiation treatment. | 3 year | 
| Late toxicity | Toxicity will be assessed by the gastrointestinal (GI) and genitourinary (GU) Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). Acute toxicity is defined as toxicity occurring within 90 days after the first radiation treatment. Late toxicity is defined as toxicity occurring after at least 90 days after the first radiation treatment. | 3 year | 
| Patient-Reported Outcome Measures (PROMs) 1 | PROMs will be assessed using the International Prostate Symptom Score (IPSS) questionnaire | 3 year | 
| Patient-Reported Outcome Measures (PROMs) 2 | PROMs will be assessed using the Expanded Prostate Cancer Index Composite-26 (EPIC-26) questionnaire | 3 year | 
| Patient-Reported Outcome Measures (PROMs) 3 | PROMs will be assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire | 3 year | 
| Survival 1 | Disease-free survival | 5 year | 
| Survival 2 | Distant metastases-free survival | 5 year | 
| Survival 3 | Prostate cancer-specific survival | 5 year | 
| Survival 4 | Overall survival | 5 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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radiotherapy, hypofractionation, prostate cancer, stereotactic radiotherapy