Image-guided Focal Dose Escalation- Primary pc Treated With Primary External Beam Hypofract.Stereotactic rt (HypoF-SBRT)

Image-guided Focal Dose Escalation in Patients With Primary Prostate Cancer Treated With Primary External Beam Hypofractionated Stereotactic Radiation Therapy (HypoFocal-SBRT) - a Prospective, Multicenter, Randomized Phase III Study

Technical advances in radiotherapy (RT) treatment planning and delivery have substantially changed RT concepts for primary prostate cancer (PCa) by (i) enabling a reduction of treatment time and by (ii) enabling a safe delivery of high RT doses. Several studies proposed a dose-response relationship for patients with primary prostate cancer (PCa) and especially in patients with high-risk features a dose escalation should lead to improved tumor control. In parallel to the improvements in RT techniques, diagnostic imaging techniques like multiparametric magnetic resonance imaging (mpMRI) and positron-emission tomography (PET) evolved and enable an accurate depiction of the intraprostatic tumor mass for the first time. The HypoFocal-SBRT study combines ultra-hypofractionated RT / stereotactic body RT (reduction of treatment time) with a focal RT dose escalation on intraprostatic tumor sides by applying state of the art diagnostic imaging and most modern RT concepts. This novel concept will be compared with moderate hypofractionated RT (MHRT), one option for the curative primary treatment of PCa, which has been proven by several prospective trials and is recommended and carried out worldwide. We suspect an increase in relapse-free survival (RFS) and we will also assess quality of life in order to detect potential changes.

Study Overview

• Status: Recruiting
• Conditions: Prostate Cancer
• Intervention / Treatment: Radiation: Radiotherapy (RT) Arm A - IMRT/IGRT/SBRT; Radiation: Radiotherapy (RT) Arm B - IMRT/IGRT

Detailed Description

Prostate cancer (PCa) is the most frequent diagnosed malignancy in male patients in Europe and radiation therapy (RT) is a main treatment option. Conventional RT for patients with primary PCa aims at delivering a homogeneous dose to the entire prostatic gland. However, recent studies proved that modern medical imaging is able to detect accurately the intraprostatic tumour mass (ITM). Consequently, RT concepts for PCa have an imminent need to be rectified in order to individualize the RT strategy by considering the individual tumor localization. In addition, the radiobiological characteristics of the major organs at risk, the rectum and urinary bladder / urethra, as well as of the PCa itself speak for clear advantages of hypofractionated radiation therapy. High-precision stereotactic body radiation therapy (SBRT) significantly shortens the duration of treatment, with clear implications for quality of life and socio-economic aspects.

The aim of this prospective, randomized, multicenter phase III study is the personalization of RT for patients with primary PCa based on individual tumor geometry derived from modern imaging techniques (mpMRI and PSMA-PET/CT). In the experimental (arm A) simultaneous RT dose escalation to the ITM will be performed under strict adherence to the organs at risks' dose constraints by using SBRT (ultra-hypofractionated radiation therapy) in a shorter treatment time (5 fractions vs. 20 fractions). In the control arm (arm B) the entire prostatic gland will receive a homogeneous moderately hypofractionated RT according to the current guidelines. RFS after RT (calculated from randomization) will be assessed as the primary endpoint as well as toxicities and patient reported quality of life as secondary endpoints. For the patients in the experimental arm we expect a significant benefit in relapse free survival (from 80% to 90% at 5 years). The improvement in relapse free survival could increase the metastatic free survival, prostate cancer survival and overall survival in high risk PCa patients. Considering the epidemiological importance of the PCa these results could have a significant socio-economic impact. In parallel a translational research program will address the identification of novel biomarkers/bio-imaging-markers predictive for outcome after RT. Furthermore, involvement of patient representatives includes information about the studies status and contributes to patient empowerment. These aspects will facilitate the evolution from an individualized RT to a personalized RT.

• Study Type: Interventional
• Enrollment (Estimated): 374
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sabine Schneider-Fuchs, DR; Phone Number: +4976127074040; Email: sabine.schneider-fuchs@uniklinik-freiburg.de
• Study Contact Backup: Name: Sonja Adebahr, MD; Phone Number: +4976127095200; Email: sonja.adebahr@uniklinik-freiburg.de

Study Locations

• Germany
  • Baden-Württemberg
    • Freiburg, Baden-Württemberg, Germany, 79106
      • Recruiting
      • Medical Center - University Of Freiburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Histologically confirmed adenocarcinoma of the prostate (histological confirmation can be based on tissue taken at any time, but a re-biopsy should be considered if the biopsy is more than 12 months old)

2. Primary localized PCa (cN0 and cM0 in mpMRI and PSMA PET):

   • high- or very high-risk according to NCCN v2.2021 (see 20.3) OR
   • unfavorable intermediate-risk disease according to NCCN v2.2021 (see 20.3)
3. Signed, written informed consent for HypoFocal-SBRT study
4. Age > 18 years
5. Previously conducted PSMA-PET/CT and mpMRI scans or PSMA-PET/MR, fulfilling standard requirements for PCa (see also 6.5)
6. ECOG Performance score 0 or 1
7. IPSS Score ≤15
8. Prostate volume ≤75 ml at RT planning

Exclusion Criteria:

1. Evidence of neuroendocrine tumor cells
2. Prior radiotherapy to the prostate or pelvis
3. Prior radical prostatectomy
4. Prior focal therapy approaches to the prostate
5. Time gap between the beginning of ADT and conduction of mpMRI and PSMA PET scans is >1 month
6. Radiologically suspicious or pathologically confirmed lymph node involvement (cN+) in mpMRI and/or PSMA PET/CT
7. Evidence of metastatic disease (cM+) in mpMRI and/or PSMA PET/CT
8. Evidence of cT4 disease in mpMRI or PSMA PET/CT
9. PSA >30 ng/ml prior to starting ADT
10. Expected patient survival <5 years
11. Bilateral hip prostheses or any other implants/hardware that would introduce substantial CT artefacts
12. Contraindication to undergo a mpMRI scan
13. Prostate surgery (TURP or HOLEP) with a significant tissue cavity or prostate surgery (TURP or HOLEP) within the last 6 months prior to randomization
14. Medical conditions likely to make radiotherapy inadvisable e.g. acute inflammatory bowel disease, hemiplegia or paraplegia
15. Previous malignancy within the last 2 years (except basal cell carcinoma or squamous cell carcinoma of the skin), or if previous malignancy is expected to significantly compromise 5 year survival
16. Any other contraindication to external beam radiotherapy (EBRT) to the pelvis
17. In mpMRI and PSMA PET/CT or PSMA PET/MRI scans no visible tumor
18. Participation in any other interventional clinical trial within the last 30 days before the start of this trial
19. Simultaneous participation in other interventional trials which could interfere with this trial; simultaneous participation in registry and diagnostic trials is allowed
20. Patient without legal capacity who is unable to understand the nature, significance and consequences of the trial;
21. Known or persistent abuse of medication, drugs or alcohol
22. Patients expected to have severe set up problems
23. Dose constraints for organs at risk cannot be adhered to

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A - IMRT/IGRT/SBRT; Prostate and seminal vesicles RT with 30 Gy in 6 Gy / fraction; prostate RT with 35 Gy in 7 Gy / fraction including a simultaneous integrated boost (SIB) on the intraprostatic tumour mass (ITM) with 40- 42 Gy in 8 - 8.4 Gy / fraction. If the boost volume is ≥10 ml and/ or ≥ 1/3 of the prostate, the SIB on the ITM has to be restrained to 40 Gy in 8 Gy / fraction. SBRT will be performed twice a week, with at least 2 days between two RT fractions, 5 fractions in 3 weeks (technique: IMRT/IGRT/SBRT).	Radiation: Radiotherapy (RT) Arm A - IMRT/IGRT/SBRT; technique: IMRT/IGRT/SBRT The HypoFocal-SBRT study combines ultra-hypofractionated RT / stereotactic body RT (reduction of treatment time) with a focal RT dose escalation on intraprostatic tumor sides by applying state of the art diagnostic imaging and most modern RT concepts.; Other Names: Stereotactic Body Radiation Therapy (SBRT); Intensity modulated radiotherapy (IMRT); Image guided radiotherapy (IGRT)
Active Comparator: Arm B - IMRT/IGRT; Prostate and seminal vesicles RT with 46.4 Gy in 2.32 Gy per fraction, prostate RT with 60 and 62 Gy in 3 and 3.1 Gy per fraction for unfavorable intermediate-risk and high-risk patients, respectively, 20 fractions, 5 fractions /week, (technique: IMRT/IGRT).	Radiation: Radiotherapy (RT) Arm B - IMRT/IGRT; technique: IMRT/IGRT Moderate hypofractionated RT (MHRT), one option for the curative primary treatment of PCa, which has been proven by several prospective trials and is recommended and carried out worldwide.; Other Names: Intensity modulated radiotherapy (IMRT); Image guided radiotherapy (IGRT)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse free survival	Primary endpoint is relapse free survival (RFS), defined as time from randomization to relapse or death. Relapse free survival times will be censored at the time see last alive without relapse. Analysis will be conducted after finalization of the study.	7 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to local failure after randomization	Time to local failure after randomization. Local recurrences have to be confirmed by biopsy	7 years
Metastatic free survival after randomization	Metastatic free survival after randomization (all metastases have to be confirmed by imaging, preferably PSMA-PET/CT or mpMR imaging)	7 years
Overall (OS) and prostate cancer specific (PCSS) survival after randomization	Overall (OS) and prostate cancer specific (PCSS) survival after randomization	7 years
Time to biochemical failure (phoenix definition) after randomization	Time to biochemical failure (phoenix definition) after randomization	7 years
Patient reported acute quality of life (QOL) - Expanded Prostate Index Composite-26 (EPIC-26)	Patient reported acute quality of life (QOL). Acute QOL will be assessed with the Expanded Prostate Index Composite-26 (EPIC-26) Short Form and International Prostate Symptom Score (IPSS) questionnaires at the following time points: before treatment (baseline), last day of treatment, FU visits at months 3 and 6 after randomization	at months 3 and 6 after randomization
Patient reported late quality of life (QOL)	Patient reported late quality of life (QOL). Late QOL will be assessed with the Expanded Prostate Index Composite-26 (EPIC-26) Short Form and International Prostate Symptom Score (IPSS) questionnaires at the following time points: FU visits at months 9,12,15,18 21, 24, 30, 36, 42, 48 and months 54, 60, 66, 72, 78, 84 up to 90 after randomization	up to 90 after randomization
Cumulative acute GU and GI toxicities during and up to 3 months after RT using the CTCAEv5.0 criteria	Cumulative acute GU and GI toxicities during and up to 3 months after RT using the CTCAEv5.0 criteria	up to 3 months
Cumulative Chronic GU and GI toxicities after RT using the CTCAEv5.0 criteria	Cumulative Chronic GU and GI toxicities after RT using the CTCAEv5.0 criteria	7 years
Dose constraints and prescription doses / recruited patients	Feasibility and adherence to dose constraints by measuring the ratio between: number of patients with fulfilled dose constraints and prescription doses / recruited patients	7 years
Characterization of safety: adverse events	Characterization of safety: adverse events	7 years

Collaborators and Investigators

• Sponsor: University Hospital Freiburg
• Collaborators: German Federal Ministry of Education and Research
• Investigators: Study Chair: Anca-Ligia Grosu, Prof., Medical Center- University of Freiburg

Study record dates

Study Major Dates

• Study Start (Actual): August 18, 2022
• Primary Completion (Estimated): August 1, 2025
• Study Completion (Estimated): February 1, 2030

Study Registration Dates

• First Submitted: May 23, 2023
• First Submitted That Met QC Criteria: March 19, 2024
• First Posted (Actual): March 26, 2024

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 19, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Prostate Cancer; HypoFocal; HypoFocal-SBRT
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms
• Other Study ID Numbers: P003103; DRKS00022915 (Other Identifier: Deutsches Register Klinische Studien)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No