Whole-pelvis Hypofractionated Radiotherapy Combined With Dose-escalation to the Prostate and Androgen Deprivation Therapy in Primary Localized, NCCN and MMAI High-risk Prostate Cancer - a Prospective, Single-arm, Phase II Study
Trial Snapshot
- Phase
- Phase 2
- Status
- Recruiting
- Sponsor
- Enrollment
- 30
- Locations
- 2
- Primary Endpoint
- cumulative GU toxicity
Study Overview
Brief Summary
A prospective, single-arm phase II study is the individualization of RT for patients with high-risk localized PCa based on multimodal artificial intelligence (MMAI). All patients will receive the current standard of care: (i) a dose escalation to the prostate via HDR brachytherapy, (ii) two years of ADT and (iii) whole-pelvis UHF-RT (5 fractions).
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. For primary high-risk localized PCa patients, NCCNv4.2023 guidelines recommend normo- or hypofractionated RT to the prostate ± the elective pelvic lymphatics and systemic treatment in terms of ADT. Although the standard of care, the benefit of this therapy regimen is controversially discussed: the benefit of (i) an RT dose escalation using brachytherapy (2) or focal dose escalated RT(3) or (ii) an elective RT of the pelvic lymph nodes (1) is not finally proven yet. In parallel, first studies proposed a reduction in treatment fractions in terms of ultra-hypofractionated RT (UHF-RT) (4).
The aim of this prospective, single-arm phase II study is the individualization of RT for patients with high-risk localized PCa based on MMAI. All patients will receive the current standard of care: (i) a dose escalation to the prostate via HDR brachytherapy, (ii) two years of ADT and (iii) whole-pelvis UHF-RT (5 fractions).
For the HypoElect patients we expect no significant differences in toxicity rates compared to the randomized controlled POP-RT trial (1) which treated the patients with moderately-hypofractionated RT to the prostate and the elective pelvic lymph nodes in parallel to 24 months of ADT. Secondary endpoints like relapse free survival, metastatic free survival, prostate cancer survival and overall survival will depict the oncologic efficacy in this patient cohort. Thus, the safety and oncologic outcome results of this study might be the first in this highly selected treatment group: NCCN high-risk, PSMA PET cN0/cM0 and MMAI high-risk. 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 to predict the treatment outcome.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Male
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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)
- •Primary PCa (in PSMA-PET imaging and multiparametric magnetic resonance imaging (mpMRI)
- •High- or very high-risk according to NCCNv1.2023 criteria
- •Signed written informed consent for this study
- •Age >18 years
- •Previously conducted PSMA-PET/CT, mpMRI or PSMA-PET/MR
- •MMAI high-risk
- •ECOG Performance score 0 or 1
- •IPSS Score ≤15
Exclusion Criteria
- •Prior radiotherapy to the prostate or pelvis
- •Prior radical prostatectomy
- •Prior focal therapy approaches to the prostate
- •Evidence of pelvic nodal disease (cN+) in mpMRI and/or PSMA-PET/CT
- •Evidence of distant metastatic disease (cM+) in mpMRI and/or PSMA-PET/CT
- •Time gap between the beginning of any systemic therapyADT and conduction of PSMA-PET scans is >2 months
- •Evidence of cT4 disease in mpMRI and/or PSMA-PET/CT
- •PSA >50 ng/ml prior to starting of systemic therapy
- •Expected patient survival <5 years
- •Bilateral hip prostheses or any other implants/hardware that would introduce substantial CT artifacts
- •Contraindication to undergo a MRI scan
- •Contraindication to undergo HDR brachytherapy (brachytherapy not feasible due to large prostate volume, prostate anatomy, tumor in distant seminal vesicles and/or unfit for anesthesia)
- •Prostate surgery (TURP or HOLEP) with a significant tissue cavity or prostate surgery (TURP or HOLEP) within the last 6 months prior to randomization
- •Medical conditions likely to make radiotherapy inadvisable e.g. acute inflammatory bowel disease, hemiplegia or paraplegia
- •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
- •Any other contraindication to external beam radiotherapy (EBRT) to the pelvis
- •Participation in any other interventional clinical trial within the last 30 days before the start of this trial
- •Simultaneous participation in other interventional trials which could interfere with this trial; simultaneous participation in registry and diagnostic trials is allowed
- •Patient without legal capacity who is unable to understand the nature, significance and consequences of the trial
- •Known or persistent abuse of medication, drugs or alcohol
Arms & Interventions
Single experimental arm
RT prostate (HDR brachytherapy): 15 Gy (D90) in 1 fraction HDR RT prostate
EBRT elective pelvis (Ultra-hypofractionated RT - UHF): 25 Gy in 5 Gy per fraction
Technique: IMRT/IGRT/HDR brachytherapy
Duration: 6 fractions, 3 weeks
Androgen deprivation therapy (ADT) - Goserelin: all patients receive ADT; luteinising-hormone-releasing hormone agonists or antagonists for 24 months
Follow-up (FU) per patient: minimum FU time is 5 years (60 months), the study ends when the last enrolled patients reaches 60 months of FU time
Further FU: by the end of this clinical trial it will be decided whether further FU is necessary, amendment to this clinical trial protocol will be done in appropriate time
Intervention: Androgen Deprivation Therapy (ADT) - Goserelin (Drug)
Single experimental arm
RT prostate (HDR brachytherapy): 15 Gy (D90) in 1 fraction HDR RT prostate
EBRT elective pelvis (Ultra-hypofractionated RT - UHF): 25 Gy in 5 Gy per fraction
Technique: IMRT/IGRT/HDR brachytherapy
Duration: 6 fractions, 3 weeks
Androgen deprivation therapy (ADT) - Goserelin: all patients receive ADT; luteinising-hormone-releasing hormone agonists or antagonists for 24 months
Follow-up (FU) per patient: minimum FU time is 5 years (60 months), the study ends when the last enrolled patients reaches 60 months of FU time
Further FU: by the end of this clinical trial it will be decided whether further FU is necessary, amendment to this clinical trial protocol will be done in appropriate time
Intervention: High-Dose-Rate Interstitial Brachytherapy (HDR BRT) (Radiation)
Single experimental arm
RT prostate (HDR brachytherapy): 15 Gy (D90) in 1 fraction HDR RT prostate
EBRT elective pelvis (Ultra-hypofractionated RT - UHF): 25 Gy in 5 Gy per fraction
Technique: IMRT/IGRT/HDR brachytherapy
Duration: 6 fractions, 3 weeks
Androgen deprivation therapy (ADT) - Goserelin: all patients receive ADT; luteinising-hormone-releasing hormone agonists or antagonists for 24 months
Follow-up (FU) per patient: minimum FU time is 5 years (60 months), the study ends when the last enrolled patients reaches 60 months of FU time
Further FU: by the end of this clinical trial it will be decided whether further FU is necessary, amendment to this clinical trial protocol will be done in appropriate time
Intervention: radiotherapy (Radiation)
Outcomes
Primary Outcomes
cumulative GU toxicity
Time Frame: two years
Primary endpoint is cumulative GU toxicity according to RTOG grading after minimum FU time of two years.
Secondary Outcomes
- Time to local or regional failure(two and five years after RT)
- MMAI classifier(5-year and 10-year risk prediction of distant metastasis and 10-year risk of prostate-specific mortality.)
- Testosterone(assessment at 6,9,12,18 and 24 months after randomization (± 14 days for each visit) and at 30, 36, 42, 48, 54, 60 months after Ultra-hypofractionated RT - UHF (± 1 month)
- Metastatic free survival (MFS)(two and five years after RT)
- Overall Survival (OS)(1, 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54 and 60 months after RT)
- Prostate cancer specific survival (PCSS)(1, 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54 and 60 months after RT)
- Biochemical failure(two and five years after RT)
- Quality of Life (QoL)(Assessments at 6, 9,12, 18, and 24 months after randomization (± 14 days for each visit) and at 30, 36, 42, 48, 54, 60 months after Ultra-hypofractionated RT - UHF (± 1 month))
- Genitourinary (GU) acute toxicities(during, 1 and 3 months after RT)
- GU acute toxicities(during, 1 and 3 months after RT)
- GU chronic toxicities(6, 9, 12, 18 and 24 months after RT)
- Gastrointestinal (GI) acute toxicities(during, 1 and 3 months after RT)
- GI acute toxicities(during, 1 and 3 months after RT)
- GI chronic toxicities(6, 9, 12, 18 and 24 months after RT)
- QoL(Assessments at 6, 9,12, 18, and 24 months after randomization (± 14 days for each visit) and at 30, 36, 42, 48, 54, 60 months after Ultra-hypofractionated RT - UHF (± 1 month))
- Dose contrainsts(during, 1 and 3 months after RT)