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

NCT05705921 | Recruiting

• 1 other identifier: M21HYP
• Study Type: interventional
• Target: 484
• Locations: 1 country
• Sites: 1

Brief Summary

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:

1. 1.Standard treatment; moderately hypofractionated radiotherapy 62 Gy in 20 fractions of 3.1Gy
2. 2.Experimental treatment; SBRT 5x7Gy with an iso-toxic integrated focal boost up to 50 Gy (Hypo-FLAME).

Conditions

Prostate Cancer

Keywords

radiotherapy; hypofractionation; prostate cancer; stereotactic radiotherapy

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (9)

• Acute toxicity

  3 year

• Late toxicity

  3 year

• Patient-Reported Outcome Measures (PROMs) 1

  3 year

• Patient-Reported Outcome Measures (PROMs) 2

  3 year

• Patient-Reported Outcome Measures (PROMs) 3

  3 year

Study Arms (2)

Standard treatment

ACTIVE COMPARATOR

moderately hypofractionated radiotherapy 62 Gy in 20 fractions of 3.1 Gy

Radiation: Radiotherapy standard

Experimental treatment

EXPERIMENTAL

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

Interventions

Radiotherapy standard RADIATION

Standard moderately hypofractionated radiotherapy in prostate cancer

Standard treatment

Radiotherapy Hypo-FLAME RADIATION

Ultra-hypofractionated focal lesion ablative microboost in prostate cancer

Experimental treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• The Netherlands Cancer Institute: lead
• Radboud University Medical Center: collaborator
• Universitaire Ziekenhuizen KU Leuven: collaborator

Study Sites (1)

Netherlands Cancer Institute

Amsterdam, 1066 CX, Netherlands

RECRUITING

Related Publications (22)

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MeSH Terms

Conditions

Prostatic Neoplasms

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Study Officials

• Floris Pos, MD PhD

  The Netherlands Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Floris Pos, MD PhD

CONTACT

+31 20 512 9111; f.pos@nki.nl

Uulke van der Heide, PhD

CONTACT

+31 20 512 9111; u.vd.heide@nki.nl

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Phase III multi-centre randomized trial

Study Record Dates

• First Submitted: November 21, 2022
• First Posted: January 31, 2023
• Study Start: April 26, 2023
• Primary Completion (Estimated): January 1, 2032
• Study Completion (Estimated): January 1, 2032
• Last Updated: January 20, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)