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

May 15, 2023 updated by: The Netherlands Cancer Institute

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

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

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Anticipated)

484

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Floris Pos, MD PhD
  • Phone Number: +31 20 512 9111
  • Email: f.pos@nki.nl

Study Contact Backup

  • Name: Uulke van der Heide, PhD
  • Phone Number: +31 20 512 9111
  • Email: u.vd.heide@nki.nl

Study Locations

  • Netherlands
      • Amsterdam, Netherlands, 1066 CX
        • Recruiting
        • Netherlands Cancer Institute
        • Contact:
          • Floris Pos, MD
          • Phone Number: +31205129111
          • Email: f.pos@nki.nl

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Standard treatment
moderately hypofractionated radiotherapy 62 Gy in 20 fractions of 3.1 Gy
Radiation: Radiotherapy standard
Standard moderately hypofractionated radiotherapy in prostate cancer
Experimental: Experimental treatment
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
Ultra-hypofractionated focal lesion ablative microboost in prostate cancer

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
5-year bDFS
Time Frame: 5 year
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
Time Frame: 3 year

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
Time Frame: 3 year

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
Time Frame: 3 year
PROMs will be assessed using the International Prostate Symptom Score (IPSS) questionnaire
3 year
Patient-Reported Outcome Measures (PROMs) 2
Time Frame: 3 year
PROMs will be assessed using the Expanded Prostate Cancer Index Composite-26 (EPIC-26) questionnaire
3 year
Patient-Reported Outcome Measures (PROMs) 3
Time Frame: 3 year
PROMs will be assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire
3 year
Survival 1
Time Frame: 5 year
Disease-free survival
5 year
Survival 2
Time Frame: 5 year
Distant metastases-free survival
5 year
Survival 3
Time Frame: 5 year
Prostate cancer-specific survival
5 year
Survival 4
Time Frame: 5 year
Overall survival
5 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Netherlands Cancer Institute

Collaborators

Radboud University Medical Center
Universitaire Ziekenhuizen KU Leuven

Investigators

  • Principal Investigator: Floris Pos, MD PhD, The Netherlands Cancer Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 26, 2023

Primary Completion (Anticipated)

January 1, 2032

Study Completion (Anticipated)

January 1, 2032

Study Registration Dates

First Submitted

November 21, 2022

First Submitted That Met QC Criteria

January 30, 2023

First Posted (Actual)

January 31, 2023

Study Record Updates

Last Update Posted (Actual)

May 17, 2023

Last Update Submitted That Met QC Criteria

May 15, 2023

Last Verified

May 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • M21HYP

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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