Hypofractionated Focal Lesion Ablative Microboost in prostatE Cancer (Hypo-FLAME)

Hypofractionated Focal Lesion Ablative Microboost in prostatE Cancer (Hypo-FLAME)

The hypo-FLAME study is a multicenter phase II study (n=100) to investigate whether a focal SBRT boost to the MRI-defined macroscopic tumor volume is feasible and associated with acceptable toxicity in addition to whole gland prostate SBRT.

Study Overview

• Status: Completed
• Conditions: Prostate Cancer Adenocarcinoma
• Intervention / Treatment: Radiation: Hypo-FLAME study

Detailed Description

Rationale: Hypofractionation with a stereotactic body radiotherapy (SBRT) technique for prostate cancer produces excellent treatment outcome in terms of survival and toxicity and is much more convenient than the current fractionation scheme. Local recurrence occurs most frequently at the site of the primary or dominant tumor location prior to treatment. Therefore dose escalation at the site of the primary tumor may improve disease control.

Objective: The main goal of this phase II study is to investigate whether a focal ablative SBRT boost to the macroscopic tumor is feasible and associated with acceptable toxicity in addition to whole gland prostate SBRT. The secondary objectives of this study are: late toxicity, quality of life (QoL) and biochemical disease free survival (bDFS). Furthermore, two side-studies are incorporated in this phase II study: 1) a weekly MRI will be performed to prepare for future MRI-guided (MR-linac) treatment without gold fiducial markers and 2) blood sampling for translational research (radiogenomics) and Biobank purposes.

Study design: Prospective multicenter interventional study on whole gland prostate SBRT using MRI for focal boost in 100 consecutive intermediate or high risk prostate cancer patients.

Study population: One hundred patients with histologically proven prostate adenocarcinoma with intermediate risk or high risk disease. Patients referred for external beam radiotherapy (EBRT) who fulfill the inclusion criteria and without any of the exclusion criteria will be included in the present trial after written informed consent.

Intervention: Patients will be treated by external beam radiotherapy with a SBRT technique with 35 Gy in 5 weekly fractions and an additional simultaneously integrated focal boost to the tumor nodule(s) visible on MRI up to 50 Gy. In addition, patients will be asked to undergo 5 additional MRI scans (~15 min/scan) without contrast enhancement prior to each radiation session as well as blood sampling for translational research (radiogenomics) and Biobank purposes.

Main study parameters/endpoints: The primary endpoints of this study are acute gastrointestinal (GI) and genitourinary (GU) toxicity using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Secondary endpoints are late GI and GU toxicity, QoL, and bDFS. Simultaneously, two side-studies will be performed, i.e. to prepare for MRI-guided radiotherapy and blood sampling for translational research (radiogenomics) and Biobank purposes.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium
    • UZ Leuven
• Netherlands
  • Amsterdam, Netherlands
    • NKI-AvL
  • Nijmegen, Netherlands
    • Radboudumc
  • Utrecht, Netherlands
    • UMC Utrecht

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Men ≥ 18 years with histologically confirmed prostate adenocarcinoma
• Intermediate-risk prostate cancer or high-risk prostate cancer, defined as at least one of the following risk criteria: clinical T-stage T2b, T2c or T3a (defined on MRI) or T3b with less than 5 mm invasion in the seminal vesicle, Gleason sum score ≥ 7, PSA ≥ 10 ng/mL
• Prostate tumor nodule visible on MRI
• Ability to give written informed consent and willingness to return for follow-up

Exclusion Criteria:

• Prior pelvic radiotherapy, transurethral prostate resection or prostatectomy
• Unsafe to have gold fiducial marker implantation
• Contraindications to MRI according to the Radiology Department guidelines (metal implants, non-compatible cardiac device, allergy to Gadolinium, severe renal dysfunction or severe claustrophobia)
• Evidence of lymph node involvement or distant metastatic disease
• Clinical T-stage > T3b with ≥ 5 mm invasion in the seminal vesicle
• World Health Organization (WHO) performance score > 2
• International prostate symptoms score (IPSS score) ≥ 15
• PSA > 30 ng/mL

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Hypo-FLAME; External beam radiotherapy, 5 additional MRI scans, blood sampling

Radiation: Hypo-FLAME study; SBRT technique with 35 Gy in 5 weekly fractions and an additional simultaneously integrated focal boost to the tumor nodule(s) visible on MRI up to 50 Gy. In addition, patients will be asked to undergo 5 additional MRI scans (~15 min/scan) without contrast enhancement prior to each radiation session as well as blood sampling for translational research (radiogenomics) and Biobank purposes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute toxicity	The goal of the present study is to investigate whether a focal SBRT boost to the macroscopic tumor is feasible and associated with acceptable toxicity in addition to whole gland prostate SBRT. Toxicity will be assessed by the acute gastrointestinal (GI) and genitourinary (GU) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Acute toxicity is defined as toxicity occurring within 90 days after the first radiation treatment.	90 days after first radiation treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Late toxicity	Late toxicity, assessed by the late GI and GU Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Late toxicity is defined as toxicity occurring after at least 90 days after the first radiation treatment.	10 years after last radiation treatment
Quality of life - general	European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire	5 years after last radiation treatment
Biochemical disease free survival (bDFS)	Biochemical disease free survival	10 years after last radiation treatment
Quality of life - prostate specific	EORTC QLQ- PR25 questionnaire	5 years after last radiation treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRI side study	Quantify intrafraction motion of the prostate (in mm)	Within 5 weeks from start of radiotherapy
Blood sampling	Radiogenomic analyses	Within 5 weeks from start of radiotherapy

Collaborators and Investigators

• Sponsor: UMC Utrecht
• Collaborators: Radboud University Medical Center; Universitaire Ziekenhuizen KU Leuven; The Netherlands Cancer Institute
• Investigators: Principal Investigator: Linda GW Kerkmeijer, MD, PhD, UMC Utrecht

Publications and helpful links

General Publications

• Goodman CD, Fakir H, Pautler S, Chin J, Bauman GS. Dosimetric Evaluation of PSMA PET-Delineated Dominant Intraprostatic Lesion Simultaneous Infield Boosts. Adv Radiat Oncol. 2019 Sep 27;5(2):212-220. doi: 10.1016/j.adro.2019.09.004. eCollection 2020 Mar-Apr.
• Draulans C, van der Heide UA, Haustermans K, Pos FJ, van der Voort van Zyp J, De Boer H, Groen VH, Monninkhof EM, Smeenk RJ, Kunze-Busch M, De Roover R, Depuydt T, Isebaert S, Kerkmeijer LGW. Primary endpoint analysis of the multicentre phase II hypo-FLAME trial for intermediate and high risk prostate cancer. Radiother Oncol. 2020 Jun;147:92-98. doi: 10.1016/j.radonc.2020.03.015. Epub 2020 Apr 1.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 1, 2016
• Primary Completion (ACTUAL): November 1, 2018
• Study Completion (ACTUAL): November 1, 2018

Study Registration Dates

• First Submitted: June 24, 2016
• First Submitted That Met QC Criteria: July 28, 2016
• First Posted (ESTIMATE): August 2, 2016

Study Record Updates

• Last Update Posted (ACTUAL): December 20, 2018
• Last Update Submitted That Met QC Criteria: December 18, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: MRI, stereotactic body radiotherapy, hypofractionation
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms
• Other Study ID Numbers: NL53719.041.15a

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED