Clinical trial NCT01168479: FLAME: Investigate the Benefit of a Focal Lesion Ablative Microboost in Prostate Cancer
Official title: FLAME: Single Blind Randomized Phase III Trial to Investigate the Benefit of a Focal Lesion Ablative Microboost in Prostate Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Prostate Cancer
Radiotherapy
MRI
Keywords: prostate cancer
external beam radiotherapy
dose escalation
dose painting
95Gy in 35 fractions
MRI
FLAME
Lead sponsor: UMC Utrecht
Sponsor class: OTHER
First posted: 2010-07-23
Enrollment: 571
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Rationale: Dose escalation in external-beam irradiation has proven to benefit outcome in local prostate cancer. Randomized trials were performed up to doses of 78 Gy in 2 Gy fractions. Nevertheless, the five-year biochemical relapse rate still was approximately 35% in the high-dose arm. Therefore further dose escalation seems to be required. A feasibility study up to appr. 85 Gy on the entire prostate has already been performed and showed acceptable toxicity when combined with adequate position verification. Higher doses to the entire prostate are expected to increase severe toxicity. As local recurrences only occur at the site of the primary macroscopic tumour area the next step in increasing the dose should be an ablative boost to the macroscopic tumour alone, while electively irradiating the rest of the prostate to the current gold standard dose. Feasibility of this approach has been shown for an ablative dose of 95 Gy to the macroscopic tumour within the prostate.

Detailed description: Objective:

* Primary study objective: To demonstrate the superiority of the ablative microboost dose schedule regarding 5-year biochemical no evidence of disease rate compared to the current standard of care.
* Secondary study objectives: Establish and compare the rates of treatment-related toxicity, quality of life and disease-free survival.

Study design: Single blind prospective randomized controlled phase III trial.

Study population: Patients with intermediate or high risk adenocarcinoma of the prostate. Intermediate or high risk is defined according to the Ash et al. 2000 criteria as:

* One (intermediate-risk) or more (high-risk) factors: T2, or Gleasonscore=7, or iPSA 10-20 ng/mL
* One or more (high-risk) factors: T3, or Gleasonscore \>7, or iPSA \>20 ng/mL

Intervention: The standard arm receives the current gold standard, namely 77Gy to the prostate in 35 fractions of 2.2 Gy, 5 times per week. In the experimental arm patients receive in addition to the current gold standard of 77 Gy to the prostate an integrated boost to the macroscopically visible tumour to reach a total dose of 95 Gy in 35 fractions of 2.7 Gy, 5 times per week.

Main study endpoint: To decrease the five-year biochemical relapse rate with at least 10%.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

Patients will have to fill in a quality of life questionnaire before and after the radiotherapy treatments. The risk associated with the increased dose to the macroscopic tumour is an increase of toxicity and a reduction of quality of life.

Eligibility criteria: Inclusion Criteria:

* Prostate cancer patients scheduled for external beam radiotherapy using IMRT and fiducial marker-based position verification
* Intermediate and high risk prostate cancer, defined by Ash et al. 2000, namely:

  * One or more factors: T2, or Gleasonscore \>7, or iPSA \> 10 ng/mL
  * WHO score 0-2

Exclusion Criteria:

* Low risk prostate cancer, defined by Ash et al. 2000
* World Heath Organisation (WHO) score \>2
* International Prostate Symptom Score (IPSS) \>20
* If for any patient related reason an MRI cannot be performed
* If anticoagulation cannot be stopped temporarily regarding the implant of fiducial markers
* Previous prostatectomy (except from Trans Urethral Prostatectomy (TURP))
* TURP within 3 months from start treatment
* Previous pelvic irradiation

Primary outcomes:
measure: To demonstrate the superiority of the ablative microboost dose schedule regarding 5-year biochemical no evidence of disease rate compared to the current standard of care.
timeFrame: Every six months for 10 years
Secondary outcomes:
measure: Establish and compare the rates of treatment-related toxicity.
timeFrame: Every six months until 10 years
measure: quality of life
timeFrame: every six months until 10 year
measure: Disease specific survival
timeFrame: every 6 montths until 10 years
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: University Hospitals Leuven
state: Vlaans-Brabant
city: Nijmegen
country: Netherlands
facility: Radboud UMC
state: Gelderland
city: Amsterdam
country: Netherlands
facility: NKI-AvL
state: Noord-Holland
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
Study officials:
affiliation: UMC Utrecht
name: Linda Kerkmeijer, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: NKI
name: Uulke van der Heide, PhD
role: STUDY_DIRECTOR
References:
citation: Kowalchuk RO, Kim H, Harmsen WS, Jeans EB, Morris LK, Mullikin TC, Miller RC, Wong WW, Vargas CE, Trifiletti DM, Phillips RM, Choo CR, Davis BJ, Beriwal S, Tendulkar RD, Stish BJ, Breen WG, Waddle MR. Cost effectiveness of treatment strategies for high risk prostate cancer. Cancer. 2022 Nov 1;128(21):3815-3823. doi: 10.1002/cncr.34450. Epub 2022 Sep 7.
citation: Groen VH, Haustermans K, Pos FJ, Draulans C, Isebaert S, Monninkhof EM, Smeenk RJ, Kunze-Busch M, de Boer JCJ, van der Voort van Zijp J, Kerkmeijer LGW, van der Heide UA. Patterns of Failure Following External Beam Radiotherapy With or Without an Additional Focal Boost in the Randomized Controlled FLAME Trial for Localized Prostate Cancer. Eur Urol. 2022 Sep;82(3):252-257. doi: 10.1016/j.eururo.2021.12.012. Epub 2021 Dec 23.
citation: Kerkmeijer LGW, Groen VH, Pos FJ, Haustermans K, Monninkhof EM, Smeenk RJ, Kunze-Busch M, de Boer JCJ, van der Voort van Zijp J, van Vulpen M, Draulans C, van den Bergh L, Isebaert S, van der Heide UA. Focal Boost to the Intraprostatic Tumor in External Beam Radiotherapy for Patients With Localized Prostate Cancer: Results From the FLAME Randomized Phase III Trial. J Clin Oncol. 2021 Mar 1;39(7):787-796. doi: 10.1200/JCO.20.02873. Epub 2021 Jan 20.
citation: van Schie MA, Janssen TM, Eekhout D, Walraven I, Pos FJ, de Ruiter P, Kotte ANTJ, Monninkhof EM, Kerkmeijer LGW, Draulans C, de Roover R, Haustermans K, Kunze-Busch M, Smeenk RJ, van der Heide UA. Knowledge-Based Assessment of Focal Dose Escalation Treatment Plans in Prostate Cancer. Int J Radiat Oncol Biol Phys. 2020 Nov 15;108(4):1055-1062. doi: 10.1016/j.ijrobp.2020.06.072. Epub 2020 Jul 3.
citation: Monninkhof EM, van Loon JWL, van Vulpen M, Kerkmeijer LGW, Pos FJ, Haustermans K, van den Bergh L, Isebaert S, McColl GM, Smeenk RJ, Noteboom J, Walraven I, Peeters PHM, van der Heide UA. Standard whole prostate gland radiotherapy with and without lesion boost in prostate cancer: Toxicity in the FLAME randomized controlled trial. Radiother Oncol. 2018 Apr;127(1):74-80. doi: 10.1016/j.radonc.2017.12.022. Epub 2018 Jan 11.
citation: Lips IM, van der Heide UA, Haustermans K, van Lin EN, Pos F, Franken SP, Kotte AN, van Gils CH, van Vulpen M. Single blind randomized phase III trial to investigate the benefit of a focal lesion ablative microboost in prostate cancer (FLAME-trial): study protocol for a randomized controlled trial. Trials. 2011 Dec 5;12:255. doi: 10.1186/1745-6215-12-255.