Clinical trial NCT06480721: FET-PET-Guided Management of Pseudoprogression in Glioblastoma
Official title: FET-PET-Guided Management of Pseudoprogression in Glioblastoma
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Glioblastoma
Radionecrosis of Brain
Keywords: Glioblastoma
[¹⁸F] FET PET
Tumor progression
Pseudoprogression
Unnecessary interventions
Health-related quality of life
Healthcare costs
Lead sponsor: UMC Utrecht
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
name: Curium PET France
First posted: 2024-06-28
Enrollment: 144
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be randomised in equal proportions between two arms: the investigational arm and the control arm.
Primary purpose: DIAGNOSTIC

Brief summary: The goal of this diagnostic randomised clinical trial is to determine, in glioblastoma patients with diagnostic uncertainty between pseudoprogression and tumor progression on follow-up MRI after chemoradiation, the added value of a direct \[¹⁸F\] FET-PET scan for clinical management.

The main questions it aims to answer are:

* Does the clinical management guided by an additional FET-PET scan leads to fewer unnecessary interventions, compared with management based on MRI only?
* Does the clinical management guided by an additional FET-PET scan leads to better health-related quality of life after 12 weeks, compared with management based on MRI only?
* Does the clinical management guided by an additional FET-PET scan leads to reduced net healthcare costs, compared with management based on MRI only?

Researchers will compare the investigational arm, where clinical management is based on the index MRI scan and an additional FET-PET scan, with the control arm, where clinical management is based solely on the index MRI scan, to investigate the added value of the FET PET scan for clinical management.

Participants in the investigational arm will undergo the FET PET scan. All participants will complete health-related quality of life questionnaires at four different timepoints.

Detailed description: During follow-up of glioblastoma patients after chemoradiation, expert teams often observe MRI abnormalities with difficulty in distinguishing between tumor growth and pseudoprogression. Although techniques such as perfusion MRI provide additional information, diagnostic uncertainty often remains, leading to incorrect or delayed diagnosis and, inappropriate treatment, such as unnecessary surgery. Despite the good discriminating power of \[¹⁸F\] Fluoro-ethyl-tyrosine-PET (FET-PET), this diagnostic tool is not used frequently in the Netherlands due to costs, logistics, and misconceptions about clinical benefit. In the FET POPPING study we aim to determine the added value of \[¹⁸F\] FET-PET for clinical management. A multicenter diagnostic randomised clinical trial will be performed, from July 2024 until December 2027. 144 adult patients with isocitrate dehydrogenase (IDH)-wildtype glioblastoma will be included, who, after the concomitant phase of chemoradiation, have increased contrast enhancement on MRI, causing doubt between tumor growth or pseudoprogression. Included patients will be randomised 1:1 in two arms. The investigational arm receives an additional \[¹⁸F\] FET-PET scan, and clinical management is based on the index MRI and \[¹⁸F\] FET-PET together. Clinical management of the control arm is based on the index MRI alone. Exact clinical management, following from the available imaging, is chosen at the discretion of a multidisciplinary board. The primary study endpoints are (a) the percentage of patients undergoing unnecessary interventions and (b) health-related quality of life after 12 weeks. Secondary endpoints include time-to-diagnosis, overall survival and cost-effectiveness. We hypothesize that the clinical management guided by an additional \[¹⁸F\] FET-PET scan leads to fewer unnecessary interventions, better health-related quality of life after 12 weeks and among others reduced net healthcare costs, compared with management based on MRI only.

Eligibility criteria: Inclusion Criteria:

* Patients with a glioblastoma, IDH-wildtype, World Health Organization (WHO) grade 4, according to WHO 2021 criteria.
* Age ≥18 years
* New or increased enhancement within the high-dose radiation field (defined as within the 80% isodose line) on follow-up MRI
* Follow up MRI ≥3 months after the end of the standard-of-care temozolomide-based concomitant chemoradiation (60 Gy/30 fractions or 40 Gy/15 fractions). Of note, very early increase - within 3 months of last radiation - will not be grounds for inclusion because of the high rate of pseudoprogression and slightly lower diagnostic performance of FET-PET compared to the situation of increase beyond 3 months after last radiation. Patients with such very early increase may have subsequent further increase after 3 months post-radiation, causing (further) diagnostic doubt; these may be included at that later timepoint if they meet the other inclusion criteria.
* First moment of clinicoradiological uncertainty regarding the diagnosis (≥3 months after the end of chemoradiation): pseudoprogression or tumor recurrence. The determination of 'uncertainty' is made by the treating physician, preferably in the multidisciplinary tumor board, based on available clinical and standard-of-care MRI-data, which generally includes perfusion-MRI.
* Previous usage of bevacizumab as a symptom treatment is allowed. However, inclusion is only allowed at the first moment of clinical doubt between pseudoprogression and tumor recurrence, not at later timepoints.

Exclusion Criteria:

* Previous treatment for recurrence of disease
* An enhanced lesion size of less than 1 cm on the index MRI. In the newest RANO PET criteria, it is advised to use FET-PET for increasing lesions only in cases with a minimum lesion size.
* Life expectancy of less than 6 months, determined by the treating physician
* Contra-indications for PET (claustrophobia, inability to lay still)
* Women of childbearing potential without adequate contraception
* Any other concomitant disease that may influence PET imaging or clinical outcomes of this study, this includes but is not limited to: cerebral inflammatory diseases and other cancers with brain- or leptomeningeal metastases

Primary outcomes:
measure: Composite score of proportion (0-100%) of patients undergoing unnecessary interventions.
timeFrame: at six months
measure: Health-related quality of life: general
timeFrame: at twelve weeks
measure: Health-related quality of life: brain tumor specific
timeFrame: at twelve weeks
measure: Health-related quality of life: productivity
timeFrame: at twelve weeks
measure: Health-related quality of life: medical consumption
timeFrame: at twelve weeks
Secondary outcomes:
measure: Cost-effectiveness
timeFrame: at six months
measure: Cost-effectiveness
timeFrame: at six months
measure: Time-to-diagnosis
timeFrame: During the study period (but expected within three months)
measure: Overall survival
timeFrame: Through study completion (expected median of less than 1.5 year)
measure: Number of unnecessary treatment cycles
timeFrame: at six months
measure: Health-related quality of life: general
timeFrame: at six weeks and six months
measure: Health-related quality of life: brain tumor specific
timeFrame: at six weeks and six months
measure: Health-related quality of life: productivity
timeFrame: at six weeks and six months
measure: Health-related quality of life: medical consumption
timeFrame: at six weeks and six months
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC
city: Den Haag
country: Netherlands
facility: Haaglanden MC
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Groningen
country: Netherlands
facility: UMC Groningen
city: Maastricht
country: Netherlands
facility: Maastricht UMC
city: Nijmegen
country: Netherlands
facility: Radboud UMC
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Utrecht
country: Netherlands
facility: UMC Utrecht
Study officials:
affiliation: UMC Utrecht
name: Tom J Snijders, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: UMC Utrecht
name: Nelleke Tolboom, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hygino da Cruz LC Jr, Rodriguez I, Domingues RC, Gasparetto EL, Sorensen AG. Pseudoprogression and pseudoresponse: imaging challenges in the assessment of posttreatment glioma. AJNR Am J Neuroradiol. 2011 Dec;32(11):1978-85. doi: 10.3174/ajnr.A2397. Epub 2011 Mar 10.
citation: Popperl G, Gotz C, Rachinger W, Gildehaus FJ, Tonn JC, Tatsch K. Value of O-(2-[18F]fluoroethyl)- L-tyrosine PET for the diagnosis of recurrent glioma. Eur J Nucl Med Mol Imaging. 2004 Nov;31(11):1464-70. doi: 10.1007/s00259-004-1590-1. Epub 2004 Jul 10.
citation: Galldiks N, Dunkl V, Stoffels G, Hutterer M, Rapp M, Sabel M, Reifenberger G, Kebir S, Dorn F, Blau T, Herrlinger U, Hau P, Ruge MI, Kocher M, Goldbrunner R, Fink GR, Drzezga A, Schmidt M, Langen KJ. Diagnosis of pseudoprogression in patients with glioblastoma using O-(2-[18F]fluoroethyl)-L-tyrosine PET. Eur J Nucl Med Mol Imaging. 2015 Apr;42(5):685-95. doi: 10.1007/s00259-014-2959-4. Epub 2014 Nov 20.
citation: Galldiks N, Stoffels G, Filss C, Rapp M, Blau T, Tscherpel C, Ceccon G, Dunkl V, Weinzierl M, Stoffel M, Sabel M, Fink GR, Shah NJ, Langen KJ. The use of dynamic O-(2-18F-fluoroethyl)-l-tyrosine PET in the diagnosis of patients with progressive and recurrent glioma. Neuro Oncol. 2015 Sep;17(9):1293-300. doi: 10.1093/neuonc/nov088. Epub 2015 May 24.
citation: Richtlijnendatabase. Onderscheiden tumorprogressie en therapie-effect bij gliomen. 2020; Available from: https://richtlijnendatabase.nl/richtlijn/gliomen/follow-up_na_gliomen/onderscheiden_tumorprogressie_en_therapie-effect_bij_gliomen.html.
citation: Albert NL, Weller M, Suchorska B, Galldiks N, Soffietti R, Kim MM, la Fougere C, Pope W, Law I, Arbizu J, Chamberlain MC, Vogelbaum M, Ellingson BM, Tonn JC. Response Assessment in Neuro-Oncology working group and European Association for Neuro-Oncology recommendations for the clinical use of PET imaging in gliomas. Neuro Oncol. 2016 Sep;18(9):1199-208. doi: 10.1093/neuonc/now058. Epub 2016 Apr 21.
citation: Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009 May;10(5):459-66. doi: 10.1016/S1470-2045(09)70025-7. Epub 2009 Mar 9.
citation: Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B, Toms S, Idbaih A, Ahluwalia MS, Fink K, Di Meco F, Lieberman F, Zhu JJ, Stragliotto G, Tran D, Brem S, Hottinger A, Kirson ED, Lavy-Shahaf G, Weinberg U, Kim CY, Paek SH, Nicholas G, Bruna J, Hirte H, Weller M, Palti Y, Hegi ME, Ram Z. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. JAMA. 2017 Dec 19;318(23):2306-2316. doi: 10.1001/jama.2017.18718.
citation: Singnurkar A, Poon R, Detsky J. 18F-FET-PET imaging in high-grade gliomas and brain metastases: a systematic review and meta-analysis. J Neurooncol. 2023 Jan;161(1):1-12. doi: 10.1007/s11060-022-04201-6. Epub 2022 Dec 11.
citation: de Zwart PL, van Dijken BRJ, Holtman GA, Stormezand GN, Dierckx RAJO, Jan van Laar P, van der Hoorn A. Diagnostic Accuracy of PET Tracers for the Differentiation of Tumor Progression from Treatment-Related Changes in High-Grade Glioma: A Systematic Review and Metaanalysis. J Nucl Med. 2020 Apr;61(4):498-504. doi: 10.2967/jnumed.119.233809. Epub 2019 Sep 20.
citation: Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng HK, Pfister SM, Reifenberger G, Soffietti R, von Deimling A, Ellison DW. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021 Aug 2;23(8):1231-1251. doi: 10.1093/neuonc/noab106.
citation: Albert NL, Galldiks N, Ellingson BM, van den Bent MJ, Chang SM, Cicone F, de Groot J, Koh ES, Law I, Le Rhun E, Mair MJ, Minniti G, Ruda R, Scott AM, Short SC, Smits M, Suchorska B, Tolboom N, Traub-Weidinger T, Tonn JC, Verger A, Weller M, Wen PY, Preusser M. PET-based response assessment criteria for diffuse gliomas (PET RANO 1.0): a report of the RANO group. Lancet Oncol. 2024 Jan;25(1):e29-e41. doi: 10.1016/S1470-2045(23)00525-9.
citation: Chow R, Lao N, Popovic M, Chow E, Cella D, Beaumont J, Lam H, Pulenzas N, Bedard G, Wong E, DeAngelis C, Bottomley A. Comparison of the EORTC QLQ-BN20 and the FACT-Br quality of life questionnaires for patients with primary brain cancers: a literature review. Support Care Cancer. 2014 Sep;22(9):2593-8. doi: 10.1007/s00520-014-2352-7.
citation: Nederland, Z. Richtlijn voor het uitvoeren van economische evaluaties in de gezondheidszorg (versie 2024). 2024; Available from: https://www.zorginstituutnederland.nl/over-ons/publicaties/publicatie/2024/01/16/richtlijn-voor-het-uitvoeren-van-economische-evaluaties-in-de-gezondheidszorg.
citation: iMTA. iMTA Productivity Cost Questionnaire. Available from: https://www.imta.nl/questionnaires/ipcq/.
citation: iMTA. iMTA Medical Consumption Questionnaire. Available from: https://www.imta.nl/questionnaires/imcq/.
citation: European Medicines Agency (Science Medicines Health). 2015. Guideline on adjustment for baseline covariates in clinical trials. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-adjustment-baseline-covariates-clinical-trials_en.pdf
citation: ZonMw. Budget Impact Analyses in de praktijk - Leidraad en rekentool. Februari 2020. Available from: https://www.zonmw.nl/sites/zonmw/files/typo3-migrated-files/Budget_Impact_Analyses_in_de_praktijk_-_Leidraad_en_rekentool.pdf
citation: Netherlands Commission on Radiation Dosimetry. Human Exposure to Ionising Radiation for Clinical and Research Purposes: Radiation Dose & Risk Estimates. 2020.