FET-PET-Guided Management of Pseudoprogression in Glioblastoma

Обзор

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.

Подробное описание

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.

Вмешательства

• Другое Clinical management based on the index MRI and an additional [¹⁸F] FET PET scan
  Patients in the investigational arm will undergo the extra FET-PET scan, with use of the O-(2- ¹⁸F-fluoroethyl)-L-tyrosine (¹⁸F-FET) tracer. FET-PET scanning will be performed according to the joint European Association of Nuclear Medicine (EANM)/European Association of Neuro-Oncology (EANO)/Response Assessment in Neuro-oncology (RANO) guidelines. In most patients, a static scan (20-40 minutes post-injection) will performed. If the logistics of the research site allow for a dynamic scan (0-60 m

Первичные конечные точки

• Composite score of proportion (0-100%) of patients undergoing unnecessary interventions. [Срок оценки: at six months]
• Health-related quality of life: general [Срок оценки: at twelve weeks]
• Health-related quality of life: brain tumor specific [Срок оценки: at twelve weeks]
• Health-related quality of life: productivity [Срок оценки: at twelve weeks]
• Health-related quality of life: medical consumption [Срок оценки: at twelve weeks]

Вторичные конечные точки (9)

• Cost-effectiveness [Срок оценки: at six months]
• Cost-effectiveness [Срок оценки: at six months]
• Time-to-diagnosis [Срок оценки: During the study period (but expected within three months)]
• Overall survival [Срок оценки: Through study completion (expected median of less than 1.5 year)]
• Number of unnecessary treatment cycles [Срок оценки: at six months]
• Health-related quality of life: general [Срок оценки: at six weeks and six months]
• Health-related quality of life: brain tumor specific [Срок оценки: at six weeks and six months]
• Health-related quality of life: productivity [Срок оценки: at six weeks and six months]
• Health-related quality of life: medical consumption [Срок оценки: at six weeks and six months]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Диагностика

Центры проведения

Нидерланды · 8 центров

• Amsterdam UMC — Amsterdam
• Medisch Spectrum Twente — Enschede
• UMC Groningen — Groningen
• Maastricht UMC — Maastricht
• Radboud UMC — Nijmegen
• Erasmus MC — Rotterdam
• Haaglanden MC — The Hague
• UMC Utrecht — Utrecht

Публикации

• 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. PMID 21393407
• 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. PMID 15248032
• 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 N PMID 25411133
• 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. PMID 26008606
• 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.
• 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 PMID 27106405
• 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 Insti PMID 19269895
• 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 o PMID 29260225

Идентификаторы

NCT: NCT06480721 · NL86008.041.24 · 10390022210022

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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