Application of FET-PET in Fusion With MRI in the Treatment of Glioblastoma Multiforme [TYR-GLIO]

Official title

Application of FET-PET in Fusion With MRI in the Surgical Treatment and Postoperative Radiotherapy of Glioblastoma Multiforme - a Randomized, Blinded, Prospective Study

Overview

Glioblastoma multiforme (GBM WHO IV) is the most common and aggressive primary brain tumor in adults, carrying a poor prognosis with a median survival of 12-16 months. The annual incidence is approximately 5 per 100,000 (roughly 600 cases annually in Poland), predominantly affecting individuals in their prime productive years. The standard of care consists of maximal safe resection followed by the Stupp protocol (60 Gy fractionated radiotherapy and temozolomide chemotherapy). Routine surgical management relies on contrast-enhanced MRI. Gross total resection (GTR) is defined as the complete removal of the contrast-enhancing lesion. Although GTR improves progression-free survival (PFS) and overall survival (OS), local recurrence at the operative site occurs in up to 51% of patients within a year. This rapid regrowth is driven by glioblastoma stem cells infiltrating the surrounding non-enhancing brain tissue. Consequently, standard contrast-enhanced MRI lacks the sensitivity required to define true tumor boundaries for optimal patient outcomes. To overcome this, positron emission tomography (PET-CT) using amino acid tracers like 18F-fluoroethyl-L-tyrosine (18F-FET) offers a promising alternative. Unlike 18-FDG, which is obscured by physiologically high glucose uptake in healthy brain tissue, 18F-FET provides high specificity and sensitivity for glial tumors. Crucially, studies show that MRI contrast enhancement overlaps with only 58% of the hypermetabolic area identified by 18F-FET. While "supramarginal" resections based on FLAIR MRI abnormalities (assumed to contain infiltrating stem cells) improve PFS by roughly 2 months, the FLAIR sequence cannot definitively distinguish active tumor infiltration from standard peritumoral edema. This proposed experiment carries significant innovative value: it aims to use the fusion of 18F-FET PET and contrast-enhanced MRI to precisely guide both primary surgical resection and postoperative radiotherapy. By redefining the primary target volume to include the area of true biological tumor activity rather than just the MRI-enhancing mass (incorporating it into GTV, CTV, and PTV planning), the procedure directly targets residual glioblastoma stem cells. While PET has been evaluated for radiotherapy planning in recurrent GBM, high-quality data regarding its use for primary surgical planning is lacking. This study aims to fill that crucial gap in the literature.

Interventions

• Other MRI & PET fusion
  MRI+T1C in fusion with FET-PET will be used for tumor resection and/or radiotherapy planning. Resection will be terminated after removal of PET-assigned tumor margin or in case any neuromonitoring-based indications regarding neurological damage occur.
• Other MRI+T1C
  MRI+T1C will be used for tumor resection and radiotherapy planning. Resection will be terminated after removal of contrast-enhancing part regardless of 5-ALA fluorescence or in case any neuromonitoring-based indications regarding neurological damage occur.

Primary outcome measures

• Progression-free survival [Time frame: 36 months post surgery]
• Overall survival [Time frame: 36 months post surgery]

Secondary outcome measures (5)

• Assessment of tumor volume (GTV) in MRI with contrast in relation to the tumor borders in PET-CT [Time frame: 1 day before radiotherapy]
• Volumetric assessment of the planned radiotherapy volume based on PET-MRI and MRI planning. [Time frame: 1 day before radiotherapy]
• Long-term survival rate and prognostic factors (longer than 1 year from diagnosis). [Time frame: 36 months post surgery]
• Pattern of local recurrence based on postoperative PET-MRI. Assessment of the nature and location of local recurrence based on the postoperative SUV parameter FET-PET and MRI examination. [Time frame: 36 months post surgery]
• Assessment of quality of life related (SF-36 questionnaire) to the increase in the volume of the tumor undergoing treatment. [Time frame: 7 days post surgery, 1 day before and after radiotherapy]

Eligibility criteria

Inclusion criteria

• Single macroscopic tumor focus with the appearance of glioblastoma multiforme on MRI with contrast - contrast-enhancing lesion, completely or with central necrosis, with surrounding edema.
• No history of cancer in other organs. No suspicious lesions on X-ray of the chest and abdomen (CT with contrast).
• No clinical suspicion of brain abscess - no meningeal symptoms, signs of neuroinfection, fever, elevated inflammatory parameters.
• Primary tumor, without neurosurgical, radiotherapy or oncology intervention. Prior tumor biopsy is allowed.
• Tumor eligible for surgical treatment - craniotomy and tumor resection.
• Age ≥ 18 years but < 70 years old.
• Quality of life assessment: KPS ≥ 70.
• Informed patient consent to the study and proposed treatment.
• No allergy to contrast agents used in PET and MRI.
• No medical contraindications to neurosurgery - craniotomy and resection.

Exclusion criteria

• Multifocal brain tumor.
• Recurrence of glioblastoma multiforme.
• Clinical or radiological suspicion of brain metastasis or brain abscess.
• Postoperative histopathological diagnosis other than WHO grade IV glioblastoma.
• Medical contraindications to any surgery under general anesthesia.
• Pregnancy, breastfeeding.
• Known allergy to gadolinium contrast or radiopharmaceutical tracing agent.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

Poland · 1 center

• Copernicus Memorial Hospital in Łódź, Poland — Lodz

Publications

• Hutterer M, Nowosielski M, Putzer D, Jansen NL, Seiz M, Schocke M, McCoy M, Gobel G, la Fougere C, Virgolini IJ, Trinka E, Jacobs AH, Stockhammer G. [18F]-fluoro-ethyl-L-tyrosine PET: a valuable diagnostic tool in neuro-oncology, but not all that glitters is glioma. Neuro Oncol. 2013 Mar;15(3):341-51. doi: 10.1093/neuonc/nos300. Epub 2013 Jan 17. PMID 23335162
• Dunet V, Pomoni A, Hottinger A, Nicod-Lalonde M, Prior JO. Performance of 18F-FET versus 18F-FDG-PET for the diagnosis and grading of brain tumors: systematic review and meta-analysis. Neuro Oncol. 2016 Mar;18(3):426-34. doi: 10.1093/neuonc/nov148. Epub 2015 Aug 4. PMID 26243791
• Robert JA, Leclerc A, Ducloie M, Emery E, Agostini D, Vigne J. Contribution of [18F]FET PET in the Management of Gliomas, from Diagnosis to Follow-Up: A Review. Pharmaceuticals (Basel). 2024 Sep 18;17(9):1228. doi: 10.3390/ph17091228. PMID 39338390
• Ort J, Hamou HA, Kernbach JM, Hakvoort K, Blume C, Lohmann P, Galldiks N, Heiland DH, Mottaghy FM, Clusmann H, Neuloh G, Langen KJ, Delev D. 18F-FET-PET-guided gross total resection improves overall survival in patients with WHO grade III/IV glioma: moving towards a multimodal imaging-guided resection. J Neurooncol. 2021 Oct;155(1):71-80. doi: 10.1007/s11060-021-03844-1. Epub 2021 Oct 1. PMID 34599479
• Harat M, Rakowska J, Harat M, Szylberg T, Furtak J, Miechowicz I, Malkowski B. Combining amino acid PET and MRI imaging increases accuracy to define malignant areas in adult glioma. Nat Commun. 2023 Jul 29;14(1):4572. doi: 10.1038/s41467-023-39731-8. PMID 37516762
• Herholz K, Holzer T, Bauer B, Schroder R, Voges J, Ernestus RI, Mendoza G, Weber-Luxenburger G, Lottgen J, Thiel A, Wienhard K, Heiss WD. 11C-methionine PET for differential diagnosis of low-grade gliomas. Neurology. 1998 May;50(5):1316-22. doi: 10.1212/wnl.50.5.1316. PMID 9595980
• Kracht LW, Miletic H, Busch S, Jacobs AH, Voges J, Hoevels M, Klein JC, Herholz K, Heiss WD. Delineation of brain tumor extent with [11C]L-methionine positron emission tomography: local comparison with stereotactic histopathology. Clin Cancer Res. 2004 Nov 1;10(21):7163-70. doi: 10.1158/1078-0432.CCR-04-0262. PMID 15534088
• Singhal T, Narayanan TK, Jain V, Mukherjee J, Mantil J. 11C-L-methionine positron emission tomography in the clinical management of cerebral gliomas. Mol Imaging Biol. 2008 Jan-Feb;10(1):1-18. doi: 10.1007/s11307-007-0115-2. Epub 2007 Oct 24. PMID 17957408

Identifiers

NCT: NCT06466031 · 2023/ABM/01/00010

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗