Norbert Galldiks

Integrated boost IMRT with FET-PET-adapted local dose escalation in glioblastomas. Results of a prospective phase II study.

PurposeDose escalations above 60xa0Gy based on MRI have not led to prognostic benefits in glioblastoma patients yet. With positron emission tomography (PET) using [18F]fluorethyl-L-tyrosine (FET), tumor coverage can be optimized with the option of regional dose escalation in the area of viable tumor tissue.Methods and materialsIn a prospective phase II study (January 2008 to December 2009), 22xa0patients (median age 55xa0years) received radiochemotherapy after surgery. The radiotherapy was performed as an MRI and FET-PET-based integrated-boost intensity-modulated radiotherapy (IMRT). The prescribed dose was 72 and 60xa0Gy (single dose 2.4 and 2.0xa0Gy, respectively) for the FET-PET- and MR-based PTV-FET(72xa0Gy) and PTV-MR(60xa0Gy). FET-PET and MRI were performed routinely for follow-up. Quality of life and cognitive aspects were recorded by the EORTC-QLQ-C30/QLQ Brain20 and Mini-Mental Status Examination (MMSE), while the therapy-related toxicity was recorded using the CTC3.0 and RTOG scores.ResultsMedian overall survival (OS) and disease-free survival (DFS) were 14.8 and 7.8 months, respectively. All local relapses were detected at least partly within the 95% dose volume of PTV-MR(60xa0Gy). No relevant radiotherapy-related side effects were observed (excepted alopecia). In 2xa0patients, a pseudoprogression was observed in the MRI. Tumor progression could be excluded by FET-PET and was confirmed in further MRI and FET-PET imaging. No significant changes were observed in MMSE scores and in the EORTC QLQ-C30/QLQ-Brain20 questionnaires.ConclusionOur dose escalation concept with a total dose of 72xa0Gy, based on FET-PET, did not lead to a survival benefit. Acute and late toxicity were not increased, compared with historical controls and published dose–escalation studies.ZusammenfassungZielSteigerungen der Strahlendosis über 60xa0Gy, basierend auf der MRT, führten bisher nicht zu einer Prognoseverbesserung bei Glioblastomen. Die [18F]Fluorethyl-L-Tyrosin (FET)-PET erlaubt eine optimierte Erfassung der Tumorausdehnung, womit die Option einer fokussierten Dosiserhöhung im Bereich viabler Tumorareale verbunden ist.Material und MethodenIn einer prospektiven Phase-II-Studie (2008–2009) erhielten 22xa0Glioblastom-Patienten eine Strahlenchemotherapie nach erfolgter Resektion. Die Bestrahlung erfolgte als Integrated-Boost-IMRT (IB-IMRT), basierend auf MRT- und postoperativer FET-PET-Bildgebung. Die Dosisverschreibung betrug 72 bzw. 60xa0Gy (ED 2,4 bzw. 2,0xa0Gy) für das FET-PET- bzw. MRT-basierte PTV-FET(72xa0Gy) bzw. PTV-MRT(60xa0Gy). Das Follow-Up basierte auf regelmäßigen FET-PET- sowie MRT-Untersuchungen. Lebensqualität und kognitive Aspekte wurden mittels EORTC-QLQ-C30 und QLQ-Brain20 sowie „Mini Mental Status“-Test (MMST) erfasst. Die Toxizitätserfassung erfolgte mittels CTC3.0- bzw. RTOG-Score.ErgebnisseGesamt- und rezidivfreies Überleben lagen bei 14,8 und 7,8xa0Monaten. Alle lokalen Rezidive lagen zumindest partiell innerhalb der 95%-Isodose des PTV-MRT(60xa0Gy). Höhergradige strahlentherapiespezifische Nebenwirkungen traten nicht auf. Bei 2xa0Patienten zeigte sich eine Pseudoprogression im MRT. Ein Tumorprogress wurde mittels FET-PET ausgeschlossen und durch weitere Bildgebung bestätigt.Hinsichtlich der Lebensqualität und Kognition zeigten sich im zeitlichen Verlauf keine signifikanten Veränderungen.SchlussfolgerungUnser Dosiseskalationskonzept mit bis zu 72xa0Gy, basierend auf der FET-PET, führte nicht zu einer Überlebensverbesserung. Eine Erhöhung der Toxizität oder eine signifikante Verschlechterung der Lebensqualität zeigte sich im Vergleich zur historischen Kontrolle nicht.

Prognostic impact of postoperative, pre-irradiation 18F-fluoroethyl-l-tyrosine uptake in glioblastoma patients treated with radiochemotherapy

BACKGROUND AND PURPOSEnResection is considered as essential for the efficacy of modern adjuvant treatment of glioblastoma multiforme (GBM). Previous studies have indicated that amino acid PET is more specific than contrast enhancement on MRI for detecting residual tumor tissue after surgery. In a prospective study we investigated the prognostic impact of postoperative tumor volume and tumor/brain ratios (TBR) in PET using O-(2-[(18)F]fluoroethyl)-l-tyrosine (FET) in comparison with MRI.nnnMATERIALS AND METHODSnForty-four patients with GBM were investigated by FET PET and MRI after surgery. Tumor volume in FET PET with a tumor/brain ratio (TBR)>1.6 and a TBR>2, mean and maximum TBR and gadolinium contrast-enhancement on MRI (Gd-volume) were determined. Thereafter patients received a fractionated radiotherapy with concomitant temozolomide (RCX). The median follow-up was 15.4 (3-35) months. The prognostic value of postoperative residual tumor volume in FET PET, TBR(mean,) TBR(max) and Gd-volume was evaluated using Kaplan-Maier estimates for disease-free survival (DFS) and overall survival (OS).nnnRESULTSnPostoperative tumor volume in FET PET had a significant independent influence on OS and DFS (OS 20.0 vs. 6.9 months; DFS 9.6 vs. 5.1 months, p<0.001; cut-off 25 ml). Similar results were observed when a TBR ≥ 2 (cut-off 10 ml) was used to define the tumor volume in (18)F-FET PET. The TBR(mean) and TBR(max) of FET uptake had a significant influence on DFS (p<0.05). Gd-volume in MRI had significant effect on OS and DFS in the univariate analysis. No independent significant influence in OS or DFS could be observed for Gd-volume in MRI.nnnCONCLUSIONSnOur data indicate that the tumor volume in FET PET after surgery of GBM has a strong prognostic impact for these patients. FET PET appears to be helpful to determine the residual tumor volume after surgery of GBM and may serve as a valuable tool for optimal planning of radiation treatment.

Integrated boost IMRT with FET-PET-adapted local dose escalation in glioblastomas

PurposeDose escalations above 60xa0Gy based on MRI have not led to prognostic benefits in glioblastoma patients yet. With positron emission tomography (PET) using [18F]fluorethyl-L-tyrosine (FET), tumor coverage can be optimized with the option of regional dose escalation in the area of viable tumor tissue.Methods and materialsIn a prospective phase II study (January 2008 to December 2009), 22xa0patients (median age 55xa0years) received radiochemotherapy after surgery. The radiotherapy was performed as an MRI and FET-PET-based integrated-boost intensity-modulated radiotherapy (IMRT). The prescribed dose was 72 and 60xa0Gy (single dose 2.4 and 2.0xa0Gy, respectively) for the FET-PET- and MR-based PTV-FET(72xa0Gy) and PTV-MR(60xa0Gy). FET-PET and MRI were performed routinely for follow-up. Quality of life and cognitive aspects were recorded by the EORTC-QLQ-C30/QLQ Brain20 and Mini-Mental Status Examination (MMSE), while the therapy-related toxicity was recorded using the CTC3.0 and RTOG scores.ResultsMedian overall survival (OS) and disease-free survival (DFS) were 14.8 and 7.8 months, respectively. All local relapses were detected at least partly within the 95% dose volume of PTV-MR(60xa0Gy). No relevant radiotherapy-related side effects were observed (excepted alopecia). In 2xa0patients, a pseudoprogression was observed in the MRI. Tumor progression could be excluded by FET-PET and was confirmed in further MRI and FET-PET imaging. No significant changes were observed in MMSE scores and in the EORTC QLQ-C30/QLQ-Brain20 questionnaires.ConclusionOur dose escalation concept with a total dose of 72xa0Gy, based on FET-PET, did not lead to a survival benefit. Acute and late toxicity were not increased, compared with historical controls and published dose–escalation studies.ZusammenfassungZielSteigerungen der Strahlendosis über 60xa0Gy, basierend auf der MRT, führten bisher nicht zu einer Prognoseverbesserung bei Glioblastomen. Die [18F]Fluorethyl-L-Tyrosin (FET)-PET erlaubt eine optimierte Erfassung der Tumorausdehnung, womit die Option einer fokussierten Dosiserhöhung im Bereich viabler Tumorareale verbunden ist.Material und MethodenIn einer prospektiven Phase-II-Studie (2008–2009) erhielten 22xa0Glioblastom-Patienten eine Strahlenchemotherapie nach erfolgter Resektion. Die Bestrahlung erfolgte als Integrated-Boost-IMRT (IB-IMRT), basierend auf MRT- und postoperativer FET-PET-Bildgebung. Die Dosisverschreibung betrug 72 bzw. 60xa0Gy (ED 2,4 bzw. 2,0xa0Gy) für das FET-PET- bzw. MRT-basierte PTV-FET(72xa0Gy) bzw. PTV-MRT(60xa0Gy). Das Follow-Up basierte auf regelmäßigen FET-PET- sowie MRT-Untersuchungen. Lebensqualität und kognitive Aspekte wurden mittels EORTC-QLQ-C30 und QLQ-Brain20 sowie „Mini Mental Status“-Test (MMST) erfasst. Die Toxizitätserfassung erfolgte mittels CTC3.0- bzw. RTOG-Score.ErgebnisseGesamt- und rezidivfreies Überleben lagen bei 14,8 und 7,8xa0Monaten. Alle lokalen Rezidive lagen zumindest partiell innerhalb der 95%-Isodose des PTV-MRT(60xa0Gy). Höhergradige strahlentherapiespezifische Nebenwirkungen traten nicht auf. Bei 2xa0Patienten zeigte sich eine Pseudoprogression im MRT. Ein Tumorprogress wurde mittels FET-PET ausgeschlossen und durch weitere Bildgebung bestätigt.Hinsichtlich der Lebensqualität und Kognition zeigten sich im zeitlichen Verlauf keine signifikanten Veränderungen.SchlussfolgerungUnser Dosiseskalationskonzept mit bis zu 72xa0Gy, basierend auf der FET-PET, führte nicht zu einer Überlebensverbesserung. Eine Erhöhung der Toxizität oder eine signifikante Verschlechterung der Lebensqualität zeigte sich im Vergleich zur historischen Kontrolle nicht.

Radiation injury vs. recurrent brain metastasis: combining textural feature radiomics analysis and standard parameters may increase

AbstractObjectivesWe investigated the potential of textural feature analysis of O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) PET to differentiate radiation injury from brain metastasis recurrence.MethodsForty-seven patients with contrast-enhancing brain lesions (nu2009=u200954) on MRI after radiotherapy of brain metastases underwent dynamic 18F-FET PET. Tumour-to-brain ratios (TBRs) of 18F-FET uptake and 62 textural parameters were determined on summed images 20-40xa0min post-injection. Tracer uptake kinetics, i.e., time-to-peak (TTP) and patterns of time-activity curves (TAC) were evaluated on dynamic PET data from 0-50xa0min post-injection. Diagnostic accuracy of investigated parameters and combinations thereof to discriminate between brain metastasis recurrence and radiation injury was compared.ResultsDiagnostic accuracy increased from 81xa0% for TBRmean alone to 85xa0% when combined with the textural parameter Coarseness or Short-zone emphasis. The accuracy of TBRmax alone was 83xa0% and increased to 85xa0% after combination with the textural parameters Coarseness, Short-zone emphasis, or Correlation. Analysis of TACs resulted in an accuracy of 70xa0% for kinetic pattern alone and increased to 83xa0% when combined with TBRmax.ConclusionsTextural feature analysis in combination with TBRs may have the potential to increase diagnostic accuracy for discrimination between brain metastasis recurrence and radiation injury, without the need for dynamic 18F-FET PET scans.Key points• Textural feature analysis provides quantitative information about tumour heterogeneityn • Textural features help improve discrimination between brain metastasis recurrence and radiation injuryn • Textural features might be helpful to further understand tumour heterogeneityn • Analysis does not require a more time consuming dynamic PET acquisition

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Antiangiogenic treatment using bevacizumab in brain tumor patients may cause difficulties in the diagnosis of tumor progression (ie, nonenhancing tumor progression). Newly defined criteria for treatment assessment and diagnosis of tumor progression (ie, RANO [Response Assessment in Neuro-Oncology] criteria) have implemented signal alterations on T2/fluid-attenuated inversion recovery (FLAIR) sequences to changes in contrast enhancement. However, T2/FLAIR hyperintensity may be influenced by other causes (eg, radiation-induced leukoencephalopathy, peritumoral edema, gliosis). Positron emission tomography using the radiolabeled amino acid O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET-PET) may help detect the metabolically active tumor extent. We present 18F-FET-PET imaging findings in a glioblastoma patient during bevacizumab treatment suggesting an earlier diagnosis of tumor progression than magnetic resonance imaging changes, which are based on the RANO criteria.

F-FET PET accuracy without dynamic scans

Background Metabolic imaging technologies such as 5-aminolevulinic acid (ALA) fluorescence-guided resection and positron-emission tomography (PET) imaging have improved glioma surgery within the last decade. At present, these tools are not routinely used in meningioma surgery. Objective We present a case of a complex-shaped, recurrent skull base meningioma where 5-ALA fluorescence-guidance and (18)F-fluoroethyltyrosine (FET)-PET-imaging facilitated surgical resection. Material and Methods The patient underwent surgery via a combined transcranial/transnasal endoscopic approach. What was original is that both the microscope and the endoscope were equipped for 5-ALA fluorescence-guided surgery, respectively. Furthermore, preoperative FET-PET imaging was fused with computed tomography (CT) and magnetic resonance imaging (MRI) data for intraoperative navigation. The case richly illustrated the performance of the different modalities. Conclusions Metabolic imaging tools such as 5-ALA fluorescence-guided resection and navigated FET-PET were helpful for the resection of this complex-shaped, recurrent skull base meningioma. 5-ALA fluorescence was useful to dissect the adherent interface between tumor and brain. Furthermore, it helped to delineate tumor margins in the nasal cavity. FET-PET improved the assessment of bony and dural infiltration. We hypothesize that these imaging technologies may reduce recurrence rates through better visualization of tumor tissue that might be left unintentionally. This has to be verified in larger, prospective trials.

Earlier Diagnosis of Progressive Disease during Bevacizumab Treatment Using O-(2-18F-Fluorethyl)-L-Tyrosine Positron Emission Tomography in Comparison with Magnetic Resonance Imaging

BACKGROUNDnPatients with WHO grade II glioma may respond to chemotherapy that is currently not standardized regarding timing and treatment duration. Metabolic changes during chemotherapy may precede structural tumor volume reductions. We therefore compared time courses of amino acid PET and MRI responses to temozolomide (TMZ) and assessed whether responses correlated with seizure control and progression-free survival (PFS).nnnMETHODSnPET and MRI were performed before and during TMZ chemotherapy. Tumor volumes were calculated using regions-of-interest analysis. Amino acid uptake was also quantified as metabolically active tumor volume and tumor-to-cerebellum uptake ratio.nnnRESULTSnOne hundred twenty-five PET and 125 MRI scans from 33 patients were analyzed. Twenty-five patients showed metabolic responses that exhibited an exponential time course with a 25% reduction of the active volume on average after 2.3 months. MRI responses followed a linear course with a 25% reduction after 16.8 months. Reduction of metabolically active tumor volumes, but not reduction of PET uptake ratios or MRI tumor volumes, correlated with improved seizure control following chemotherapy (P = .012). Receiver-operating-characteristic curve analysis showed that a decrease of the active tumor volume of ≥80.5% predicts a PFS of ≥60 months (P = .018) and a decrease of ≥64.5% a PFS of ≥48 months (P = .037).nnnCONCLUSIONSnAmino acid PET is superior to MRI for evaluating TMZ responses in WHO grade II glioma patients. The response delay between both imaging modalities favors amino acid PET for individually tailoring the duration of chemotherapy. Additional studies should investigate whether this personalized approach is appropriate with regard to outcome.

5-Aminolevulinic Acid and 18F-FET-PET as Metabolic Imaging Tools for Surgery of a Recurrent Skull Base Meningioma

PurposeThe molecular features isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion have gained major importance for both glioma typing and prognosis and have, therefore, been integrated in the World Health Organization (WHO) classification in 2016. The aim of this study was to characterize static and dynamic O-(2-18F-fluoroethyl)-L-tyrosine (18F–FET) PET parameters in gliomas with or without IDH mutation or 1p/19q co-deletion.MethodsNinety patients with newly diagnosed and untreated gliomas with a static and dynamic 18F–FET PET scan prior to evaluation of tumor tissue according to the 2016 WHO classification were identified retrospectively. Mean and maximum tumor-to-brain ratios (TBRmean/max), as well as dynamic parameters (time-to-peak and slope) of 18F–FET uptake were calculated.ResultsSixteen (18%) oligodendrogliomas (IDH mutated, 1p/19q co-deleted), 27 (30%) astrocytomas (IDH mutated only), and 47 (52%) glioblastomas (IDH wild type only) were identified. TBRmean, TBRmax, TTP and slope discriminated between IDH mutated astrocytomas and IDH wild type glioblastomas (Pxa0<xa00.01). TBRmean showed the best diagnostic performance (cut-off 1.95; sensitivity, 89%; specificity, 67%; accuracy, 81%). None of the parameters discriminated between oligodendrogliomas (IDH mutated, 1p/19q co-deleted) and glioblastomas or astrocytomas. Furthermore, TBRmean, TBRmax, TTP, and slope discriminated between gliomas with and without IDH mutation (pxa0<xa00.01). The best diagnostic performance was obtained for the combination of TTP with TBRmax or slope (accuracy, 73%).ConclusionData suggest that static and dynamic 18F–FET PET parameters may allow determining non-invasively the IDH mutation status. However, IDH mutated and 1p/19q co-deleted oligodendrogliomas cannot be differentiated from glioblastomas and astrocytomas by 18F–FET PET.

Amino acid positron emission tomography to monitor chemotherapy response and predict seizure control and progression-free survival in WHO grade II gliomas

PET using the amino-acid O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) is gaining increasing interest for brain tumour management. Semi-quantitative analysis of tracer uptake in brain tumours is based on the standardized uptake value (SUV) and the tumour-to-brain ratio (TBR). The aim of this study was to explore physiological factors that might influence the relationship of SUV of 18F-FET uptake in various brain areas, and thus affect quantification of 18F-FET uptake in brain tumours. Negative 18F-FET PET scans of 107 subjects, showing an inconspicuous brain distribution of 18F-FET, were evaluated retrospectively. Whole-brain quantitative analysis with Statistical Parametric Mapping (SPM) using parametric SUV PET images, and volumes of interest (VOIs) analysis with fronto-parietal, temporal, occipital, and cerebellar SUV background areas were performed to study the effect of age, gender, height, weight, injected activity, body mass index (BMI), and body surface area (BSA). After multivariate analysis, female gender and high BMI were found to be two independent factors associated with increased SUV of 18F-FET uptake in the brain. In women, SUVmean of 18F-FET uptake in the brain was 23% higher than in men (p < 0.01). SUVmean of 18F-FET uptake in the brain was positively correlated with BMI (r = 0.29; p < 0.01). The influence of these factors on SUV of 18F-FET was similar in all brain areas. In conclusion, SUV of 18F-FET in the normal brain is influenced by gender and weakly by BMI, but changes are similar in all brain areas.

Static and dynamic 18F–FET PET for the characterization of gliomas defined by IDH and 1p/19q status

We have read with interest the review by Ryken et al. about the role of imaging in the management of progressive glioblastoma [1]. In general, we agree with this review but we cannot support the opinion that the routine use of Positron-Emission-Tomography (PET) to identify progression of glioblastoma is not recommendable. The authors have considered PET using the amino acid tracer C-methyl-L-methionine (MET), but the use of MET is limited to PET centers with an on-site cyclotron due the short half-life of C (20.4 min). In recent years, the clinical application of F-labeled amino acids such as O-(2-F-fluoroethyl)-L-tyrosine (FET) or 3,4-dihydroxy-6[F]fluoro-L-phenylalanine (FDOPA) has spread considerably due to the logistical advantages of the F label (half-life, 109.8 min) [2]. FET can be produced with high yields similar to the widely used FDG and distributed in a satellite concept [3]. In Europe, MET PET has been replaced in many centers by the more convenient PET tracer FET, which is now established as a routine tool for brain tumor imaging in more than 30 neuro-oncological centers in Germany, Austria and Switzerland (personal communication). In these countries, the clinical acceptance is high and more than 10.000 FET PET scans in brain tumor patients have been performed alone in the centers in Jülich, Munich and Zurich in the last years. The diagnostic accuracy of FET PET in the differentiation of tumor progression or recurrence from radiationinduced changes is convincing. A sensitivity and specificity of FET PET for the detection of tumor progression or recurrence of 100 and 93 %, respectively, has been reported, compared with 93 and 50 % for MRI alone [4]. The additional use of dynamic FET PET allows a differentiation of high-grade and low-grade recurrences with a sensitivity and specificity of [90 % [5]. Similar results have also been reported for the differentiation of recurrent brain metastases from radiation-induced changes with an accuracy of 93 % [6]. Furthermore, a prospective study evaluated the prognostic value of early changes of FET uptake after postoperative radiochemotherapy in patients with glioblastoma [7]. PET responders with a decrease of the tumor/brain ratio of FET uptake of more than 10 % had a significantly longer disease-free survival and overall survival than patients with stable or increasing tracer uptake after radiochemotherapy. Additionally, a reliable treatment monitoring was also demonstrated in various experimental approaches (e.g., radioimmunotherapy [8], convection enhanced delivery of paclitaxel [9]) and for antiangiogenic treatment with bevacizumab and irinotecan [10, 11]. Using FDOPA PET, a recent study including 110 patients reported an accuracy of 82 % to detect recurrent K.-J. Langen (&) N. Galldiks Institute of Neuroscience and Medicine, Forschungszentrum Jülich, Leo-Brandt-Str. 5, 52425 Jülich, Germany e-mail: k.j.langen@fz-juelich.de