Advanced MRI and PET Imaging for Assessment of Treatment Response in Patients With Gliomas

906 www.thelancet.com/neurology Vol 9 September 2010

Review

Lancet Neurol 2010; 9: 90620

Published OnlineAugust 11, 2010

DOI:10.1016/S1474-4422(10)70181-2

Department of Radiation Oncology and Physics, Institut

Gustave Roussy, Villejuif Cedex, Paris, France (F G Dhermain MD);

Department of Neurology, Medical School, University of

Regensburg, Regensburg, Germany (P Hau MD); Institute

of Diagnostic and Interventional Neuroradiology,

Hannover Medical School, Hannover, Germany

(Prof H Lanfermann MD); European Institute for

Molecular Imaging, University of Mnster, Mnster, Germany

(Prof A H Jacobs MD); Laboratory for Gene Therapy

and Molecular Imaging, Max Planck Institute for

Neurological Research Cologne, Cologne, Germany (A H Jacobs);

and Neuro-Oncology Unit, Daniel den Hoed Cancer

Centre/Erasmus University Medical Centre, Rotterdam,

Netherlands (Prof M J van den Bent MD)

Correspondence to:Prof Martin J van den Bent,

Neuro-Oncology Unit, Daniel den Hoed Cancer Centre/Erasmus

University Hospital, PO Box 5201, 3008AE Rotterdam, [email protected]

Advanced MRI and PET imaging for assessment of treatment response in patients with gliomasFrederic G Dhermain, Peter Hau, Heinrich Lanfermann, Andreas H Jacobs, Martin J van den Bent

Imaging techniques are important for accurate diagnosis and follow-up of patients with gliomas. T1-weighted MRI, with or without gadolinium, is the gold standard method. However, this technique only re ects biological activity of the tumour indirectly by detecting the breakdown of the bloodbrain barrier. Therefore, especially for low-grade glioma or after treatment, T1-weighted MRI enhanced with gadolinium has substantial limitations. Development of more advanced imaging methods to improve outcomes for individual patients is needed. New imaging methods based on MRI and PET can be employed in various stages of disease to target the biological activity of the tumour cells (eg, increased uptake of aminoacids or nucleoside analogues), the changes in di usivity through the interstitial space (di usion-weighted MRI), the tumour-induced neovascularisation (perfusion-weighted MRI or contrast-enhanced MRI, or increased uptake of aminoacids in endothelial wall), and the changes in concentrations of metabolites (magnetic resonance spectroscopy). These techniques have advantages and disadvantages, and should be used in conjunction to best help individual patients. Advanced imaging techniques need to be validated in clinical trials to ensure standardisation and evidence-based implementation in routine clinical practice.

IntroductionIn neuro-oncology, decisions about continuation or discontinuation of treatment for individual patients usually depend on adequate imaging. Similarly, identi cation of new active drugs often depends on assessment of an objective response rate or determination of progression-free survival, which is established by changes in the tumour seen on imaging. The basic assumption for imaging of tumours is that changes in imaging ndings represent the biological activity of the tumour. However, conventional imaging strategies can be non-speci c and not a direct measurement of tumour size or tumour activity.1

For management of individual patients and trial participants, advanced imaging techniques such as aminoacid PET, cerebral blood volume (CBV) assessment with perfusion-weighted MRI, and magnetic resonance spectroscopy (MRS) might o er more reliable assessment of treatment outcomes. However, the usefulness of these techniques depends on understanding of the relation between changes in the image and tumour activity or patient outcomes, and their predictive values need to be validated in clinical trials. This report reviews the functional and molecular background of the most relevant imaging techniques, their usefulness for assessment of outcomes of patients with brain tumours after treatment, and how these techniques can be implemented in outcome criteria.

Pseudoprogression and pseudoresponseAssessment of response to treatment is key to routine patient care and for clinical trials. Traditionally, response assessment in neuro-oncology is done on the basis of assessment by contrast (gadolinium)-enhanced T1-weighted MRI.2 However, this technique does not provide a speci c measure of tumour size and activity, but is mainly in uenced by vascular leakage.1 In many situations, changes in enhancement do not correlate with

response. One example of this occurrence is pseudo-progression, in which an increase in contrast uptake does not re ect tumour progression. Another one is the reverse e ect of pseudoresponse, in which a decrease in contrast enhancement does not re ect tumour regression in patients treated with antiangiogenic agents.35 Pseudo-progression can occur after radiotherapy with or without temozolomide.6,7 Pseudoresponse is due to a normalisation of abnormally permeable microvessels, mostly noted with antiangiogenic treatment, leading to a rapid decrease of contrast enhancement of gadolinium T1-weighted MRI, but not re ecting a real decrease in tumour activity or size.1,8,9 As a result, high rates of response (3550%) and 6 month progression-free survival rates have been reported in trials10,11 of inhibitors of the VEGF-receptor signalling pathway. However, relapses in these patients are visible as a growth of an abnormal area on uid-attenuated inversion recovery (FLAIR) or T2-weighted images without contrast enhancement. These enlarged regions can be distant to the primary site of the tumour and can resemble gliomatosis cerebri ( gure 1).5 Thus, conventional magnetic resonance techniques for response are not appropriate for the assessment of treatment response to antiangiogenic therapies.

Advanced imaging methods and biological endpointsTo overcome limitations of conventional MRI, advanced imaging techniques need to be assessed for their potential to visualise the biological changes of the tumour, to detect proliferative activity, hypoxia, apoptosis, necrosis, and tumour vasculature. Any imaging technique that reliably distinguishes responders from non-responders to treatment at an early stage will allow more rational treatment administration and early discontinuation of ine ective treatment strategies. Advanced MRI and PET imaging techniques may allow early detection of treatment-induced changes in tumour biology and physiology.

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Tumour metabolism is one of the most intensively investigated topics in tumour biology. Many aspects of tumour metabolism, including turnover of glucose, aminoacids, and nucleosides; hypoxia; production of lactate or choline as markers for membrane turnover; angiogenesis; perfusion; and invasiveness can be non-invasively assessed with modern imaging techniques such as perfusion-weighted MRI, di usion-weighted MRI, MRS, and PET ( gure 2, table). For example, hypoxia within tumours selects cells to undergo metabolic adaptationtermed glycolytic switchthrough which glycolysis becomes the main source of ATP production.18 Furthermore, the Warburg e ect, in which anaerobic glycolysis occurs despite su cient concentrations of oxygen, is characteristic of cancer cells and advanced cancers.19 These metabolic changes have a role in the increased uptake of radiolabelled F- uorodeoxyglucose (F-FDG) in tumours, which can be detected by PET. An increased turnover of aminoacids and nucleosides for protein and DNA synthesis in cancer cells compared with healthy cells is the basis for PET imaging with radiolabelled C-methionine, F- uoroethyltyrosine (F-FET), and F- uorothymidine (F-FLT).

Once e ective molecular targeted drugs become available for the treatment of glioma, decisions about treatment continuation or discontinuation could rely on a speci c imaging method that targets the action of the tested compound (eg, perfusion and permeability MRI for the assessment of treatment response to antiangiogenic therapy). This test could then show decreasing biological activity of the tumour that would signify clinical bene t. Suitable biological endpoints may be genetic, epigenetic, proteomic, or metabolic factors, tumour stem cells or progenitor cells, and patterns of angiogenesis, invasion, proliferation, and immunoin ltration. Few of these factors can be imaged presently ( gure 2), and development of these new techniques will become especially relevant once e ective targeted agents are available.

Advanced MRI techniquesPerfusion-weighted imagingMRI can be used for detection of various metabolic and physiological variables, and is available in routine clinical settings. MRI techniques are able to assess changes in metabolic tissue pro le, tissue blood perfusion, microvessel permeability, and water mobility, which are biomarkers for pathophysiological and microstructural changes.20

Assessment of perfusion and permeabilityHigh-grade gliomas are characterised by an increased macrovasculature and microvasculature compared with those in healthy tissue. The amount of hyperperfusion is a marker of the biological behaviour and aggressiveness of the tumour, and the estimated relative cerebral blood volume (CBV) is a semiquantitative parameter that correlates with the amount of capillaries. Relative CBV

can be used to assess perfusion characteristics ( gure 2), and such perfusion imaging techniques require bolus tracking after gadolinium injection with a T2* dynamic susceptibility-contrast technique. Integration of the area under the signal curve gives an estimate of CBV, which correlates with increased vascularisation.21,22 Especially for high-grade gliomas, a disrupted bloodbrain barrier can lead to false estimates of CBV because of T1 leakage e ects caused by contrast agent extravasation. This incorrect estimation can be corrected in part by use of a contrast preloading dose or by advanced mathematical models.23,24

Another key characteristic of tumour angiogenesis is the extravasation of contrast agent into the extravascular compartment. Microvascular leakage suggests abnormal permeability of immature capillaries and relates to glioma grade.25 Recruitment of permeable vessels at the tumour periphery could be an early process in the natural history of low-grade gliomas as they slowly develop anaplastic features.26 T1-weighted dynamic contrast-enhanced MRI ( gure 3) relies on compartmental model estimations and provides estimates of the leakiness of the vasculature and breakdown of the bloodbrain barrier.21,28 The quanti able variable of the transport constant (ktrans) of contrast media from the intravascular to the extravascular compartment gives an estimate of vascular permeability. Use of this technique is demanding and

Figure 1: Pseudoresponse in a patient with glioblastoma after 6 weeks of treatment with a VEGF antagonistContrast-enhanced T1-weighted MRI (A) before treatment and (B) after treatment, showing a large decrease in contrast-enhanced area. However, T2-weighted images (C) before treatment and (D) after treatment show an increase in contrast-enhanced area with abnormal signal intensity (arrows), which is suggestive of development of gliomatosis cerebri. The patient deteriorated clinically during the 6 weeks of treatment.

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Figure 2: Imaging targets in gliomas and their microenvironmentImaging targets from increased tumour cell metabolism and proliferation, microenvironment (eg, matrix metalloproteinases), and tumour vasculature (eg, V3 integrins). (A) Fluid-attenuated inversion recovery MRI of entire tissue volume of di use tumour in ltration. (B) Contrast-enhanced T1-weighted MRI, showing breakdown of bloodbrain barrier. (C) Perfusion-weighted MRI, localising areas with increased perfusion. (D) F-FDG-PET, localising tumour areas with high cellular density and extent of secondary inactivation of cortical areas. (E) C-methionine-PET is a marker for expression of aminoacid transporters, and a surrogate marker for neovascularisation. (F) F-FLT-PET is a marker for expression of nucleoside transporters and thymidine kinase 1, and a surrogate marker for cell proliferation. C-AcOH=C-acetate. C-MET=C-methionine. F-FAZA=F- uoroazomycin arabinoside. F-FDG=F- uorodeoxyglucose. F-FDOPA=F- uorodopa. F-FES= uoroestradiol. F-FET=F- uoroethyltyrosine. F-FHGB=F- uoro-3-(hydroxymethyl)butylguanine. F-FLT=F- uorothymidine. F-FMISO=F- uoromisonidazole. F-RGD=F-arginine-glycine-aspartic acid. Ga-DOTATOC=Ga-Ga-DOTA(0)-Phe(1)-Tyr(3)-octreotide. APUD=amine precursor uptake and decarboxylation system. CHT=choline transporter. CNT=concentrative nucleoside transporter. DAT=dopamine reuptake transporter. EGFR=epidermal growth factor receptor. ENT=equilibrative nucleoside transporter. FASE=fatty acid synthase. GLUT=glucose transporter. GRP=gastric releasing peptide. LAT=L-aminoacid transporter. MMP=matrix metalloproteinase. NERT=norepinephrine reuptake transporter. PS=phosphatidylserine. SERT=serotonine reuptake transporter. sst=somatostatin. VEGFR=VEGF receptor. Adapted with permission from Wester.12

Blood vessel

Peptides18F-RGD

18F-FDG-6-phosphate

18F-FES

18F-choline-phosphateProtein synthesis APUD system

FASE

DNA

Annexin-V

Apoptosis

PS

Peptides18F-RGD

Nucleosides18F-FLTAmine precursors

18F-FDOPA, 18C-HTP Antibodies68Ga-anti-Her2-fragment

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Aminoacids18F-FET, 11C-methionine

18F-choline

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Monitoring gene therapy18F-FHBG Perfusion15O-H2O

11C-AcOH

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LAT 1/2 DAT/NET/SERT

ENT/CNT EGFR/Her

2sst/GRP

CD20/Her2

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pO2

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Hexokinase

18F-FAZA, 18F-MISOCu(ATSM)

IntegrinsVEGFRMMPs

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assumes a direct linear relationship between the contrast concentration and the measured T1 signal, which is not entirely true for biological systems.29 A new MRI sequence that employs a short T2*-weighted magnetic resonance acquisition has been proposed,30 which simultaneously estimates both permeability and perfusion characteristics in one examination. Furthermore, a corrected perfusion map calculation has been tested,31 which takes into account the extravascular extravasation of gadolinium. An improved correlation between perfusion estimate and glioma grade could be reported with this technique.31

Nonetheless, techniques of quanti cation of perfusion and permeability in patients with gliomas need to be developed, and variables related to data interpretation, such as histology, previous treatments, and steroid administration (which in uences microvasculature), should be taken into account.32,33

Determination of treatment outcomesIn a series16 of 189 patients with low-grade and high-grade glioma, baseline assessment of relative CBV with a cuto value of 175 for T2*-weighted dynamic

susceptibility contrast parameter predicted time to progression and clinical outcome. Another study34 has shown that very early temporal changes of relative CBV during radiotherapy in regions with high or low perfusion predict physiological response to treatment in patients with high-grade gliomas and correlates with survival. However, this method is di cult to reproduce, in particular because of tumour heterogeneity, which leads to di culty choosing the optimum region of interest for perfusion measurement. The same group35 showed, with a voxel-by-voxel quanti cation of relative CBV variations, that perfusion rates change within the entire tumour volume. In a series35 of 44 patients with high-grade gliomas, who were treated with combined chemoradiotherapy and scanned at week 3 of radiotherapy, this parametric response map predicted overall survival better than did conventional hotspot techniques that rely on baseline estimates of relative CBV. Results from another study36 showed that baseline determination of microvascular leakage was a strong and independent factor for prognosis and outcome in 46 patients with low-grade gliomas, who were treated with radiotherapy or temozolomide.

Pathophysiology MRI or MRS PET

Threshold Advantages Limitations Threshold Advantages Limitations

Proliferation Progression of tumour

MRS: Chomax of 202, Chomean of 152 (compared with healthy tissue13), and Cho:NAA ratio of 172

Speci city Partial volume e ects, availability

F-FLT: to be established Does not cross the intact bloodbrain barrier

Dedi erentiation Increased rate of proliferation

MRS: creatine14,15 >093; MRI: CBV >175 (compared with healthy tissue)16

Speci city Partial volume e ects

Structural complexity

Microstructural changes

Di usion kurtosis imaging:17 >052 for solid parts of high-grade gliomas

Speci city Availability

Energy metabolism

High rate of proliferation

MRS: creatine 0, no lactate accumulation in healthy tissue

Speci city Not standardised F-FMISO: to be established

Identi cation of areas which will be resistant to radiation

Primarily experimental application so far

Necrosis Increased lipid turnover

MRS: lipids >0, no lipid accumulation in healthy tissue

Speci city Not standardised

MRS=magnetic resonance spectroscopy. Chomax=maximum concentration of choline-containing compounds. Chomean=mean concentration of choline-containing compounds. NAA=N-acetyl-aspartate. F-FLT=F- uorothymidine. CBV=cerebral blood volume. =not available. F-FDG=F- uorodeoxyglucose. F-FET=F- uoroethyltyrosine. F-RGD=F-arginine-glycine-aspartic acid. FLAIR= uid-attenuated inversion recovery. ADC=apparent di usion coe cient. FA=fractional anisotropy. F-FMISO=F- uoromisonidazole.

Table: Characteristics of advanced MRI and PET imaging methods for assessment of glioma


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Assessment of outcome after treatment with antiangiogenic drugsDynamic susceptibility contrast can e ectively track antiangiogenic response. The size of microvessels decreases after antiangiogenic therapy and that change can be detected with this technique.8,37 Additionally, in antiangiogenic-based treatment strategies, T1-weighted dynamic contrast-enhanced MRI can assess treatment-induced normalisation of bloodbrain barrier permeability.38 A decrease in microvessel density as assessed by histology before and after treatment correlated with classic radiographic response ndings in one cohort of patients.38 Mean Ktrans values were signi cantly reduced as early as 2 h after oral cediranib was given.39 This nding con rms the rapid reversal of abnormal permeability in patients with recurrent high-grade gliomas following treatment with antiangiogenic drugs, which should not be confused with a true antitumour e ect.8 In patients with recurrent glioblastoma who received one dose of cediranib, a combination of perfusion and permeability assessmentsintegrated within a vascular normalisation indexwas identi ed as a very early biomarker of survival.37

Di erentiation of recurrent tumour from radiation-induced tissue changesAnalysis by perfusion-weighted MRI allows for distinction between recurrent tumour and pseudoprogression after radiotherapy (with or without temozolomide).24,4043 Radiation-induced necrosis is histopathologically char-acterised by brinoid necrosis and endothelial damage,

whereas recurrent glioblastoma tissue contains areas of increased vasculature. Therefore, an increase in relative CBV is expected in contrast-enhancing tissue changes that are caused by recurrent tumours, but not in those caused by radionecrosis ( gures 46). Investigators from one series44 noted an association between increased relative CBV and tumour recurrence, although three of eight patients with relative CBV lower than the threshold value still had tumour progression.

In a series43 of 13 patients, histopathology by imaging-guided biopsy correlated with localised perfusion-weighted MRI measurements with a threshold value of 071, and localised perfusion di erentiated recurrence of high-grade gliomas from radiation-induced necrosis with a high degree of accuracy. A very similar result was reported in a series of 57 patients.41 These studies suggest that perfusion-weighted MRI might be equivalent to C-methionine-PET for assessment of treatment in patients with high-grade gliomas.41,45 Investigators from a study of 27 patients46 were able to distinguish pseudo progression from true progression in high-grade gliomas more accurately by calculation of a parametric response map of relative CBV at week 3 during chemoradiotherapy than they were with conventional relative CBV or cerebral blood ow maps.35

Potential advantages and limitationsPerfusion-weighted MRI for T2* acquisition adds less than 10 min to conventional MRI examinations, and several commercial software packages are available that enable comparatively easy quanti cation of permeability and perfusion factors. However, some limitations exist. First,

Figure 3: Dynamic contrast-enhanced-MRI showing tissue heterogeneity in a patient with glioblastoma(A) Axial T1-weighted postcontrast magnetic resonance scan, (B) corresponding relative enhancement map of a dynamic contrast-enhanced 3D T1-weighted sequence, and (C) signal intensity curves of di erent tumour areas. Areas with a strong uptake of contrast have high signal intensity values during the rst 2 min, with a subsequent washout phenomenon (blue region of interest and curve), which is indicative of a substantial microvascular leak with progressive accumulation of contrast agent in the tumour interstitial space. Areas with low microvascular permeability values have low tumour enhancement (pink region of interest and curve). Necrotic tumour areas only have a minor uptake of contrast media (black region of interest and curve). Tumour heterogeneity and di erent areas of microvascular permeability within an individual tumour mass are characteristic ndings of malignant tumours, and are only visible on dynamic imaging sequences (B) and not on conventional MRI (A). Reprinted with permission from Jacobs et al.27

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by contrast with MRI anatomical structural measures, these functional parameters are semi quantitative (because of inherent methodological limitations) and dynamic (because absolute values can vary with time and can be

in uenced by many factors such as steroids). Second, the optimum timing for these assessments is not established. Third, acquisition and postprocessing techniques can vary, with di erences in the software packages used.47,48

Figure 4: Relative cerebral blood volume images of a patient with 1p/19q codeleted oligoastrocytoma and necrosis after radiation(A) Preradiation T1-weighted MRI with gadolinium and (B) uid-attenuated inversion recovery MRI. (C) CT scan of radiotherapy target volume de nition (red) and the 95% isodose (green) of radiotherapy dose (504 Gy). (D) 6 months after radiation, T1-weighted MRI with gadolinium showing two new contrast-enhanced regions (arrows) with central necrosis and surrounding oedema. (E) Perfusion-weighted MRI coregistered with gadolinium-enhanced T1-weighted MRI shows vessels with high cerebral blood volume (red), and contrast-enhanced regions (arrows) with low cerebral blood volume values (blue). (F) Gadolinium-enhanced T1-weighted MRI and (G) uid-attenuated inversion recovery MRI after 4 years of follow-up without further treatment, without evidence of tumour activity and in a still asymptomatic patient. Relative cerebral blood volume images courtesy of Denis Ducreux (Neuroradiology Department, Kremlin Bictre University Hospital, Paris, France).

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Threshold relative CBV values and threshold accuracies can vary depending on acquisition and postprocessing methods. The clinical and research community needs to adopt an accurate and standardised protocol for perfusion

MRI that should be validated with stereotactic biopsy.49 Besides, high-grade gliomas are often large and very heterogeneous, with cystic, necrotic, and cellular regions.50 Only solid, non-necrotic regions of the tumour are assessable for perfusion and permeability rates. Finally, image analysis methods that highlight areas of high activity within the tumour volume as regions of interest (the hotspot technique) are dependent on the operator, and mean values of whole tumour tissue might include necrosis or healthy vasculature. Therefore, there is a need for an automatic parametric technique for the assessment of vasculature of the whole tumour.35

Di usion-weighted imagingDi usion-weighted imaging (DWI) probes the mobility of water within tissue. In biological tissues, this water mobility is caused by thermal agitation (ie, Brownian motion) and is a ected by cellular and extracellular tissue structures, viscosity of the medium, and tortuosity of the extracellular space. DWI parameters are quanti able, can be obtained easily and rapidly, and can be used to determine tumour tissue characteristics before and after therapy.51 E ective therapies alter the cellular density of the tumour, the cytoarchitecture, and the water homoeostasis; these changes at the cellular level are detectable on DWI before morphological changes such as to tumour size occur.52

The DWI measure that is most widely used is the apparent di usion coe cient (ADC; mm/s). ADC values provide a measure of the di usion properties of water in brain tissue at the voxel level, and these values can then be used to create an ADC map.

Di usion-weighted MRI is helpful for grading of gliomas.53 In solid parts of gliomas, low ADC values are currently used as indicators for high-grade tumours, and high values are used as indicators of low-grade tumours. However, formation of oedema can strikingly a ect the ADC value, giving the appearance of low-grade tumours, and could be a confounding factor for assessment of therapeutic e ects. Results from clinical studies54,55 suggest that DWI can be used to predict prognosis in patients with gliomas within 3 weeks after initiation of therapy. Moreover, Pope and colleagues56 showed that pretreatment data from DWI could predict response to bevacizumab. In their study,56 the hazard ratio for progression at 6 months was signi cantly increased in bevacizumab-treated patients who had an ADC value

Figure 5: Relative cerebral blood volume and local recurrence in a patient with glioblastoma(A) T1-weighted MRIs with gadolinium enhancement after gross total resection for a glioblastoma, but before radiation, showing surgical cavity with Gliadel wafers. (B) T1-weighted MRIs with gadolinium, 1 month after concomitant chemoradiation (60 Gy) and six cycles of adjuvant temozolomide, showing new contrast-enhanced regions (arrows). (C) Perfusion-weighted MRI coregistered with gadolinium-enhanced T1-weighted MRI, showing healthy vessels and the new lesion, both with high cerebral blood volume values (red) which is suggestive of tumour recurrence. The patient had another operation, and active glioblastoma tissue was detected on histological examination of the lesion. Relative cerebral blood volume images courtesy of Denis Ducreux (Neuroradiology Department, Kremlin Bictre University Hospital, Paris, France).

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lower than their mean. In another study,57 increased DWI signal combined with low ADC, resulting in an ischaemic MRI phenotype, during treatment allowed investigators to identify patients with an improved outcome during bevacizumab therapy, suggesting a role for DWI in assessment of treatment response to anti-VEGF therapy in patients with glioblastoma. Further validation in large clinical trials is in progress and developments of the di usion technique, such as di usion kurtosis imaging, which enables characterisa tion of tissue microstructure through quanti ca tion of the non-Gaussian di usion properties of water,58 might add valuable information about tissue structure for interpretation of changes on DWI in the tumour and surrounding tissue.17

MRSMRS provides information about metabolic tissue composition. Advanced spectroscopic methods can quantify markers of tumour metabolism (eg, glucose), membrane turnover and proliferation (eg, choline), energy homoeostasis (eg, creatine), intact glioneural structures (eg, N-acetyl-aspartate), and necrosis (eg, lactate or lipids). Data can be acquired with 2D or 3D techniques. Information can be derived about the volume of interest on the basis of relative and absolute metabolite concentrations, including rates of cellular membrane turnover, neuronal viability, or accumulation of free lipids as markers of necrosis. Increased concentrations of choline, raised or reduced creatine concentrations and decreased N-acetyl-aspartate con-centrations from base line can usually be found in untreated malignant gliomas. Raised creatine concentrations can be an indicator of decreased progression-free survival in low grade and anaplastic glioma; therefore, creatine should not be used as a denominator in metabolite ratios (panel).14,15 Elevation of choline concentration, which might represent higher cellular membrane turnover, correlates with immuno-histo chemical prolifera tion markers such as Ki-67.60 Maximum choline concentrations derived by 2D-H-MRS provided the highest accuracy for discrimination between low and high grade gliomas.13 During radio therapy, the choline concentration in the treated tissue can decrease, suggesting a therapy e ect.61 A temporary rise in choline concentration can occur during necrosis, but H-MRS cannot discern between membrane production or degradation.62 Some investigators suggest that tumour recurrence after radiotherapy is linked to an increase in choline-containing compounds within the tissue, whereas necrosis or therapy response are linked to an increase in lactate or lipid concentrations ( gure 6).6366 In one study,63 analysis with MRS detected tumour recurrence or increase of grade with a positive predictive value of 916% and a negative predictive value of 100%. A decrease in choline concentration parallels tumour shrinkage after chemotherapy with temozolomide or procarbazine, lomustine, and vincristine.67,68

A limitation of MRS is that voxel sizes are most often restricted to at least 071 cm on clinical scanners because of signal-to-noise ratio requirements, which can lead to partial volume e ects between recurrent tumour and post-treatment radiation e ects. This limitation makes assessment of smaller lesions unreliable. In clinical practice, MRS is technically challenging because of the need to suppress or exclude signal contamination from tissues adjacent to the tumour and treatment bed, such as lipids (from the scalp) and water (from the ventricles). Surgical clips from adjacent craniotomies also disrupt the local eld homogeneity and may a ect the quality of data.

Integration of advanced MRI techniques: perfusion, di usion, and spectroscopyPerfusion-weighted MRI, di usion-weighted MRI, and MRS can help to characterise di erent pathophysiological aspects of brain tumours and changes related to

Figure 6: Magnetic resonance spectroscopy in a patient with anaplastic oligoastrocytoma and radionecrosisThe patient was initially managed with surgery and subsequent chemoradiotherapy. Hypofractionated reradiation was administered after 1 year because of tumour progression at the site of the initial resection. 2 years after initial treatment, an enhancing lesion on T1-weighted MRI was noted; however, both magnetic resonance spectroscopy and perfusion-weighted imaging suggested radiation necrosis. This was con rmed histologically with a re-resection. (A) Progressive enhancement on T1-weighted images, without elevation of choline on magnetic resonance spectroscopy. (B) The green line represents the normal spectrum of uninvolved contralateral healthy tissue (green voxel position in [A]). White and red lines (white voxel position in [A]) show high lipid concentrations and choline reduction compared with healthy tissue. (C) Progressive enhancement on T1-weighted image (as depicted in [A]), without elevation of relative cerebral blood volume.

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treatment. Individually, these techniques have shown their potential usefulness for diagnostic purposes, estimation of prognosis, and assessment of early treatment response. Combination of these techniques is promising for di erentiation between tumour recurrence and radiation necrosis.69 However, large, longitudinal, prospective trials are needed to de ne and standardise cuto values and the optimum time for assessment of metabolic and physiological magnetic resonance variables in relation to histopathological changes in gliomas, treatment e ects, and patient outcomes. Cuto values might remain arbitrary because of the heterogeneity in the biological activity of brain tumours and the use of di erent imaging machines. Ultimately, implementation of these techniques in clinical practice will depend on proven improved outcomes (such as survival and better quality of life) in patients managed with them.

PET imagingAnalysis by PET can show speci c quantitative information on the metabolic state of gliomas.27 PET analysis allows investigators to quantitatively localise expression of enzymes or transporters by measurement of the respective enzyme or transporter substrates. Dependent on the radiotracer used, various molecular processes within gliomas can be visualised by PET, most of which relate to increased metabolism and cell proliferation ( gure 2). Dependent on the tumour grade of the glioma, radiolabelled F-FDG, C-methionine, F-FET, and F-FLT are incorporated into proliferating gliomas because of increased activity of membrane transporters for glucose (F-FDG), aminoacids (C-methionine or F-FET) or nucleosides (F-FLT), and increased expression of hexokinase (F-FDG) or thymidine kinase (F-FLT). Disadvantages of PET are that it is less available and costs more than does MRI, and patients are exposed to radioactive material (although exposure is low).

F-FDG-PET can monitor the rate of glucose uptake and detect metabolic di erences between healthy brain tissue, low-grade gliomas, high-grade gliomas, and radionecrosis. Amount of glucose consumption within the tumour correlates with tumour grade, cell density, biological aggressiveness, and survival in patients with primary and recurrent gliomas. Because of limitations of F-FDG-PET for assessment of brain tumours, more speci c radiotracers for glioma were developed. The radiolabelled aminoacids C-methionine and F-FET are more speci c tracers for tumour detection and tumour delineation than is F-FDG because of their low uptake in healthy brain tissue. Increased C-methionine or F-FET uptake are related to increased transport mediated by type-L aminoacid carriers. Uptake of C-methionine correlates with cell proliferation in vitro, Ki-67 expression, and nuclear antigen expression and microvessel density in proliferating cells, suggesting that C-methionine may be a marker for tumour proliferation and neovascularisation.

Panel: Requirements for the follow-up of patients with glioma by use of imaging

MRI Submission of latest MRI for proper planning of follow-up

examination Identical imaging methods at all assessments for:

Head position, MRI sequence, slice thickness, slice angulation, slice distance

T1 with and without gadolinium T2 or uid-attenuated inversion recovery Three planes (axial, coronal, and sagittal)

Same time of intravenous application of gadolinium 2472 h after surgery:

T1 with and without gadolinium Di usion-weighted image to identify periprocedural

cerebral ischaemia Avoid change of eld strength Regular follow-up during therapy

Before and immediately after therapy (resection, radiotherapy, or chemotherapy)

Every 3 months for patients with glioblastoma, 34 months for patients with anaplastic astrocytoma, and 6 months for patients with low-grade glioma

At clinical progression

H-magnetic resonance spectroscopy Multivoxel chemical shift imaging Short echo time (2030 ms) Avoid partial volume e ects Avoid ratios with creatine as denominator Comparison with healthy tissue

C-methionine-PET59

Low-protein diet (eg, tea and biscuits) on day of examination

Intravenous injection of 740 MBq C-methionine with data acquisition 2060 min after injection

Image reconstruction after correction for attenuation and scatter

3D coregistration with MRI If increased C-methionine uptake in tumour area is

visible, quanti cation with a region of interest of 8 mm in diameter in the hottest region, and comparison with contralateral mirror region (tumour:background ratio) Tumour:background ratio of more than 15 is

indicative of biologically active tumour If C-methionine uptake coincides with strong

contrast enhancement, uptake might be unspeci c Tumour:background ratio of 1015 suggests

evolving tumour activity, and indicates follow-up every 3 months

Tumour:background ratio increase of more than 15% between follow-up measurements suggests tumour progression


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Another variable that can be non-invasively assessed by PET is incorporation of nucleosides into DNA in proliferating cells. Radiolabelled thymidine (H-thymi-dine) is the gold standard for assessment of cell proliferation in cell culture, and C-thymidine and F-thymidine compounds have been radiosynthesised to allow non-invasive assessment of tumour proliferation and early response to chemotherapy by PET. F-FLT is stable in vivo and has been used for the assessment of glioma proliferation in patients.70,71

In the late 1980s and early 1990s, F-FDG-PET was very important for imaging metabolism of brain tumours. However, because of high cortical background activity ( gure 2), F-FDG-PET is not suitable for detection of residual tumour after therapy.72 Moreover, the e ects of radiotherapy and chemotherapy can only be shown by F-FDG-PET after a few weeks of treatment, with a possible transient increase of F-FDG uptake in the initial phase, which is most likely caused by the in ltration of macrophages.73,74 At subsequent follow-up, recurrent tumour and malignant transformation can be visualised by the detection of newly occurring hypermetabolism.75,76

F-FDG-PET has a sensitivity of 75% and a speci city of 81% for the detection of recurrent tumour com pared with radiation necrosis.77 In another series, after stereotactic radiotherapy for brain metastasis, co-registration of F-FDG-PET images with MRI improved the sensitivity for detection of recurrent tumour from 65% to 86%. A disadvantage of F-FDG-PET is the accumulation of F-FDG in macrophages that have in ltrated sites receiving radiotherapy, which can make radiation necrosis indistinguishable from recurrent tumour. One study72 addressed limitations of F-FDG-PET for assessment of treatment response because of its low sensitivity, such that F-FDG-PET has only negative but not positive predictive values for therapy assessment. Because of the development of improved PET for detection of aminoacids and F-FLT, centres with access to these radiotracers do not use F-FDG-PET in the assessment of patients with gliomas.70

Treatment response as assessed by aminoacid-based PET and FLT-PETC-methionine-PET and F-FET-PET are well suited to follow the e ects of radiotherapy and chemotherapy, which show as a reduction of relative radiotracer uptake ( gure 7).72,79 Preliminary data8084 suggest that outcomes are better for patients for whom planning of surgery and radiotherapy is done with tumour volumes established by C-methionine-PET or F-FET-PET and conventional MRI than they are for those for whom treatment planning is done on the basis of conventional MRI alone. After chemotherapy, C-methionine-PET and F-FET-PET can detect response after 3 months in high-grade gliomas and low-grade gliomas.8587 On the basis of these ndings, the deactivation of aminoacid transport seems to be an early sign of chemotherapy response. In a pilot study of 19 patients with recurrent glioma treated with bevacizumab in combination with irinotecan, F-FLT-PET at 2 weeks and 6 weeks after initiation of treatment allowed the distinction between responders and non-responders.88 F-FLT-PET responses at 2 weeks and 6 weeks were signi cant predictors of overall survival (p


Review

a reliable di erentiation between post-therapeutic benign lesions and tumour recurrence after treatment of low-grade tumours and high-grade tumours.93

Imaging of tumour progressionC-methionine-PET can distinguish tumour pro-gression from stable disease with high sensitivity (90%) and speci city (923%) by a more than 146% increase in C-methionine uptake ( gure 8).94 Equivalent ndings by F-FET-PET were reported in patients with glioma after radiotherapy, radiosurgery, and multimodal treatment such as radio immuno therapy.95 By contrast with a 929% speci city and 100% sensitivity of F-FET-PET, speci city of conventional MRI alone was

only 50%.95 After radioimmunotherapy, a threshold tumour-to-background ratio of 24 for F-FET uptake allowed best di erentiation between recurrence and reactive changes (sensitivity 82%, speci city 100%).96 In a prospective study97 of stereotactic sampling of F-FET-positive glioma recurrences in 17 patients with low-grade glioma, six patients with anaplastic glioma, and eight patients with glioblastoma, the positive predictive value of F-FET-PET was 84%.

Importantly, proper analysis of PET images relies on choice of a tumour-to-background ratio cuto . Di erent groups choose their cuto threshold on the basis of di erent brain regions as background tissue. For most PET agents, uptake in the brain is not uniform, and thus description of background region selection is crucial to the study design and the interpretation of ndings. This issue needs to be standardised for multicentre trials of PET to be implemented.

V3 integrin can be used as a marker for PET imaging and is speci cally expressed on proliferating endothelial cells and glioma cells ( gure 2). F-arginine-glycine-aspartic acid (RGD)-PET images fused with MRI were correlated with tumour samples analysed immuno histo-chemically for V3 integrin expression.98,99 In regions of high proliferation, tracer uptake in the PET images correlated with immunohistochemical V3 integrin expression of corresponding tumour samples.98,99 This method could therefore pave the way for assessment of response to integrin-targeted therapies, such as cilengitide, a compound that is currently being investi-gated in a randomised clinical trial in patients with newly diagnosed glioblastoma.100

Comparative studiesOnly a few studies45,101 are available that compare SPECT or PET with MRI or MRS, and are of restricted size, limiting conclusions that can be drawn. Hybrid MRI-PET scanners are in development, and prototype MRI scanners equipped with a PET head insert are undergoing assessment in specialised centres. The hybrid systems could allow simultaneous MRI and PET imaging without the need for patient relocation.

Implementation of new imaging techniquesNovel imaging and outcome assessment systems should be based on reliable tumour indices that are independent of the status of the bloodbrain barrier or vascular permeability. Novel techniques need to satisfy several additional requirements before they can be accepted for general use (daily patient care) or for use in clinical trials. An important prerequisite is detection of tissue heterogeneity. Regions of viable and non-viable tumour, cystic areas, necrosis, and healthy brain tissue are usually distributed in the area of interest. Ideally, imaging should cover the entire volume of pathological tissue with an acceptable slice thickness and spatial resolution. Another prerequisite is availability of well established and

Figure 8: C-methionine-PET for determination of tumour progression C-methionine-PET image of a male patient aged 39 years with a malignant transformation of a low-grade astrocytoma. (A) At initial diagnosis, without immunohistochemical VEGF expression or contrast enhancement on CT scan, and with an average uptake of C-methionine of 13 to contralateral grey matter. (B) After 1 year, the patient presented with a malignant transformation to an astrocytoma grade III with low VEGF expression; on PET imaging, a 21 fold increase of C-methionine uptake but only slight contrast enhancement was noted with MRI. (C) After a year, another resection showed further transformation of the tumour to a glioblastoma with around 35% of tumour cells expressing VEGF (original magni cation 400). A 28 fold increased uptake of C-methionine was noted, despite a marginal contrast enhancement on MRI. Reprinted with permission from Ullrich et al.94

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institution-independent cuto values for the diagnosis of tumour versus necrosis, or of response versus progression. Imaging facilities also need to be widely available to allow implementation in multicentre studies. These imaging techniques need to be validated and related to some measure of established clinical bene t (eg, survival), preferably within the context of prospective clinical trials.

Techniques that allow earlier assessment of progression do not necessarily result in an improved progression-free survival endpoint. If there is no clinical correlate to the progression (eg, improved quality of life or independent functioning), any change in imaging is of unclear clinical signi cance. Despite many reports37,41,45,56 on new techniques for outcome assessment of glioma, none of these techniques have been validated in multicentre prospective trials or are su ciently widely available to allow implementation in daily practice or in clinical trials.

Clinical follow-up for gliomasIrrespective of the method used, there are several basic principles for individual patient follow-up (panel). E ects of treatment should be visualised during and after therapy by the same imaging techniques, including the same slice thickness and angulation as were used before therapy. Images should be obtained with a regular frequency, starting before the neurosurgical intervention and including post-resection and post-radiotherapy images.83 Follow-up every 12 weeks is reasonable for standard MRI during adjuvant therapy of glioblastoma, every 34 months for anaplastic glioma, and every 46 months for low-grade gliomas. There are no prospective data for improved clinical outcome with a more intensive follow-up schedule.

Comparison of T1-weighted images with and without gadolinium allows identi cation of areas with spontaneously increased signal intensity (eg, because of haemorrhages). Postoperative di usion-weighted images can help to identify early ischaemic lesions, and need to be made within 2448 h after surgery.102 Changes of steroid dosage should be routinely considered as part of standard assessment of outcome. Tumour progression or response should not only be based on T1-weighted MRI, but also on changes on T2-weighted and FLAIR imaging. These techniques are especially relevant for assessment of grade III and low-grade gliomas, and should be compared with images of several previous follow-up scans (and not only the previous MRI). Because gadolinium is injected, the injection process can be

accompanied with dynamic susceptibility contrast data acquisition after a prebolus, allowing pathophysiological data to be obtained.

The other MRI and PET imaging techniques discussed are beyond present clinical standards, but add important information for the assessment of patients and are of prognostic relevance especially for accuracy of biopsy sampling, resection, and radiotherapy. In particular, perfusion-weighted MRI, di usion-weighted MRI, and aminoacid PET are close to being implemented by many centres into clinical routine for planning of biopsy sampling, resection, radiotherapy, di erentiation of radiation necrosis from tumour progression, and follow-up of the e ects of chemotherapy (panel). Use of a complementary imaging method (eg, PET or MRS) in case of di culty in the management of individual patients could provide important additional information on tumour activity.78

ConclusionsMorphological MRI is the basis of brain tumour assessment for primary diagnosis and therapy planning (ie, resection or radiotherapy) and during follow-up. Magnetic resonance scanners are widely available and costs are lower than they are for PET examinations. However, assessment with standard MRI does not solve issues of pseudoresponse, pseudoprogression, and radiation necrosis. Beyond standard imaging, perfusion analysis can be incorporated into daily practice since contrast injection is already required, and the added acquisition time is short (minutes). Furthermore, inclusion of di usion-weighted imaging only adds a couple of minutes to the routine acquisition time. As speci city of MRI in follow-up after therapy is low, MRI should be combined with PET or MRS.

Prospective clinical trials that investigate MRI in combination with PET and MRS to identify the best suitable markers for tumour extent (eg, FLAIR, C-methionine, or F-FET), tumour activity (eg, perfusion-weighted imaging, C-methionine, F-FET, or MRS), therapy response to antiproliferative drugs (eg, F-FLT or MRS) or antiangiogenic treatment strategies (eg, perfusion-weighted imaging, C-methionine, or F-FET), and tumour progression (eg, C-methionine, F-FET, or MRS) are needed. Multimodal imaging trials should be implemented on the basis of reader-independent image analysis and should be done as multicentre trials. From these trials, surrogate MRI techniques need to be derived that can be placed into common clinical practice, which will make time-consuming and expensive imaging techniques obsolete.Con icts of interestWe declare that we have no con icts of interest.

ContributorsAll authors contributed equally to the conception, design, review process, and writing of the report.

Search strategy and selection criteria

We searched PubMed for articles published in English between January, 1990 and July, 2010, with the terms glioma, glioblastoma, imaging, MRI, MRS, rCBV, perfusion imaging, DCE, di usion imaging, DWI, and PET. We also searched our own les for relevant reports.


Review

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Advanced MRI and PET imaging for assessment of treatment response in patients with gliomasIntroductionPseudoprogression and pseudoresponseAdvanced imaging methods and biological endpointsAdvanced MRI techniquesPerfusion-weighted imagingAssessment of perfusion and permeabilityDetermination of treatment outcomesAssessment of outcome after treatment with antiangiogenic drugsDifferentiation of recurrent tumour from radiation-induced tissue changesPotential advantages and limitations

Diffusion-weighted imaging

MRSIntegration of advanced MRI techniques: perfusion, diffusion, and spectroscopyPET imagingTreatment response as assessed by aminoacid-based PET and FLT-PETDiscriminating recurrent tumour from radiation necrosisImaging of tumour progressionComparative studies

Implementation of new imaging techniquesClinical follow-up for gliomasConclusionsReferences

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Advanced MRI and PET Imaging for Assessment of Treatment Response in Patients With Gliomas