REVIEW URRENT C OPINION
PET imaging for brain tumor diagnostics Bogdana Suchorska a, Joerg C. Tonn a, and Nathalie L. Jansen b
Purpose of review Brain tumors differ in histology, biology, prognosis and treatment options. Although structural magnetic resonance is still the gold standard for morphological tumor characterization, molecular imaging has gained an increasing importance in assessment of tumor activity and malignancy. Recent findings Amino acid PET is frequently used for surgery and biopsy planning as well as therapy monitoring in suspected primary brain tumors as well as metastatic lesions, whereas 18F-fluorodeoxyglucose (18F-FDG) remains the tracer of choice for evaluation of patients with primary central nervous system lymphoma. Application of somatostatin receptor ligands has improved tumor delineation in skull base meningioma and concurrently opened up new treatment possibilities in recurrent or surgically not assessable tumors. Recent development focuses on the implementation of hybrid PET/MRI as well as on the development of new tracers targeting tumor hypoxia, enzymes involved in neoplastic metabolic pathways and the combination of PET tracers with therapeutic agents. Summary Implementation of molecular imaging in the clinical routine continues to improve management in patients with brain tumors. However, more prospective large sample studies are needed to validate the additional informative value of PET. Keywords brain tumor, PET, therapy monitoring
INTRODUCTION In the past decades, molecular imaging methods have been increasingly implemented in clinical routine for neuro-oncological settings [1]. Although the most widely used radiotracer for metabolic imaging is still 18F-fluorodeoxyglucose (18F-FDG), many other radiopharmaceuticals have been developed, promising higher sensitivity as well as specificity for certain tumor entities [2]. Particularly, 18F-FDG has been replaced by radiolabeled amino acids or their analogues [3], which were shown to overcome the limitations of 18F-FDG. Due to physiologically low uptake in healthy brain tissue, amino acid PET enables a high tumor-to-background contrast, and due to absent or low uptake in inflammatory lesions, it allows for differentiation between tumor tissue and inflammation [4]. Tracer development is an evolving domain which promises to provide new insights and opportunities for brain tumor imaging. In the following, this review will discuss recent publications in the vast rapidly growing field of molecular imaging in brain tumors.
GLIOMA Gliomas constitute a heterogeneous group of histological subtypes: astrocytoma, oligodendroglioma,
mixed oligoastrocytoma and glioblastoma, which, depending on the WHO grade, substantially differ in natural disease course. Low-grade glioma (LGG) typically affects younger adults with a mean onset age of 35 years and has a variably long life expectancy depending on tumor location, size and initial treatment [5]. In contrast, survival probability in high-grade glioma (HGG) WHO III and IV is low. Median overall survival (OS) in glioblastoma, the most malignant of all primary brain tumors, is as short as 12–15 months and treatment options are limited [6]. Anaplastic astrocytoma, although of a slightly better prognosis with a median OS of 2–5 years, mostly leads to a rapid worsening of neurological functions and thus to a reduced life quality. In malignant glioma entities, outcome depends on histological features, performance a
Department of Neurosurgery and bDepartment of Nuclear Medicine, University Hospital, Ludwig Maximilians University, Munich, Germany Correspondence to Dr Bogdana Suchorska, Department of Neurosurgery, University Hospital, Ludwig Maximilians University, Marchioninistr. 15, 81377 Munich, Germany. Tel: +49 89 4400 72693; e-mail: bogdana. [email protected] Curr Opin Neurol 2014, 27:683–688 DOI:10.1097/WCO.0000000000000143
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KEY POINTS Dynamic analysis of amino acid tracer uptake provides further insights into metabolic properties and therapeutic effects in primary and metastatic brain tumors.
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F-FDG remains the tracer of choice in diagnosis and treatment monitoring of PCNSL. Ga-DODATATE PET becomes increasingly implemented for diagnostic and therapeutic purposes in meningiomas.
status, age at diagnosis and molecular subtypes. Although MRI still remains the keystone for assessment of morphological tumor features, such as location, mass effect and contrast enhancement, PET can provide valuable insights into biology and malignancy of the tumor tissue. Molecular imaging becomes increasingly implemented into surgical treatment planning in suspected LGG, in which identification of possible areas of increased metabolism is most essential to obtain the correct histological diagnosis. Interestingly, areas of increased PET uptake do not necessarily correlate with 5-aminolevulinic acid-induced fluorescence, thus integrating both preoperative PET and 5-aminolevulinic acid into surgery planning might provide additional insights and improve extent of resection [7]. In contrast, HGG patients benefit from an additional treatment monitoring by means of PET which can help identify early therapy failure and thus offers an opportunity for a more timely and individual therapy management.
barrier (BBB), delineation of tumor extent is reported to be more accurate with amino acid PET, and the areas with increased amino acid uptake in PET are often larger than areas with pathological contrast enhancement on MRI [20]. Therefore, amino acid PET can be effectively used for treatment planning, and a better outcome was reported for patients with radiotherapy planning on the basis of tumor extent definition by amino acid uptake [21]. Amino acid PET is not only useful in the initial setting, but also provides important information during the follow-up of glioma patients. It is a valuable tool for treatment monitoring as it helps to assess treatment response, to evaluate patients’ prognosis after therapy and to detect tumor recurrence with high accuracy [4,22,23,24 ,25,26]. The high sensitivity and specificity after different therapies is also because of the independence of the BBB, which is often the limiting factor in post-treatment evaluation of magnetic resonance (MR) images. Following locally aggressive therapies, such as combined radio–chemotherapy or stereotactic brachytherapy, an unspecific contrast enhancement can occur on MRI, which can mimic tumor progression and makes MRI-based treatment monitoring challenging. Contrariwise, the evolvement of antiangiogenic therapies has brought new challenges for conventional MRI by influencing BBB integrity toward mimicking treatment response. Inhibition of neovascularization and reduction of fragile blood vessels result in decreased pathologic contrast enhancement on MRI. Recent studies have reported amino acid PET to detect pseudoresponse in vascular endothelial growth factor antibody-treated patients and to be cost-effective [24 ,27–29,30 ]. In the direct comparison of 18F-DOPA and 18 F-FET, 18F-FET seems to have some advantages. Apart from the absent striatal tracer uptake (which can hamper tumor delineation in this location by 18 F-DOPA), 18F-FET is characterized by typical uptake behavior in LGG and HGG, which can be assessed by dynamic PET acquisition [31–34]. This property of distinguishing different time-activity curves (TACs) is not yet clarified in 18F-DOPA, as there were conflicting reports regarding this point [35 ,36,37]. In addition to tumor grading, TACs seem to provide prognostic information for patient outcome and malignant progression [38 ,39 ,40 ]. &
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Different tracers: different applications The first promising amino acid that has been investigated in many studies for glioma imaging was 11 C-methionine which was shown to be suitable for glioma imaging [8–11]. However, the short half-life of 11C, requiring an on-site cyclotron, has led to the evolution of 18F-labeled amino acid tracers and brought 18F-3,4-dihydroxyphenylalanine (18F-DOPA) and O-(2–18F-Fluoroethyl)-l-Tyrosine (18FET) into clinical use [12–15]. Interestingly, 18 F-DOPA is widely spread in the USA, whereas 18FET is more common in Europe. Amino acid tracers were shown to be extremely valuable for different clinical settings [16 ,17]. At primary diagnosis, amino acid PET is helpful for detecting anaplastic foci, so-called ‘‘hot-spots’’ [18,19], which is especially useful for biopsy guidance in noncontrast-enhancing glioma. As the tracer uptake does not depend on the blood–brain
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New targets Emerging PET tracers for glioma imaging aim at different targets. The pyrimidine analogue 3’-deoxy3’-18F-fluorothymidine reflects thymidine kinase-1 activity, which is the principle enzyme in the Volume 27 Number 6 December 2014
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PET imaging for brain tumor diagnostics Suchorska et al.
pathway of DNA synthesis and therefore depicts tumor proliferation rate. Although it is a promising tool for the differentiation between radionecrosis and vital tumor tissue [41,42], and was shown to be predictive of survival after bevacizumab therapy [43], it has limitations for clinical use because of permeability restrictions of the BBB [44]. Tumor hypoxia can be assessed by 18F-fluoromisonidazole. 18 F-Fluoromisonidazole has potential to predict response or resistance to radiotherapy and may be useful for treatment response assessment afterwards [45]. So far, it has mainly been used in a preclinical setting.
Combined PET/MRI: new prospects for tumor characterization Many recent studies focus on direct comparison between amino acid PET and sophisticated MR methods, such as MR spectroscopy, diffusionweighted imaging and perfusion MRI. So far, most studies revealed that the information gained by the different imaging methods is complementary; therefore, combination of all imaging methods might provide the best result for assessment of tumor characteristics [46–52]. The usefulness of combined PET/MR scanners is currently under investigation. Although the effect of image fusion does not play an essential role in the case of brain imaging, in which an accurate image fusion can be easily obtained by image co-registration based on fixed points (e.g., skull, sinus), it offers the chance to deliver simultaneous images, enabling the direct comparison of uptake kinetics and perfusion. However, the best effect might be provided by the introduction of a routinely combined interpretation of PET and MRI information by collaborative reading of a nuclear physician and a radiologist, as it has become the standard in clinical PET/computed tomography evaluation, which will certainly improve report quality in the future. Another important point concerning technical issues that needs to be addressed in future studies is the standardization of PET evaluation. Acquisition (dynamic vs. static, optimal time point after tracer injection and scan duration), reconstruction algorithms and method of analysis of common PET parameters [maximal and mean tumor-to-brain ratios (TBRs) biological tumor volume, region-ofinterest definition for TACs] should be harmonized to assure comparability between studies.
BRAIN METASTASES Early detection of brain metastases provided by advanced screening programs as well as
improvements of treatment in general oncology has positively influenced the course of the disease and OS in patients with metastatic disease [53,54]. With the advent of new therapeutic agents, especially immunogenic and oncogene-derived targeted inhibitors of human epidermal growth factor receptor type 2 (HER2), epidermal growth factor receptor, BRAF, however, new challenges for disease monitoring have risen [55–58]. As the new therapeutic possibilities become more important, there is an increasing demand for new imaging methods which are independent of the applied therapy. The interpretation of findings based on follow-up MRI is difficult, as post-therapeutic changes associated with treatment response can be mistaken for tumor recurrence and vice versa [59]. Unlike new treatment response criteria for solid somatic tumors [Response Evaluation Criteria in Solid Tumors (RECIST)] or updated evaluation criteria for glioma [Response Assessment in Neuro-Oncology (RANO)], the evaluation basis for treated brain metastases still remains uncertain [60–62]. PET has proven to be helpful as far as discrimination of treatment response vs. recurrence after different irradiation modalities is concerned. Current studies include evaluation of viable tumor tissue after radiotherapy and chemotherapy and differentiation of progression from radiation injury [9,63]. As far as the applied tracer is concerned, FDG is not sensitive enough to differentiate vital brain metastasis from unspecific nontumor changes related to therapy [64]. Amino acid PET is more useful as it provides a more precise contrast between normal brain and hypermetabolic tumor tissue [65]. In a recent 18F-FET-PET study, TBRmax and TBRmean as well as TACs were compared for treatment evaluation in 31 treated brain metastases. A good discrimination of TBRmean as well as TAC patterns for differentiation of responders from nonresponders was found [66]. Altogether, dynamic evaluation of tracer uptake seems to provide new promising possibilities in estimation of cerebral tumor burden in analogy to dynamic analyses which have already been performed with 18F-FET and choline PET in glioma [38 ,67]. To satisfy the need for establishment of diagnostic criteria for monitoring disease course of brain metastases after treatment with upcoming current chemotherapeutics, a baseline evaluation of the uptake characteristics of the primary untreated metastases of different histological origin is necessary. An important point for future studies would also be a correlation with established as well as upcoming molecular markers. So far, only few studies have performed a correlation between biomarkers and PET tracer uptake [58]. Dijkers et al. [68]
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used 89Zr to image HER2-positive metastases throughout the body, which revealed previously undetected brain metastases.
published until now; however, those were mostly retrospective or small-cohort, and recent publications are rare.
CENTRAL NERVOUS SYSTEM LYMPHOMA AND ASSOCIATED DISEASES
MENINGIOMA
Primary central nervous system lymphoma (PCNSL), although accounting for only 3–5% of all brain tumors, shows a rising incidence in the non-HIV population, as the life expectancy in the elderly increases [69,70]. Typical presentation on MRI is a large, well enhancing periventricular lesion and the basal ganglia; however, multiple differential diagnoses can present with a similar clinical and imaging picture. PCNSL tends to have a high cellular density and increased glycolytic metabolism and thus shows high uptake of 18F-FDG [71]. However, there is a high interference with 18F-FDG uptake in the basal ganglia, thalamus and grey matter. Furthermore, 18 F-FDG also shows a considerably high uptake in HGG, multiple sclerosis and other inflammatory processes [72,73]. Although a high sensitivity of FDG in differentiation between malignant glioma, metastases and PCNSL has been reported in small cohort studies, its additional use for PCNSL diagnostics remains unclear [74,75]. However, 18F-FDG has proven to be helpful for differentiation between HIV-related opportunistic infections such as toxoplasmosis from PCNSL-related lesions as toxoplasmosis shows a typically decreased 18F-FDG uptake [76]. Furthermore, 18F-FDG has been reported to provide sufficient and prognostic information after methotrexate treatment in PCNSL patients. Treatment response could even be detected earlier than by MRI alone [77,78]. As far as amino acid tracers are concerned, 11MET-PET was the second frequently used tracer, as lymphoma cells are dependent on the external supply of methionine. Thus, 11MET provides a better contrast than 18F-FDG and represents a good option for therapy monitoring after radiotherapy [79]. However, comparing sensitivity and specificity, similar results were obtained in a study comparing 11MET with 18F-FDG in PCNSL [71]. A new promising PET-based treatment approach might be the application of 90Yttrium-radiolabeled or 111Indium-radiolabeled mAbs aimed against cluster of differentiation-20 (CD-20) which can be found in membrane-associated phosphoproteins of B-cellderived PCNSL [80–82]. However, permeation of the BBB and thus the necessity of administration of BBB-disrupting agents are still limiting factors for anti-CD20 immunotherapy in PCNSL. Altogether, numerous studies investigating lymphoma with PET, mainly 18F-FDG, have been 686
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Meningiomas are the most frequently encountered primary brain tumors and usually affect more frequently women, typically after their 3rd decade. In 90% of all cases, they are benign, whereas in up to 10% of patients, atypical and anaplastic tumors occur [83]. Surgical resection is the first treatment whenever possible. However, in selected cases, radiosurgery or fractionated stereotactic radiotherapy is an alternative treatment option [84]. Although morphological imaging by means of computed tomography and MRI is sufficient for surgical and radiation target definition in most cases, skull base or orbital affection as well as recurrent tumor within scar tissue requires a more accurate biological imaging. In the past years, several studies have been conducted applying different amino acid tracers, such as choline, tyrosine and methionine in meningioma [85–87]. However, none has proven superior to standard MRI methods in allowing an additional differentiation between the different WHO grades or to improve tumor-tobone contrast in skull affecting tumors. Recently, although due to the high level of somatostatin receptor subtype 2 expression in meningioma, PET imaging with somatostatin receptor ligands, such as 68Ga tetra-azacyclododecane tetra-acetic acid-octreotate (68Ga-DOTATATE) or 1,4,7,10-tetraazacyclododecane-N,N’,N,N"-tetraacetic-acid-D-Phe1-Tyr3-octreotide (68Ga-DOTATOC), has opened up new possibilities to solve the problem of target delineation in skull base tumors before surgery and prior to radiotherapy [88–90]. Furthermore, 68Ga-DOTATE/TOC not only enables accurate target volume delineation for therapy planning, it also enables treatment delivery when labelled with 90Yttrium or 177Lutetium [91,92] and might disclose a high potential for combined treatment planning and monitoring. Of note, treatment success is linked to WHO grade, as grade I meningioma responds better than higher tumor grades [92].
CONCLUSION Application of molecular imaging has already improved therapy planning and management of brain tumors. However, most studies, published so far, were still small sample-sized, of retrospective nature and lacking comparability because of different acquisition and data evaluation methods. Volume 27 Number 6 December 2014
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PET imaging for brain tumor diagnostics Suchorska et al.
Further tracers for brain tumor imaging are currently under development. Combination of different tracers might provide more detailed information on tumor biology and course of the disease, thus overcoming currently existing limitations in the near future. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
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PET imaging for brain tumor diagnostics Bogdana Suchorska a, Joerg C. Tonn a, and Nathalie L. Jansen b
Purpose of review Brain tumors differ in histology, biology, prognosis and treatment options. Although structural magnetic resonance is still the gold standard for morphological tumor characterization, molecular imaging has gained an increasing importance in assessment of tumor activity and malignancy. Recent findings Amino acid PET is frequently used for surgery and biopsy planning as well as therapy monitoring in suspected primary brain tumors as well as metastatic lesions, whereas 18F-fluorodeoxyglucose (18F-FDG) remains the tracer of choice for evaluation of patients with primary central nervous system lymphoma. Application of somatostatin receptor ligands has improved tumor delineation in skull base meningioma and concurrently opened up new treatment possibilities in recurrent or surgically not assessable tumors. Recent development focuses on the implementation of hybrid PET/MRI as well as on the development of new tracers targeting tumor hypoxia, enzymes involved in neoplastic metabolic pathways and the combination of PET tracers with therapeutic agents. Summary Implementation of molecular imaging in the clinical routine continues to improve management in patients with brain tumors. However, more prospective large sample studies are needed to validate the additional informative value of PET. Keywords brain tumor, PET, therapy monitoring
INTRODUCTION In the past decades, molecular imaging methods have been increasingly implemented in clinical routine for neuro-oncological settings [1]. Although the most widely used radiotracer for metabolic imaging is still 18F-fluorodeoxyglucose (18F-FDG), many other radiopharmaceuticals have been developed, promising higher sensitivity as well as specificity for certain tumor entities [2]. Particularly, 18F-FDG has been replaced by radiolabeled amino acids or their analogues [3], which were shown to overcome the limitations of 18F-FDG. Due to physiologically low uptake in healthy brain tissue, amino acid PET enables a high tumor-to-background contrast, and due to absent or low uptake in inflammatory lesions, it allows for differentiation between tumor tissue and inflammation [4]. Tracer development is an evolving domain which promises to provide new insights and opportunities for brain tumor imaging. In the following, this review will discuss recent publications in the vast rapidly growing field of molecular imaging in brain tumors.
GLIOMA Gliomas constitute a heterogeneous group of histological subtypes: astrocytoma, oligodendroglioma,
mixed oligoastrocytoma and glioblastoma, which, depending on the WHO grade, substantially differ in natural disease course. Low-grade glioma (LGG) typically affects younger adults with a mean onset age of 35 years and has a variably long life expectancy depending on tumor location, size and initial treatment [5]. In contrast, survival probability in high-grade glioma (HGG) WHO III and IV is low. Median overall survival (OS) in glioblastoma, the most malignant of all primary brain tumors, is as short as 12–15 months and treatment options are limited [6]. Anaplastic astrocytoma, although of a slightly better prognosis with a median OS of 2–5 years, mostly leads to a rapid worsening of neurological functions and thus to a reduced life quality. In malignant glioma entities, outcome depends on histological features, performance a
Department of Neurosurgery and bDepartment of Nuclear Medicine, University Hospital, Ludwig Maximilians University, Munich, Germany Correspondence to Dr Bogdana Suchorska, Department of Neurosurgery, University Hospital, Ludwig Maximilians University, Marchioninistr. 15, 81377 Munich, Germany. Tel: +49 89 4400 72693; e-mail: bogdana. [email protected] Curr Opin Neurol 2014, 27:683–688 DOI:10.1097/WCO.0000000000000143
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KEY POINTS Dynamic analysis of amino acid tracer uptake provides further insights into metabolic properties and therapeutic effects in primary and metastatic brain tumors.
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F-FDG remains the tracer of choice in diagnosis and treatment monitoring of PCNSL. Ga-DODATATE PET becomes increasingly implemented for diagnostic and therapeutic purposes in meningiomas.
status, age at diagnosis and molecular subtypes. Although MRI still remains the keystone for assessment of morphological tumor features, such as location, mass effect and contrast enhancement, PET can provide valuable insights into biology and malignancy of the tumor tissue. Molecular imaging becomes increasingly implemented into surgical treatment planning in suspected LGG, in which identification of possible areas of increased metabolism is most essential to obtain the correct histological diagnosis. Interestingly, areas of increased PET uptake do not necessarily correlate with 5-aminolevulinic acid-induced fluorescence, thus integrating both preoperative PET and 5-aminolevulinic acid into surgery planning might provide additional insights and improve extent of resection [7]. In contrast, HGG patients benefit from an additional treatment monitoring by means of PET which can help identify early therapy failure and thus offers an opportunity for a more timely and individual therapy management.
barrier (BBB), delineation of tumor extent is reported to be more accurate with amino acid PET, and the areas with increased amino acid uptake in PET are often larger than areas with pathological contrast enhancement on MRI [20]. Therefore, amino acid PET can be effectively used for treatment planning, and a better outcome was reported for patients with radiotherapy planning on the basis of tumor extent definition by amino acid uptake [21]. Amino acid PET is not only useful in the initial setting, but also provides important information during the follow-up of glioma patients. It is a valuable tool for treatment monitoring as it helps to assess treatment response, to evaluate patients’ prognosis after therapy and to detect tumor recurrence with high accuracy [4,22,23,24 ,25,26]. The high sensitivity and specificity after different therapies is also because of the independence of the BBB, which is often the limiting factor in post-treatment evaluation of magnetic resonance (MR) images. Following locally aggressive therapies, such as combined radio–chemotherapy or stereotactic brachytherapy, an unspecific contrast enhancement can occur on MRI, which can mimic tumor progression and makes MRI-based treatment monitoring challenging. Contrariwise, the evolvement of antiangiogenic therapies has brought new challenges for conventional MRI by influencing BBB integrity toward mimicking treatment response. Inhibition of neovascularization and reduction of fragile blood vessels result in decreased pathologic contrast enhancement on MRI. Recent studies have reported amino acid PET to detect pseudoresponse in vascular endothelial growth factor antibody-treated patients and to be cost-effective [24 ,27–29,30 ]. In the direct comparison of 18F-DOPA and 18 F-FET, 18F-FET seems to have some advantages. Apart from the absent striatal tracer uptake (which can hamper tumor delineation in this location by 18 F-DOPA), 18F-FET is characterized by typical uptake behavior in LGG and HGG, which can be assessed by dynamic PET acquisition [31–34]. This property of distinguishing different time-activity curves (TACs) is not yet clarified in 18F-DOPA, as there were conflicting reports regarding this point [35 ,36,37]. In addition to tumor grading, TACs seem to provide prognostic information for patient outcome and malignant progression [38 ,39 ,40 ]. &
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Different tracers: different applications The first promising amino acid that has been investigated in many studies for glioma imaging was 11 C-methionine which was shown to be suitable for glioma imaging [8–11]. However, the short half-life of 11C, requiring an on-site cyclotron, has led to the evolution of 18F-labeled amino acid tracers and brought 18F-3,4-dihydroxyphenylalanine (18F-DOPA) and O-(2–18F-Fluoroethyl)-l-Tyrosine (18FET) into clinical use [12–15]. Interestingly, 18 F-DOPA is widely spread in the USA, whereas 18FET is more common in Europe. Amino acid tracers were shown to be extremely valuable for different clinical settings [16 ,17]. At primary diagnosis, amino acid PET is helpful for detecting anaplastic foci, so-called ‘‘hot-spots’’ [18,19], which is especially useful for biopsy guidance in noncontrast-enhancing glioma. As the tracer uptake does not depend on the blood–brain
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New targets Emerging PET tracers for glioma imaging aim at different targets. The pyrimidine analogue 3’-deoxy3’-18F-fluorothymidine reflects thymidine kinase-1 activity, which is the principle enzyme in the Volume 27 Number 6 December 2014
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PET imaging for brain tumor diagnostics Suchorska et al.
pathway of DNA synthesis and therefore depicts tumor proliferation rate. Although it is a promising tool for the differentiation between radionecrosis and vital tumor tissue [41,42], and was shown to be predictive of survival after bevacizumab therapy [43], it has limitations for clinical use because of permeability restrictions of the BBB [44]. Tumor hypoxia can be assessed by 18F-fluoromisonidazole. 18 F-Fluoromisonidazole has potential to predict response or resistance to radiotherapy and may be useful for treatment response assessment afterwards [45]. So far, it has mainly been used in a preclinical setting.
Combined PET/MRI: new prospects for tumor characterization Many recent studies focus on direct comparison between amino acid PET and sophisticated MR methods, such as MR spectroscopy, diffusionweighted imaging and perfusion MRI. So far, most studies revealed that the information gained by the different imaging methods is complementary; therefore, combination of all imaging methods might provide the best result for assessment of tumor characteristics [46–52]. The usefulness of combined PET/MR scanners is currently under investigation. Although the effect of image fusion does not play an essential role in the case of brain imaging, in which an accurate image fusion can be easily obtained by image co-registration based on fixed points (e.g., skull, sinus), it offers the chance to deliver simultaneous images, enabling the direct comparison of uptake kinetics and perfusion. However, the best effect might be provided by the introduction of a routinely combined interpretation of PET and MRI information by collaborative reading of a nuclear physician and a radiologist, as it has become the standard in clinical PET/computed tomography evaluation, which will certainly improve report quality in the future. Another important point concerning technical issues that needs to be addressed in future studies is the standardization of PET evaluation. Acquisition (dynamic vs. static, optimal time point after tracer injection and scan duration), reconstruction algorithms and method of analysis of common PET parameters [maximal and mean tumor-to-brain ratios (TBRs) biological tumor volume, region-ofinterest definition for TACs] should be harmonized to assure comparability between studies.
BRAIN METASTASES Early detection of brain metastases provided by advanced screening programs as well as
improvements of treatment in general oncology has positively influenced the course of the disease and OS in patients with metastatic disease [53,54]. With the advent of new therapeutic agents, especially immunogenic and oncogene-derived targeted inhibitors of human epidermal growth factor receptor type 2 (HER2), epidermal growth factor receptor, BRAF, however, new challenges for disease monitoring have risen [55–58]. As the new therapeutic possibilities become more important, there is an increasing demand for new imaging methods which are independent of the applied therapy. The interpretation of findings based on follow-up MRI is difficult, as post-therapeutic changes associated with treatment response can be mistaken for tumor recurrence and vice versa [59]. Unlike new treatment response criteria for solid somatic tumors [Response Evaluation Criteria in Solid Tumors (RECIST)] or updated evaluation criteria for glioma [Response Assessment in Neuro-Oncology (RANO)], the evaluation basis for treated brain metastases still remains uncertain [60–62]. PET has proven to be helpful as far as discrimination of treatment response vs. recurrence after different irradiation modalities is concerned. Current studies include evaluation of viable tumor tissue after radiotherapy and chemotherapy and differentiation of progression from radiation injury [9,63]. As far as the applied tracer is concerned, FDG is not sensitive enough to differentiate vital brain metastasis from unspecific nontumor changes related to therapy [64]. Amino acid PET is more useful as it provides a more precise contrast between normal brain and hypermetabolic tumor tissue [65]. In a recent 18F-FET-PET study, TBRmax and TBRmean as well as TACs were compared for treatment evaluation in 31 treated brain metastases. A good discrimination of TBRmean as well as TAC patterns for differentiation of responders from nonresponders was found [66]. Altogether, dynamic evaluation of tracer uptake seems to provide new promising possibilities in estimation of cerebral tumor burden in analogy to dynamic analyses which have already been performed with 18F-FET and choline PET in glioma [38 ,67]. To satisfy the need for establishment of diagnostic criteria for monitoring disease course of brain metastases after treatment with upcoming current chemotherapeutics, a baseline evaluation of the uptake characteristics of the primary untreated metastases of different histological origin is necessary. An important point for future studies would also be a correlation with established as well as upcoming molecular markers. So far, only few studies have performed a correlation between biomarkers and PET tracer uptake [58]. Dijkers et al. [68]
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used 89Zr to image HER2-positive metastases throughout the body, which revealed previously undetected brain metastases.
published until now; however, those were mostly retrospective or small-cohort, and recent publications are rare.
CENTRAL NERVOUS SYSTEM LYMPHOMA AND ASSOCIATED DISEASES
MENINGIOMA
Primary central nervous system lymphoma (PCNSL), although accounting for only 3–5% of all brain tumors, shows a rising incidence in the non-HIV population, as the life expectancy in the elderly increases [69,70]. Typical presentation on MRI is a large, well enhancing periventricular lesion and the basal ganglia; however, multiple differential diagnoses can present with a similar clinical and imaging picture. PCNSL tends to have a high cellular density and increased glycolytic metabolism and thus shows high uptake of 18F-FDG [71]. However, there is a high interference with 18F-FDG uptake in the basal ganglia, thalamus and grey matter. Furthermore, 18 F-FDG also shows a considerably high uptake in HGG, multiple sclerosis and other inflammatory processes [72,73]. Although a high sensitivity of FDG in differentiation between malignant glioma, metastases and PCNSL has been reported in small cohort studies, its additional use for PCNSL diagnostics remains unclear [74,75]. However, 18F-FDG has proven to be helpful for differentiation between HIV-related opportunistic infections such as toxoplasmosis from PCNSL-related lesions as toxoplasmosis shows a typically decreased 18F-FDG uptake [76]. Furthermore, 18F-FDG has been reported to provide sufficient and prognostic information after methotrexate treatment in PCNSL patients. Treatment response could even be detected earlier than by MRI alone [77,78]. As far as amino acid tracers are concerned, 11MET-PET was the second frequently used tracer, as lymphoma cells are dependent on the external supply of methionine. Thus, 11MET provides a better contrast than 18F-FDG and represents a good option for therapy monitoring after radiotherapy [79]. However, comparing sensitivity and specificity, similar results were obtained in a study comparing 11MET with 18F-FDG in PCNSL [71]. A new promising PET-based treatment approach might be the application of 90Yttrium-radiolabeled or 111Indium-radiolabeled mAbs aimed against cluster of differentiation-20 (CD-20) which can be found in membrane-associated phosphoproteins of B-cellderived PCNSL [80–82]. However, permeation of the BBB and thus the necessity of administration of BBB-disrupting agents are still limiting factors for anti-CD20 immunotherapy in PCNSL. Altogether, numerous studies investigating lymphoma with PET, mainly 18F-FDG, have been 686
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Meningiomas are the most frequently encountered primary brain tumors and usually affect more frequently women, typically after their 3rd decade. In 90% of all cases, they are benign, whereas in up to 10% of patients, atypical and anaplastic tumors occur [83]. Surgical resection is the first treatment whenever possible. However, in selected cases, radiosurgery or fractionated stereotactic radiotherapy is an alternative treatment option [84]. Although morphological imaging by means of computed tomography and MRI is sufficient for surgical and radiation target definition in most cases, skull base or orbital affection as well as recurrent tumor within scar tissue requires a more accurate biological imaging. In the past years, several studies have been conducted applying different amino acid tracers, such as choline, tyrosine and methionine in meningioma [85–87]. However, none has proven superior to standard MRI methods in allowing an additional differentiation between the different WHO grades or to improve tumor-tobone contrast in skull affecting tumors. Recently, although due to the high level of somatostatin receptor subtype 2 expression in meningioma, PET imaging with somatostatin receptor ligands, such as 68Ga tetra-azacyclododecane tetra-acetic acid-octreotate (68Ga-DOTATATE) or 1,4,7,10-tetraazacyclododecane-N,N’,N,N"-tetraacetic-acid-D-Phe1-Tyr3-octreotide (68Ga-DOTATOC), has opened up new possibilities to solve the problem of target delineation in skull base tumors before surgery and prior to radiotherapy [88–90]. Furthermore, 68Ga-DOTATE/TOC not only enables accurate target volume delineation for therapy planning, it also enables treatment delivery when labelled with 90Yttrium or 177Lutetium [91,92] and might disclose a high potential for combined treatment planning and monitoring. Of note, treatment success is linked to WHO grade, as grade I meningioma responds better than higher tumor grades [92].
CONCLUSION Application of molecular imaging has already improved therapy planning and management of brain tumors. However, most studies, published so far, were still small sample-sized, of retrospective nature and lacking comparability because of different acquisition and data evaluation methods. Volume 27 Number 6 December 2014
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PET imaging for brain tumor diagnostics Suchorska et al.
Further tracers for brain tumor imaging are currently under development. Combination of different tracers might provide more detailed information on tumor biology and course of the disease, thus overcoming currently existing limitations in the near future. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
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Volume 27 Number 6 December 2014
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