Gliomas are the most common primary malignant brain tumors. According to the World Health Organization (WHO), they are classified as astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas. In this classification, anaplastic astrocytomas and anaplastic oligodendrogliomas are considered grade III, and glioblastoma multiforme (GBM), the most common of all gliomas, is considered grade IV. GBM tumors comprise 45% to 50% of all gliomas and have a dismal prognosis. Despite new treatment strategies and advanced imaging techniques, prognosis of gliomas has been poor with maximum survival rates of 12 to 14 months for GBM.1 Accurate grading and diagnosis are important for directing the therapeutic approach and providing prognosis.
Neuroimaging plays a significant role in the detection of brain tumors, prediction of the histologic grade of tumor, evaluation of the response to treatment, differential diagnosis between the recurrent tumor and treatment-related changes, and estimation of survival prognosis.
Magnetic Resonance Imaging
The most commonly used imaging modality is magnetic resonance imaging (MRI), which has an irreplaceable role in brain tumor imaging. For evaluation of previously undiagnosed brain neoplasm, MRI is excellent to determine the size and location of the tumor and to demonstrate the secondary findings such as mass effect, edema, hemorrhage, necrosis, and possible signs of increased intracranial pressure.
MRI has certain limitations, however, in brain tumor evaluation. “Gadolinium enhancement,” which is a basic criterion in brain tumor diagnosis by MRI, is not specific for tumor. Gadolinium enhancement is a result of blood–brain disruption, which can be seen with brain tumors as well as secondary to infectious and inflammatory etiologies. It is challenging to distinguish neoplasm from vascular, inflammatory, or other processes from brain parenchymal tumors with minimal or no enhancement. In tumors with minimal or no enhancement, it is not possible to rate glial neoplasms as low grade versus high grade. Interpretation of MRI gets even more complicated in previously treated brain neoplasms. In fact, differentiation of treatment-related changes from recurrent high-grade enhancing tumor and low-grade nonenhancing infiltrative tumor is simply not possible with basic MRI sequences. With the recent addition of new adjuvant treatment options such as antiangiogenic factors and alkylating agents, namely bevacizumab and temozolomide, false-negative and false-positive MRI findings have been seen. Currently the standard therapy for glioblastoma is maximal safe tumor resection followed by radiotherapy with concurrent and adjuvant temozolomide.1 “Pseudoprogression” is a relatively new term for the glioma cases that have been undergoing concurrent radiotherapy and temozolomide treatment and that demonstrate progression-like MR findings such as increased areas of enhancement with larger areas of edema. These could be accompanied by progressive clinical signs and symptoms in a fraction of cases. In pseudoprogression cases, these findings typically eventually subside without any change in therapy.2 This scenario is seen following radiation treatment in 20% to 30% of cases and its incidence has been reported to be higher in patients who receive temozolomide in addition to radiation therapy. These findings are thought to result from transiently increased permeability of the tumor vasculature from irradiation and/or temozolomide effects. In cases that demonstrate these MRI findings, it is necessary to decide whether to continue the current medication versus ceasing and choosing an alternative treatment. Antiangiogenic agent (antivascular endothelial growth factor [VEGF] and anti-VEGF receptor) treatment for gliomas was approved by the Food and Drug Administration (FDA) in 2008. This new adjuvant treatment strategy results in marked decrease in contrast enhancement on MRI, as early as 1 to 2 days following initiation of treatment in 25% to 60% of cases. This is thought to be partly a result of normalization of abnormally permeable tumor vessels and is not necessarily indicative of a true antiglioma effect.3 Nevertheless, only modest survival benefits have been reported following antiangiogenic treatment despite high MRI response rates. This entity has been termed “pseudoresponse.” Molecular imaging is a promising modality to further evaluate these puzzling MRI findings, which could represent “pseudoresponse” or “pseudoprogression.” One of the other entities that complicate image interpretation on MRI is corticosteroid use for symptom control in glioma patients. Corticosteroids are known to decrease T2 signal abnormalities and extent of gadolinium enhancement unrelated to tumor shrinkage. Transient gadolinium enhancement can also be seen with postictal states and postsurgical states,4 and gadolinium enhancement is typically seen in subacute phase of postoperative contusion areas.5
In all the situations that could possibly be seen in glioma patients, MRI alone is not adequate to guide the management of brain tumor patients. Complementary studies such as functional and molecular imaging (i.e., MR spectroscopy, single-photon emission tomography [SPECT], and positron emission tomography [PET]) have been studied and implemented by many centers in the diagnosis of brain tumors to enhance patient care.
Single-Photon Emission Tomography
Thallium 201 [201Tl] has been used for tumor localization. The mechanism of uptake is related to multiple factors, including regional brain blood flow, blood–brain barrier [BBB] permeability, and cellular uptake that may involve transmembrane transport into viable tumor cells.6,7 201Tl, as the thallous ion, behaves physiologically like potassium, and is transported through the cell membrane by the Na-K ATPase membrane pump.7 Its transport is related to blood flow, which is linked to growth rate.8 201Tl uptake reflects viable tumor and not simply BBB breakdown.6,7 Sun et al.9 demonstrated on 201Tl SPECT that delayed imaging at 3 hours was superior to early imaging at 10 minutes to differentiate higher-grade tumors because there is continuous accumulation of the tracer in high-grade brain tumors. A disadvantage of 201Tl SPECT imaging of brain tumors is their lower resolution which limits evaluation of smaller tumors.
Single-Photon Emission Tomography/Computed Tomography and Positron Emission Tomography/Computed Tomography
The concept of integrated imaging with SPECT/computed tomography (CT) evolved in the late 1980s10,11 and with PET/CT in 1998.12 In both cases, the more functional imaging methods of SPECT and PET are combined with anatomical CT imaging information within a single examination. With the advent of clinical PET/CT in early 2001, it was shown that integration of PET and CT into a single system is advantageous and synergistic as it provides anatomic referencing and at the same time permits attenuation correction in a much shorter time,13,14 thus making PET/CT more accurate15 and faster16 imaging modality than PET alone, CT alone, and even PET and CT read side by side.17–19 In a PET/CT examination, PET and CT are performed in rapid sequence, and as the CT is very fast and provides data for PET attenuation correction, a PET/CT examination is typically 25% to 30% less time consuming than the acquisition of an attenuation-corrected PET scan. Since its clinical introduction in early 2001, it is evident that imaging with PET/CT has an impact on therapeutic management in 20% to 50% of the examined oncology cases.20
POSITRON EMISSION TOMOGRAPHY TRACERS
Several PET radiotracers have been studied for brain tumor imaging. These can be classified into three main groups (Table 1.1):
• Marker of glucose metabolism
• Markers of cellular proliferation
• Hypoxia imaging
Marker of Glucose Metabolism
18F-fluorodeoxy glucose (18F-FDG) is a marker of glucose metabolism and is the only FDA-approved radiotracer used in tumor imaging in the United States at the present time. 18F-FDG PET is the first PET oncologic application. The pathophysiology of 18F-FDG PET is based on the following: Cancer cells are known to have higher levels of metabolic activities because of higher levels of glucose transporters, higher hexokinase levels, and low glucose 6 phosphatase levels. Brain tumor imaging is based on the fact that malignant transformation of gliomas and higher grades of gliomas are related to high 18F-FDG uptake.21 However, although generally high-grade tumors demonstrate hypermetabolism and low-grade tumors demonstrate lower metabolism compared with contralateral gray matter in most cases, it is also known that there is a high variability of 18F-FDG uptake among the glial tumors of the same grade (Fig. 1.1).22 The limitations of 18F-FDG PET in brain tumor imaging are because of high physiologic activity of the normal gray matter limiting the detectability of modest increases in glucose metabolism in low-grade tumors and the nonspecific nature of the 18F-FDG uptake. Increased 18F-FDG uptake can be seen in tumor, inflammation, and tissue healing. In differentiation of recurrent tumor from radiation necrosis (a common indication of 18F-FDG PET imaging in many centers), PET/CT should be performed at least 6 weeks after completion of radiation treatment because within the first 6 weeks following treatment, radiation-related inflammatory changes might result in increased 18F-FDG uptake regardless of tumor presence. This will affect the image interpretation. In cases of recurrent tumor evaluation following radiation treatment, having MRI images on site and, if possible, reviewing MRI–PET fusion images is critical for correct interpretation. 18F-FDG uptake equal to or more than the background in an area of MRI abnormality is suggestive of recurrent tumor (Fig. 1.2).
FIGURE 1.1. 18F-FDG PET of newly diagnosed tumors: Glioblastoma (A) and grade II oligodendroglioma (B). (Reprinted by permission of SNMMI from Chen W. Clinical applications of PET in brain tumors. J Nucl Med. 2007;48(9):1468–1481. Figure 1.)
To increase the performance of 18F-FDG PET interpretation, delayed imaging, imaging 3 to 8 hours rather than 60 minutes following 18F-FDG injection, was studied and shown to improve distinction between the tumor and normal gray matter, and could help in distinguishing recurrent tumor from radiation necrosis. The rationale for this is that glucose washout from normal brain tissue and necrotic tissue is greater than in tumor at delayed times.23Because of these described inborn limitations of 18F-FDG in brain tumor imaging, other hallmarks of tumor have been widely studied.
Markers of Cellular Proliferation
Uncontrolled cellular proliferation is a hallmark of tumor. Although increased glucose uptake is nonspecific, rapid proliferation of cells is specific for tumor. This property makes the radiotracers used to demonstrate cellular proliferation very promising for “tumor” diagnosis. In addition, they also have potential in the evaluation of early treatment response because the earliest events in response to successful treatment of tumors are decreased in cellular proliferation. The most commonly investigated radiotracers to evaluate cellular proliferation are 11C-methionine (11C-Met), 18F-fluoroethyl tyrosine (18F-FET), 18F-fluoro L phenylalanine (18F-F DOPA), 18F-fluorothymidine (18F-FLT), and 11C-choline (11C-Cho). Markers for proliferation in a cell can further be broken down to:
• Protein synthesis
• DNA synthesis
• Choline (lipid) synthesis for better understanding of the mechanism of radiotracer uptake
FIGURE 1.2. A: Postgadolinium T1-weighted MR image shows nodular enhancement along the medial aspect of the surgical cavity in the right frontotemporal region. B: FDG PET image shows photopenia in the areas of signal abnormalities seen on MR, compatible with postradiation and postsurgical changes. (Reprinted by permission of SNMMI from Langleben DD, Segall GM. PET in differentiation of recurrent brain tumor from radiation injury. J Nucl Med. 2000;41:447–452.)
In 1998, it was shown in animal models that the mechanism responsible for increased amino acid transport into tumor cells is the upregulation of the amino acid transporter in the vasculature of tumor tissues.24 Increased amino acid transport occurs within the tumor cell regardless of the phase of the cell cycle. Upregulation of amino acid transport does not depend on but is enhanced by the breakdown of the BBB. One of the advantages of the amino acid radiotracers over FDG is the lack of background brain cortical activity, which makes diagnosis of low-grade glioma more reliable. Another advantage is their specificity for tumor, which makes them potential tracers for primary diagnosis of tumor and in cases with previous treatment, a valuable tracer to detect recurrent tumor. On the other hand, amino acid tracers are less desirable in tumor grading because similar uptake will be seen in both low-grade and high-grade tumors.
The most commonly investigated amino acid PET tracer in brain tumor imaging is 11C-Met. Methionine is a natural essential amino acid. It enters the tumor cell via an amino acid transporter after activation of carrier-mediated transport at the BBB to meet demands of accelerated protein and RNA synthesis in malignant cells. Methionine accumulation is highly correlated with microvessel density (a product of angiogenesis). Terakawa et al.25 investigated the diagnostic accuracy of 11C-Met PET to differentiate recurrent tumor from radiation necrosis, and concluded that by using a threshold of mean lesion/normal tissue ratio of 1.58, the diagnosis of tumor could be made with 75% sensitivity and 75% specificity. The specificity of 11C-Met in brain tumor imaging was also shown by Chung et al.26 Their study demonstrated that all benign lesions had normal or decreased tracer uptake, whereas 31 out of 35 brain tumors (of all types) had positive 11C-Met uptake, and 22 out of 24 gliomas had positive uptake on 11C-Met PET. These lesions were all iso- or hypometabolic on 18F-FDG PET imaging. In another study, the prognostic factor role of 11C-Met was investigated. It was found that there was significant correlation between 11C-Met uptake and Ki-67 proliferative index. 11C-Met uptake was also found to be an independent prognostic factor in this study, whereas no correlation was found between the 18F-FDG uptake and the Ki-67 proliferation index, and 18F-FDG uptake and survival. The main limitation of 11C-Met in clinical use is that it has a short half-life (20 minutes). It cannot be used at sites without a cyclotron onsite. Another limitation of amino acid PET tracers in general is that increased amino acid uptake is an indirect measure of proliferation status and its intensity is not affected by the malignant nature of the tumor, which makes them not useful to grade brain tumors. Of note, caution must be taken to evaluate tumors with oligodendrial components on 11C-Met PET. In these tumors, high uptake of 11C-Met was found to be because of high microvessel count and tumor blood volume, and not the proliferative activity.
18F-FET is another amino acid that can be labeled with 18F. It has been used as a brain tumor PET imaging agent. In a study by Popperl et al.,27 42 out of 42 recurrent tumor sites were correctly diagnosed when focally increased 18F-FET uptake was considered a positive result. This pattern of uptake is because of the upregulation of amino acid transport. On the other hand, in this study, patients with no recurrent tumor showed low homogeneous uptake (uptake secondary to BBB disruption caused by treatment). One limitation with 18F-FET was that authors could not find significant difference of tracer uptake level in grade II versus grade III and IV tumors.
18F-FDOPA has been used for years to image striatal dopamine pathway in movement disorders but has also been shown to be taken up by amino acid transporters of the normal BBB. Chen et al.28 compared 18F-FDOPA with 18F-FDG in newly diagnosed and previously treated brain tumor patients. The sensitivity of tumor detection was significantly higher with 18F-FDOPA compared to 18F-FDG given lack of background physiologic uptake on 18F-FDOPA images (Figs. 1.3 and 1.4). A disadvantage of 18F-FDOPA is its limited differentiation of tumor grades.
18F-FLT uptake reflects thymidine kinase 1 activity in the cell, which is proportional to proliferation activity. Thymidine is one of the four bases that are incorporated in deoxyribonucleic acid synthesis. The 18F-FLT activity in normal brain tissue is low because of low proliferative activity and because it does not cross intact BBB. This makes the interpretation of the 18F-FLT PET brain images easier. However, a downside of 18F-FLT is that it is only retained in brain tumors with BBB breakdown. Hence, evaluation of lower-grade brain tumor with intact BBB is limited. In addition, there may be nonspecific accumulation of 18F-FLT in areas of blood brain disruption not necessarily because of the presence of high-grade tumor but because of other benign etiologies. This requires utilization of kinetic modeling to distinguish nonspecific 18F-FLT uptake from that pertaining to new DNA synthesis and cell proliferation. Chen et al.28 compared 18F-FLT and 18F-FDG in 25 patients with either newly diagnosed or previously treated gliomas. 18F-FLT imaging can be performed within 35 minutes following injection and dynamic imaging can be acquired. Because the background activity of the brain is very low, the tumor to normal uptake ratio is much higher than 18F-FDG PET imaging. This increases sensitivity of recurrent tumor detection. Specificity of high-grade tumor detection is very high with 18F-FLT imaging. According to Chen et al., the recurrent tumor cases who had 18F-FLT uptake but no 18F-FDG uptake demonstrated progression within 1 to 3 months representing better prognostic power of 18F-FLT. Hatakeyama et al.29 compared 11C-Met and 18F-FLT in 41 newly diagnosed patients with glioma. They found that 11C-Met was slightly more sensitive in tumor detection, 18F-FLT was less useful in nonenhancing tumors; both tracers were 100% sensitive in malignant glioma and 18F-FLT was valuable for tumor grading. 18F-FLT was superior to assess the cellular proliferation activity. An important downside of 18F-FLT is that any process that will damage the BBB such as radiotherapy results in passive influx of 18F-FLT and will result in false-positive 18F-FLT uptake.
FIGURE 1.3. Newly diagnosed tumors, showing glioblastoma (A) and grade II oligodendroglioma (B): MRI (LEFT), 18F-FDG PET (MIDDLE), and 18F-FDOPA PET (RIGHT). (Reprinted by permission of SNMMI from Chen W, Cloughesy T, Kamdar N, et al. Imaging proliferation in brain tumors with 18F-FLT PET: Comparison with 18F-FDG. J Nucl Med. 2005;46(6):945–952. Figure 2.)
FIGURE 1.4. Newly diagnosed glioblastoma. MRI (A; contrast-enhanced T1-weighted image) shows large area of contrast enhancement in right frontal lobe. Both 18F-FDG PET (B) and 18F-FLT PET (C)show increased uptake in the same area. (Reprinted by permission of SNMMI from Chen W, Silverman DH, Delaloye S, et al. 18F-FDOPA PET imaging of brain tumors: comparison study with 18F-FDG PET and evaluation of diagnostic accuracy. J Nucl Med. 2006;47:904–911. Figure 2.)
Choline (Lipid) Synthesis
Malignant transformation of cells is associated with induction of choline kinase activity, which results in increased levels of phosphatidyl choline (“lecithin” in cell membrane). Choline labeled with different positron emitters has been studied in brain tumor imaging. Kato et al.30 compared the utility of 11C-Met, 11C-Cho, and 18F-FDG in evaluation of gliomas. They studied 95 glioma cases, WHO grades II, III, and IV. 11C-Met tumor-to-normal ratio was significantly higher in oligodendroglial tumors than in astrocytomas. 11C-Cho uptake in tumor versus normal cortex uptake was found to show positive correlation with different grades of oligodendrogliomas. Hence, 11C-Cho is a potential useful tracer in grading the oligodendrogliomas. The background uptake of normal brain tissues is less with 11C-Cho compared with 11C-Met, making interpretation of 11C-Cho images easier. One limitation is that physiologic uptake of 11C-Cho by the choroid plexus, venous sinuses, and the pituitary gland make evaluation of tumors near these sites challenging.
Hypoxia is defined as reduction in pO2 (decreased intracellular oxygen pressure). Normal tissue pO2 is greater than 40 mm Hg. Hypoxia is a common feature of GBM. In fact, tumor hypoxia leads to necrosis, which is a mandatory criterion to establish the diagnosis of GBM. As tumor growth exceeds vascular development, and oxygen delivery is decreased, cells become hypoxic. Hypoxia-inducible factor 1-α transcription factor, which is constantly produced and only survives in hypoxic cells, results in activation of transcription of more than 100 genes that promote invasiveness, aggressiveness, and VEGF production.31 Tumor cells adapt to hypoxia by decreasing the proliferation rate, remaining longer in resting phase G0, thus escaping the impact of therapies that target cells in S phase. Two to three times the radiation dose is required to kill hypoxic tissue relative to normoxic tissue.32 This resistance to radiotherapy becomes evident when the oxygen pressure decreases below 3 mm Hg.33 By limiting the tumor response, hypoxia is an adverse prognostic factor and is an indicator of higher rates of recurrence and fatality. The discovery in the mid-1980s that some radiosensitizing drugs such as misonidazole are selectively bound to molecules in viable hypoxic cells in vitro and in vivo attracted interest from radiation biologists and nuclear medicine specialists.34
Fluoromisonidazole (FMISO) was found to bind stably to hypoxic viable cells as misonidazole. FMISO is a 2-nitroimidazole derivative that undergoes intracellular reduction by nitroreductases in viable cells generating a radical anion. Necrotic tissue lacks this enzyme. Oxygen in oxygenated cells acts as an electron acceptor for the 18F-FMISO radical anion. In the absence of oxygen, 18F-FMISO is further reduced and covalently bound to intracellular macromolecules and does not exit hypoxic cells.35 FMISO tagged with a positron emitter 18F was found to be a useful noninvasive hypoxia PET imaging agent.36 18F-FMISO is lipophilic and diffuses through cell membranes and shows passive distribution in normal tissue. 18F-FMISO concentration in normal, nonhypoxic tissue is always lower than plasma. Retention of 18F-FMISO is inversely proportional to oxygen concentration. Significant retention occurs below 3 mm Hg.36 PET with 18F-FMISO detects regions of hypoxia independent of anatomy (i.e., blood brain disruption) and of perfusion. Bruehlmeier et al.37 correlated hypoxia and perfusion characteristics of different kinds of brain tumors, including GBM, anaplastic astrocytoma, meningioma, and hemangioblastoma, using 18F-FMISO and 15O-H2O respectively (Fig. 1.5). 18F-FMSIO kinetics were calculated using two- and three-compartment models and distribution volume measurements, and tumor perfusion was calculated using 15O-H2O perfusion. The study results show that 18F-FMISO uptake within 0 to 5 minutes is increased in tumors where there is BBB disruption (such as GBM) or there is lack of BBB (such as meningioma). There was a positive correlation between 18F-MISO tumor uptake at 0 to 5 minutes and perfusion of 15O-H2O. However, there was no difference in distribution volumes of 18F-FMISO in meningioma. This was because of continuous accumulation of 18F-FMISO in cases of GBM. The results of the study show that hypoxia in GBM develops irrespective of the magnitude of perfusion. 18F-FMISO uptake can be seen in both hypo- and hyperperfused areas. Increased 18F-FMISO uptake was seen only in the periphery of the GBM, where there is viable tumor that can accumulate FMISO and delivery to necrotic tissue is low. Spence et al.38 correlated regional hypoxia in GBM with time to progression and survival using 18F-FMISO imaging. Severity of hypoxic burden on 18F-FMISO PET after initial surgery prior to radiotherapy significantly impacted time to progression and overall survival according to the results. Hypoxia imaging could be integrated into new regional and/or systemic treatment strategies to target hypoxia more aggressively in GBM. Surgical resections could target hypoxic regions using co-registered images of 18F-FMISO and MRI.
POSITRON EMISSION TOMOGRAPHY/ MAGNETIC RESONANCE IMAGING
The advantages of CT over MRI are CT’s speed, robustness, availability, and lower cost. In areas where MR excels clinically, such as neuro- and musculoskeletal applications as well as some focal applications in the upper abdomen, pelvis, and head and neck, both MR and PET/CT are frequently performed. Given the known advantages of MRI over CT such as higher soft tissue resolution, lack of radiation, and functional imaging aspects such as MR spectroscopy and other functional imaging offered by MRI, PET/MRI could have advantages over PET/CT. Integration of PET and MR data can be achieved by either software-based fusion or by integration of the hardware of the two devices. The feasibility of simultaneous PET/MR imaging of the human head has been demonstrated with an avalanche photodiode-based PET detector technology, which is insensitive to high magnetic fields.12 For PET/MRI system, a detector ring was constructed and placed in a clinical 3-Tesla MRI scanner (TRIO, Siemens Medical Solutions) with a standard bird cage transmit/receive head coil.39 All PET detector components were selected and sized to exhibit minimal interference with the magnetic fields of the MR system (Fig. 1.6). There are three ways to technically integrate PET and MR systems.
1. Separate imaging in devices placed far from each other. The patient has to move from one to the other imaging system. This approach requires integration through software-based image fusion (Figs. 1.7and 1.8). This results in some temporal gaps in the examination sequence of the patient. Separate PET/CT and MR data could alternatively be compared using “mental” fusion rather than software fusion because there are enough anatomic landmarks on both examinations. However, in the latter case, because the imaging is performed with separate imaging devices, requiring patient repositioning, there is a greater risk of voluntary and involuntary patient movements between procedures. This results in time-consuming side-by-side image interpretation.40
FIGURE 1.5. (A and B) Gadolinium contrast-enhanced T1- and T2-weighted MR images in a patient with glioblastoma multiforme in the left temporal lobe. (C) Late PET images show 18F-FMISO tumor uptake 150–170 minutes after injection. (D) Gadolinium contrast-enhanced T1-weighted MR image of a patient with meningioma in left temporal lobe. (E)18F-FMISO uptake in meningioma is visible in early PET image 0 to 5 minutes after injection but not in late PET images 150 to 170 minutes after injection (F). (Reprinted by permission of SNMMI from Bruehlmeier M, Roelcke U, Schubiger PA, et al. Assessment of hypoxia and perfusion in human brain tumors using PET with 18F-fluoromisonidazole and 15O-H2O. J Nucl Med. 2004;45(11):1851–1891. Figure 1.)
FIGURE 1.6. Simultaneously acquired (A) MR, (B) PET, and (C) superimposed combined MR/PET images of 66-year-old man after intravenous injection of 370 MBq of FDG. Tracer distribution was recorded for 20 minutes at steady state after 120 minutes. (Reproduced by permission of the Radiological Society of North America (RSNA) from Schlemmer HP, Pichler BJ, Schmand M, et al. Simultaneous MR/PET imaging of the human brain: Feasibility study. Radiology. 2008;248(3):1028–1035.)
FIGURE 1.7. 18F-FDG PET, contrast-enhanced axial T1-weighted image, PET/MR fused image. Patient with a history of treated malignant lesion with surgery and radiation therapy presents with an enhancing lesion on follow-up imaging. The enhancing lesion does not demonstrate FDG uptake on MRI, compatible with radiation necrosis.
FIGURE 1.8. 18F-FDG PET, postgadolinium axial T1-weighted, and MR/PET-fused images. Increased FDG uptake along the periphery of a surgical cavity where there is ill-defined enhancement on MR, compatible with recurrent tumor.
2. Sequential imaging by systems linked by a patient “shuttle.” Transfer of the patient is accomplished by the “shuttle.” These devices provide a “hardware-fused” data.
3. Fully integrated systems with technically simultaneous data acquisition, which eliminates patient motion or table motion between acquisitions. Currently available PET/CT and SPECT/CT systems are of the sequential imaging type. The currently described head PET/MR systems are fully integrated systems. Another challenging technical issue in the development of PET/MR system is the need for attenuation correction. This is not as straightforward with PET/MR as with PET/CT. In PET/CT, whole-body CT scans are an integral part of the PET/CT examination. CT scans can easily be incorporated into the PET reconstruction algorithm, thus correcting for patient attenuation. MRI, on the other hand, does not provide any information about photon attenuation but gives information about tissue proton densities and magnetic relaxation times. Attenuation correction of PET/MR must therefore be based on indirect voxel-by-voxel assignment of MR signal intensities to empirical values of photon attenuation coefficients.41 Several approaches have been studied to resolve this problem. One approach uses image segmentation,42 and another approach uses a combination of local pattern recognition with atlas registration for additionally capturing global variations of anatomy.43 The latter approach has been shown to be successful for brain MR/PET images because the brain tissues are relatively homogeneous. In summary, PET/MR is likely to be superior to PET/CT in brain imaging. As an increasing number of PET/CT and PET/MR scanners are installed, there will be an increasing demand for imaging specialists with appropriate training in both radiology and nuclear medicine.
DIFFERENTIATION OF RECURRENT TUMOR FROM RADIATION NECROSIS
Development of a new enhancing lesion on a gadolinium-enhanced MRI within the radiation field could indicate either recurrent tumor or radiation necrosis. It is crucial to differentiate recurrent tumors from radiation necrosis because the two entities have different treatments and different prognosis. Radiation necrosis is a delayed focal structural lesion, at or close to the original tumor site, that usually occurs within a 6-month to 2-year period after radiotherapy or stereotactic radiosurgery. This early delayed radiation effect has been described for radiation-related enhancing lesions and/or increased edema on MRI within several weeks to up to 3 months following radiation treatment. It is reported to be facilitated with concomitant chemotherapy. There are also reports of late onset radiation treatment effects (up to 20 years after treatment).44–47 Clinical presentation of radiation necrosis is nonspecific and includes seizures, focal neurologic deficits, personality changes, memory loss, dementia, and/or recurrence of the initial tumor symptoms. Differential diagnosis between recurrent glioma and radiation necrosis on conventional imaging is challenging for CT and/or MR, because radiation necrosis usually presents as a lesion with surrounding edema and nodular, linear, or curvilinear enhancement because of the BBB breakdown, often resembling residual/recurrent tumor about resection cavity. Moreover, if a radiation-induced lesion is detected at a distant site from the primary tumor site it may be misinterpreted as multifocal glioma.48 Different MRI techniques have been reported as possible tools to overcome these difficulties, including perfusion MR, diffusion MR, and MR spectroscopy.
Newer MRI techniques such as arterial spin-labeled, dynamic susceptibility, and contrast methods also show promise but require further validation.49–51 Nuclear medicine techniques, particularly PET, have been investigated. 18F-fluorodeoxyglucose (FDG) is the most studied radiopharmaceutical. It has been used to differentiate recurrent tumor from radiation necrosis for almost 30 years.52 Typical sensitivities are reported between 81% and 86%, although some results are reported to be up to 100%.53–57 Sensitivity may be complicated by high metabolic activity in adjacent cortex and partial volume effects because of the small size of lesions. Estimates of specificity are lower, ranging from 22% to 92%. Specificity may be compromised by metabolic activity in areas of posttreatment inflammatory change. Recurrent tumor is typically identified by visually appreciable increased metabolic activity in the lesion of interest compared with normal white matter (Fig. 1.9).
FIGURE 1.9. A: Postgadolinium T1-weighted MR image showing ring-enhancing lesion in the right caudate head and anterior limb of the right internal capsule. B: FDG PET image shows hypermetabolic activity of the lesion in the right caudate head suggestive of recurrent tumor. (Reprinted by permission of SNMMI from Langleben DD, Segall GM. PET in differentiation of recurrent brain tumor from radiation injury. J Nucl Med. 2000;41:447–452.)
Other than 18F-FDG, there are multiple reports of investigational PET radiotracers distinguish radiation necrosis from recurrent tumor. These include 18F-FLT, 11C-Met, and 13N-ammonia PET.58–62 18F-FLT directly assesses tumor proliferation.25,63–66 It has been shown to be a marker of tumor aggressiveness and overall therapeutic response.64–67 18F-FLT does not localize to normal brain because of low proliferative activity and because it does not cross an intact BBB. Methods have been developed and validated to model the kinetic features of 18F-FLT PET by tumors, and the necessity for the kinetic modeling is thought to be critical to distinguish in nonspecific uptake of 18F-FLT from new DNA synthesis and cell proliferation.65,68–70 Dynamic kinetic modeling requires extended dynamic imaging in a single bed position, limiting analysis to a specific target field of view. It also requires drawing multiple blood samples, ideally arterial or arterialized venous alternatives, and to process these samples by column chromatography to apply a correction to the input function to account for contribution of authentic 18F-FLT versus labeled metabolites. Even if dynamic kinetic modeling of 18F-FLT PET is proven to be of irrefutable value, these methods are unlikely to be broadly adapted in clinical practice because of the complexity of the procedure. In a study on 15 glioma patients with new enhancing lesions on MRI, 18F-FLT SUVmax was derived from data 60 to 70 minutes following injection and metabolite-corrected Patlak Kimax derived from the plasma input function.71 There was a significant difference between recurrent tumor and radiation necrosis for 18F-FLT Kimax but not for 18F-FLT SUVmax. These findings support numerous previous reports that dynamic kinetic modeling of 18F-FLT PET is necessary to ensure optimal results.69–71 The overall ranking of the performance of all quantitative and semiquantitative tests in distinguishing recurrent rumor from radiation necrosis was found to be 18F-FDG SUVmax/18F-FDG SUVmeancontralateral white matter > 18F-FDG SUVmax > 18F-FLT Kimax > 18F-FLT SUVmax. Each of these parameters showed equal specificity (75%). An optimized cutoff lesion–contralateral white matter 18F-FDG ratio of 1.83 or higher for recurrent tumor resulted in the highest sensitivity (100%) in this series to distinguish recurrent glioma from radiation necrosis. In this study, of all patients with radiation necrosis, 50% had mild 18F-FLT uptake by visual assessment, presumably because of nonspecific leakage of 18F-FLT across a disrupted BBB. Enslow et al. concluded that 18F-FLT PET offered no advantage over 18F-FDG PET in distinction between recurrent tumor and radiation necrosis for moderate and high-grade gliomas. In this series, a ratio of 1.83 or higher 18F-FDG SUVmax in the target lesion to 18F-FDG SUVmean in the contralateral white matter was the best performing indicator of recurrent glioma (sensitivity, 100%; specificity, 75%).
11C-Met is the most commonly studied amino acid tracer in brain tumor imaging. Brain tumors overexpress a variety of amino acid transporters and the amino acid uptake in normal brain is low.72 Methionine, a sulfur-containing essential amino acid, has two main metabolic functions73: Protein synthesis and conversion to S-adenosylmethionine, which is required in multiple metabolic pathways for transmethylation reactions, polyamine synthesis, transsulfuration pathway that leads to the synthesis of cysteine and other derivatives such as glutathione. In cancer cells, there is an increase in protein synthesis, transmethylation, and transsulfuration, leading to an increased uptake of methionine. In vitro methionine dependence has been demonstrated in human glioma cell lines.74,75 Moreover, it has been shown that in a human glioblastoma cell line, the uptake of radiolabeled methionine is higher in proliferating cells than in resting plateau-phase cells.76 The use of 11C-Met in brain tumor imaging is restricted to PET centers with a cyclotron facility because of the short half-life of the radionuclide.
Several studies evaluated the role of 11C-Met PET to differentiate radiation necrosis from recurrent tumor. An early study by Ogawa et al.77 presented a series of 15 patients with suspected recurrent brain tumor after radiotherapy: 10/15 patients underwent a 11C-Met PET that matched with histopathologic results in 100% of the cases (three radiation necrosis and 7seventumor recurrences). Sonoda et al.78 also reported that 5/5 patients with recurrent tumor showed increased 11C-Met uptake, whereas only 1/7 patients with radiation necrosis showed 11C-Met uptake. In 2004, Tsuyuguchi et al.79 reported a series of 11 patients with recurrent malignant glioma or radiation injury after stereotactic radiosurgery; 11C-Met PET correctly identified 6/6 patients with recurrent tumors and 3/5 cases of radiation necrosis. From this result, the 11C-Met PET sensitivity, specificity, and accuracy in detecting tumor recurrence were determined to be 100%, 60%, and 82% respectively. Van Laere et al. performed a comparison between 18FDG PET and 11C-Met PET in suspected recurrence of gliomas. They found an abnormal 11C-Met uptake in 28/30 cases, whereas only 17/30 cases showed 18FDG uptake. The main limitation of this study is the empirical classification of patients in radionecrosis and recurrence groups, because histologic evidence was available in only three cases. In fact, all cases of death were considered recurrent tumor, and all cases of surviving patients at the end of follow-up period were considered as radiation necrosis.72
More recently, Terakawa et al. reported an interesting series of 26 glioma patients who underwent conventional radiotherapy. Overall, 32 11C-Met PET scans were performed at a mean interval of 36 months from irradiation. Recurrence was confirmed by tumor resection or biopsy, whereas radiation necrosis diagnosis was based on pathologic examination or on clinical course. Mean standardized uptake value (SUVmean) and maximum standardized uptake value (SUVmax) were generated over the region of interest and the lesion-to-normal tissue (L/N) count ratios were generated by dividing the SUVmean of the lesion and the SUVmean of the contralateral frontal lobe gray matter (L/Nmean) and by dividing the SUVmax of the lesion and the SUVmax of the contralateral frontal lobe gray matter (L/Nmax). The authors found a significant difference in all of the indices except for the L/Nmax between tumor recurrence and radiation necrosis. Receiver-operating characteristic (ROC) curve analysis of each index indicated that L/Nmean is the most informative index between tumor recurrence and radiation necrosis and an L/Nmean of 1.58 provided the best sensitivity and specificity to define gliomas, 75% and 75%, respectively (Fig. 1.10). In this study, however, some necrotic tissue also had some high levels of 11C-Met uptake, which can be a factor that reduces the specificity of Met PET. This is most likely because of the BBB disruption that may occur in radiation-induced lesion.25 Therefore, some authors suggested repeating the 11C-Met PET scan after corticosteroid administration in cases with borderline 11C-Met uptake; the repeat scans may distinguish between radiation necrosis and tumor lesions by reducing the 11C-Met uptake because of the BBB breakdown in radiation injury while leaving the 11C-Met uptake because of intact active transport in gliomas.73
Other hypotheses that could explain the uptake of 11C-Met in radiation necrosis can be increased methionine metabolism induced by reactive gliosis mediated by astrocytes and microglial cells80 or methionine accumulation as a result of proliferative changes in glial cells in the area of radiation necrosis.79 On the other hand, false-negative results with 11C-Met PET are possible, mainly because of the inability to detect small lesions.
Kim et al. compared perfusion MR, 18FDG PET, and 11C-Met PET to distinguish between radiation necrosis and tumor recurrence in 10 patients with high-grade glioma who underwent surgical resection followed by radiotherapy with or without chemotherapy and showed newly enhanced lesions on follow-up conventional MRI. After co-registering the PET images with the MR, the maximum uptake values of the lesion and of the contralateral cerebral white matter as reference area were measured to calculate the lesion/reference uptake ratio. There was no difference between radiation necrosis and tumor recurrence groups in terms of lesion/reference uptake ratio as derived from the 18FDG and 11C-Met PET. The authors also stated that a perfusion MR might be superior to 18FDG and 11C-Met PET to distinguish a recurrence of high-grade glioma from radiation necrosis.81 In 2009, Nakajima et al. evaluated the usefulness of 11C-Met PET in the differential diagnosis between radiation necrosis and tumor recurrence in 18 patients with glioma. The uptake of 11C-Met was determined as the ratio of the lesion to the contralateral reference region (L/R). The final diagnoses were determined by histologic examination and/or follow-up MR imaging and clinical course. 11C-Met PET demonstrated significant difference in the L/R ratio between patients with tumor recurrence and radiation necrosis (2.18 versus 1.49, p < 0.01). According to a 2 × 2 factorial table analysis, the borderline values of L/R to differentiate recurrence from necrosis was 2.82 In their retrospective study, Yamane et al. examined the clinical efficacy of 11C-Met PET in patients with brain neoplasm, especially whether the 11C-Met PET changed the clinical management. The authors demonstrated that 11C-Met PET was useful in differentiating tumor recurrence from radiation necrosis, changing the clinical management in half of the scans.83 Recently, Okamoto et al. evaluated 29 patients suspected of recurrent brain tumors by MR after radiation therapy with C11 MET PET. Semiquantitative analysis was performed using SUVmax and L/N ratio. ROC analysis was also assessed concerning the diagnostic value of 11C-Met PET. Histologic analysis or clinical follow-up confirmed the diagnosis of tumor recurrence in 22 lesions, and radiation necrosis in 11 lesions. L/N ratios of recurrence and necrosis for all lesions were 1.98 and 1.27, respectively (p < 0.01). The areas under the ROC curve were 0.886 for L/N ratio and 0.738 for SUVmax. The authors concluded that semiquantitative analysis of 11C-Met PET provided high diagnostic value, enabling early diagnosis of brain tumor recurrence in the follow-up after the radiation therapy.84 In summary, to differentiate glioma recurrence from radiation necrosis, 11C-Met PET appears to have a high sensitivity, specificity, and accuracy.
FIGURE 1.10. 18F-FDG PET, postgadolinium axial T1-weighted, and MR/PET-fused images. Increased FDG uptake along the periphery of a surgical cavity where there is ill defined. (Reprinted by permission of SNMMI from Terakawa Y, Tsuyuguchi N, Iwai Y, et al. Diagnostic accuracy of 11C-methionine PET for differentiation of recurrent brain tumors from radiation necrosis after radiotherapy. J Nucl Med. 2008;49:694–699. Figure 1.)
CONCLUSIONS: IMAGING AND TREATMENT
Gliomas are the most common primary brain neoplasms. GBM, which is a grade IV glioma, is the most common of all and has a dismal prognosis. Survival rate is approximately 12 to 14 months despite addition of new treatment strategies. Neuroimaging plays a crucial role in management of brain tumor patients. MRI has a major role in diagnosis and follow-up of brain tumors but it has certain limitations. The recent addition of temozolomide and/or bevacizumab to surgical treatment and radiotherapy results in MRI findings that may not solely reflect tumor response or recurrence but treatment-related changes. This has made MR interpretation more challenging and created the need for molecular imaging such as PET imaging. Many PET tracers have been studied and show promise in diagnosis, grading, and differentiation of recurrence from treatment-related changes. Besides 18F-FDG which is a marker of glucose metabolism and is commonly used in many centers for brain tumor imaging, these other tracers include markers of cellular proliferation such as 11C-Met, 18F-FDOPA, 18F-FET, 18F-FLT, 11C-Cho, and 18F-FMISO (used for hypoxia imaging). These tracers have advantages over 18FDG in brain tumor imaging as they have no significant background normal gray matter activity. This makes visual interpretation easier and more reliable.
In addition to the development of these new novel tracers, there has also been technical development such as the integration of PET and MR in the same system. This is a difficult and high-cost process but has been shown to yield state-of-the-art images. Having PET/MR-fused images makes image interpretation less time consuming and more reliable. This clearly results in improvement in patient care. As an increasing number of PET/MR scanners are installed, there will be an increasing demand for imaging specialists with training in both radiology and nuclear medicine.
TARGETED RADIOTHERAPY (RADIOIMMUNOTHERAPY)
An emerging therapeutic approach for high grade (WHO grades III and IV) brain tumor treatment is targeted radiotherapy, a strategy that utilizes a molecular vehicle to selectively deliver a radionuclide to malignant cell populations. One property of gliomas that make them suitable for targeted radionuclide therapy is that they recur at or near the site of origin and are characterized by a frequent tendency to infiltrate adjacent brain tissue. They rarely metastasize outside the central nervous system.85,86 In fact, 80% of GBMs recur within 2 cm of the primary site.87 Investigations in brain tumor patients have frequently utilized monoclonal antibodies (MoAbs) as the targeting vehicle; this the term: radioimmunotherapy. MoAbs reactive with tumor-associated antigens to target radioactive agents to tumor cells for therapeutic purpose has been extensively studied.88–91 Brain tumor–associated molecular targets that have been evaluated include the epidermal growth factor receptor92 and the human neural cell adhesion molecule (NCAM) which is present both on glioma and normal neural tissue.93 However, the vast majority of radioimmunotherapy studies in brain tumor patients have utilized radiolabeled MoAbs reactive with tenascin-C molecule.
Tenascin-C Molecule and Anti-Tenascin Monoclonal Antibody
Tenascin-C is a six-armed glycoprotein that is overexpressed in the extracellular matrix of gliomas. The level of tenascin-C expression increases with advancing tumor grade.94 More than 90% of GBM biopsies exhibit very high levels of tenascin-C expression.95 Tenascin-C expression occurs primarily around tumor-supplying blood vessels. Furthermore, in grade II and grade III gliomas, there appears to be a correlation between perivascular staining and earlier tumor recurrence.94 Several anti-tenascin MoAbs have been studied for radioimmunotherapy:
• BC-2 and BC-4 anti-tenascin MoAbs. These bind to different epitopes on the tenascin molecule.
• MoAb 81C6 is another anti-tenascin MoAb. It is a murine IgG2b that reacts with an epitope present the alternatively spliced fibronectin type 3 CD segment.95 The ability of murine 81C6 to selectively localize and treat human glioma xenografts was investigated extensively in rodent models before the initiation of clinical studies.
Intravenous administration of therapeutic levels of radiolabeled MoAb to tumor was found to result in excessive doses to liver and spleen, normal organs that express tenascin.96 It has been reported that the relative reactivity with tumor compared with liver and spleen could be enhanced by utilization of antibodies reactive with alternatively spliced regions of the tenascin molecule instead of those present on all isoforms.95
Radioisotopes Used in Labeling of the Monoclonal Antibodies
The antitumor effect of radioimmunotherapy is primarily because of the associated radioactivity of the radiolabeled antibody, which emits continuous slowing-down low–dose-rate irradiation.97,98 The number of radionuclides available for the production of radiolabeled compounds has increased. Suitable radionuclides with decay properties matching the brain tumor characteristics include iodine 131 (131I), yttrium 90 (90Y), and lutetium 177 (177Lu). The two most commonly studied radionuclides in radioimmunotherapy of brain tumors are 131I and 90Y. 131I can directly be conjugated to antibodies. The use of radiometals like 90Y and 177Lu requires first conjugation of a chelator with the antibody and subsequently labeling with the radioisotope.99,100 The chelating agent frequently used for 90Y and 177Lu labeling is a macrocyclic chelating agent 1,4,7,10-tetraazacyclododecane-N, N9, N0, N-tetraacetic acid, known as DOTA. 131I and 90Y are β-emitters and deposit 95% of their energy within 0.992 and 5.94 mm, respectively.101
Systemic Versus Locoregional Administration of the Radiolabeled Monoclonal Antibody
One limitation of systemic (intravenous) administration of radiolabeled MoAbs is that the amount of immunoglobulin localized within neoplastic glial tissue has been measured to be less than 0.001% of intravenously administered MoAbs per gram of tumor tissue whereas the remainder stays in the circulation bound to the radionuclide with toxic effects on other tissues, especially bone marrow.102 Many factors contribute to this limitation of the systemic treatment. These include large size of the MoAb macromolecule, high interstitial pressure inside the neoplastic tissue, limited blood supply to the tumor, inhomogeneous and inconstant antigen expression, possible presence of physiologic barriers (necrosis and/or fibrosis), formation of immunocomplexes, and catabolism of immunoglobulins.103 Although often impaired in tumor, the BBB further hampers the accumulation of antibodies in the malignant tissue. Among strategies proposed to overcome these drawbacks and to improve the tumor/nontumor uptake is locoregional administration of the radiolabeled MoAbs via an indwelling catheter placed in the surgical resection cavity instead of systemic/intravenous administration.
Locoregional Radioimmunotherapy Versus Other Locoregional Therapies
Locoregional therapies other than radiolabeled MoAb method include reoperation and various types of radiotherapy (conventionally fractionated radiotherapy, hypofractionated stereotactic radiotherapy, interstitial brachytherapy, and radiosurgery). Reoperation may improve neurologic status and prolong survival in some cases; however, radiation therapy can provide similar benefit in a less invasive manner. Locoregional radioimmunotherapy (LR-RIT) using monoclonal antibodies (MoAbs) labeled with high-energy β-emitting radionuclides has several advantages over other types of locoregional therapies. The radioemission can kill antigen-negative tumor cells that have no specific radiolabeled antibody localized on their surface in addition to antigen-positive antibody bound cells. This phenomenon is called “crossfire effect.” Recent studies of LR-RIT using monoclonal antibodies labeled with 131I and 90Y have been encouraging from the point of view of safety profile, objective response, and overall survival. According to two phase I studies utilizing 131I 81C6 MoAb into the resection cavities of recurrent high-grade gliomas, studied by Bigner et al.104 and Cokgor et al.,105 the dose limiting toxicity was neurologic. The maximum tolerated doses were 100 mCi (3,700 MBq) and 120 mCi (4,440 MBq) respectively. Reversible hematologic toxicity was also described in a subgroup of patients in the Cokgor study. Riva et al.106 evaluated the efficacy of 131I- and 90Y-labeled BC-2 and BC-4 MoAbs for the locoregional treatment of malignant gliomas. For the 131I-labeled BC-2 and BC-4 MoAb study by Riva et al., patients received multiple cycles of radioimmunotherapy at intervals of either 1 or 3 months, with a cumulative administered activity of up to 20.35 GBq (550 mCi). The median survival was 46 months in anaplastic astrocytoma and 19 months in glioblastoma according to the study results. The response rate in glioblastoma patients was better in those with small volume (56.7%) compared with patients with larger tumors (17.8%). A subsequent study by the same group using this time 90Y-labeled MoAb therapy for recurrent GBMs has been conducted.106 Patients received between three and five cycles of 90Y-labeled MoAbs with a cumulative activity up to 3.145 GBq (85 mCi). The median survival for patients with anaplastic astrocytoma and glioblastoma was 90 months and 20 months, respectively. The response rate in glioblastoma patients was 26.3% in those with bulky disease compared with 56.3% for those with smaller lesions. In another study by Goetz et al.,107 131I- and 90Y-labeled BC-4 MoAb were evaluated in patients with grade III and IV gliomas. Multiple cycles of labeled MoAbs were administered (mean, three per patient) at various activity levels. The median survival for glioblastoma patients was 17 months.
These clinical studies confirm the potential of locoregionally administered radiolabeled MoAbs as a means to improve the survival of patients with malignant brain tumors. The low incidence of side effects, even after multiple cycles, also is encouraging. However, it remains to be determined whether the use of multiple cycles of labeled MoAb results in a significant improvement in therapeutic efficacy compared to single-dose protocols.
Significant radiolysis occurs during the interval between radiolabeling and injection, with consequent decrease in immunoreactivity when the MoAb is directly labeled with a high-energy isotope. Pretargeting has been studied to overcome this radiolysis and poor localization of radiolabeled MoAbs in the neoplastic tissues. In this method, first, modified MoAb is administered and allowed to distribute throughout the body, to bind to the cells expressing antigen and clear substantially from other tissues.108 This is followed by the radiolabeled second component that ideally localizes at sites where the modified MoAb has accumulated. If the second component has higher permeability, clearance and diffusion rates than those of MoAb, more rapid radionuclide localization to the tumor and higher tumor selectivity are achieved in the higher tumor-to-nontumor ratio.109
The Avidin–Biotin Model
One of the most clinically useful pretargeting techniques is the avidin– biotin system. This three-step pretargeting approach takes advantage of the extremely high affinity between avidin and biotin. Avidin is a small oligomeric protein made up of four identical subunits, each bearing a single binding site for biotin (vitamin H). The molecule can therefore bind up to 4 moles of biotin per mole of protein. The affinity of avidin for biotin is extremely high.110For practical purposes, their binding can be regarded as irreversible.111 Pretargeted antibody-guided radioimmunotherapy using avidin–biotin technique is based on intravenous or locoregional sequential administration of a biotinylated BC-4 MoAb, followed 24 hours later by avidin, and finally, after an additional 18 hours, a 90Y-labeled biotin conjugate.110 Paganelli’s group has studied and applied this method, both as systemic or LR-RIT in glioblastoma patients. Paganelli et al.112 performed the first trial with this pretargeting approach in patients with recurrent glioma. The three reagents were administered via a catheter placed into the surgical resection cavity in the sequence that was described. WHO grade III and IV glial tumors were included in the study and two cycles of therapy administered 8 to 10 weeks apart. The maximum tolerated dose was 1.11 GBq (30 mCi) of 90Y-labeled DOTA. The dose-limiting factor was neurologic toxicity secondary to biotin. After the second operation, median survival was 19 and 11.5 months in patients with grades III and IV, respectively. In another study by Grana et al.,113 the efficacy of pretargeting radioimmunotherapy protocol was evaluated in an adjuvant setting. Newly diagnosed patients with grade III and IV gliomas were included in this study. Following surgery and external beam radiation, a subgroup of patients received the three reagents in the described sequence with the 90Y-labeled biotin being given at a dose of 2.2 GBq/m2. A subgroup of GBM patients undergoing surgery and external beam radiotherapy (EBRT) was used as a control group. The median survival estimated for the grade IV glioma patients was 8 months in the control group (n = 12) and 33.5 months in the treated group (n = 8). The results obtained with this pretargeting protocol are highly encouraging, particularly in light of the fact that survival prolongation could be obtained even when then labeled compound was administered intravenously.
Astatine-211–Labeled Chimeric 81C6 Clinical Trial
Another radioactive material that could potentially be used for radioimmunotherapy of brain tumors is astatine-211, or 211At. A phase I trial conducted by Zalutsky et al. using astatine-211–labeled chimeric 81C6 for therapy of recurrent GBM had promising results. 211At is an α-emitter radio halogen with 7.2-hour half-life. It has high linear energy transfer radiation with higher cytotoxicity than β-emitters. Cell culture experiments have demonstrated that human tumor cell lines could be killed with only a few α-particle traversals per cell.114 Furthermore, the cytotoxicity of α-particles is nearly independent of dose rate, oxygen concentration, and cell cycle stage. Less than 0.2% of the injected dose was found in the blood pool and more than 95% of the 211At decays occurred within the tumor resection cavity. Cavity interface radiation doses were in the range of 150 to 35,000 Gy (2,986 Gy average dose) compared with 0.01 Gy for normal organs including tenascin-expressing spleen and liver. Encouraging responses have been obtained with a median survival of 60 weeks observed in all patients according to this study.
Addition of Temozolomide, an Alkylating Agent to Radioimmunotherapy
Recently, temozolomide, a novel alkylating agent with excellent properties of penetration into brain, was introduced as standard treatment for recurrent high-grade gliomas.115 Paganelli’s group added temozolomide to their LR-RIT protocol for recurrent high-grade glioma treatment.116 They studied the response rate, overall survival, and progression-free survival. Although in a major clinical study by Walker et al.,116 the median survival in GBM patients treated with surgery, with or without EBRT was reported to be 35 and 14 weeks respectively, in Paganelli’s study, within the subgroup of combined LR-RIT plus temozolomide, the overall survival was 25 months and progression-free survival was 10 months, within the subgroup of patients who underwent only LR-RIT, the overall survival was 17.5 and progression-free survival was 5 months.115 The rationale for combining LR-RIT and temozolomide is that temozolomide would kill microscopic disease outside the LR-RIT radiation field; the two treatments have different toxicity profiles and improved permeability of temozolomide into the resection cavity secondary to destructive effect of radiation on BBB.117 Regarding safety, remarkably, only a low incidence of early and late neurotoxicity have been reported both with LR-RIT alone or combined with temozolomide by Paganelli’s group. Reversible grade II and III lymphocytopenia and/or thrombocytopenia were observed in 62% of patients treated with LR-RIT and temozolomide. This is comparable to studies applying temozolomide and external radiotherapy.118 Neurotoxicity and skin infection caused by indwelling catheter are the other possible complications of the locoregional treatment. Compared with EBRT where brain is the critical organ, during locoregional RIT, the normal brain receives negligible doses. The mean absorbed doses in normal brain were 0.16 ± 0.08 mGy/MBq and 0.015 ± 0.005 mGy/MBq in the systemic and locoregional treatments, respectively.119 With local administration, systemic toxicity is reduced as well. The red marrow adsorbed dose was 0.22 mGy/MBq in the systemic treatment compared to 0.03 mGy/MBq in the locoregional treatment. The normal organs mainly involved in the biodistribution of the 90Y-biotin were liver (0.4 ± 0.3 mGy/MBq) and kidneys (0.7 ± 0.4 mGy/MBq); 65 ± 28% of the injected activity was eliminated via the kidneys in the first 24 hours after the treatment. Scintigraphic images acquired up to 48 hours after the LR-RIT with 90Y-biotin showed the radiolabeled compound to be well localized within the injection site and minimal activity in the remainder of the body.118 Low 90Y activities were found in the bloodstream. Activity in other normal organs was negligible in most cases.
Radiolabeled Peptides for Targeted Radiotherapy of Distant Tumor Cells
One of the limitations of MoAbs is that because they are large molecules, their diffusion through tissues is slow. Peptides have been studied as carrier molecules for targeted radiation therapy of distant tumor cells because they have molecular weight two orders of magnitude less than intact MoAbs. Hofer et al.119 has utilized this strategy in patients with low-grade gliomas, many of which overexpress somatostatin type 2 receptors. In this study, five patients with progressive gliomas (two WHO grade II, three WHO grade III) and five patients with surgically debulked WHO grade II gliomas were treated with the labeled somatostatin analog [90Y]-DOTA0-D-Phe1-Tyr3-octreotide. Patients received between one and five cycles of the labeled peptide at a cumulative activity of 555 to 7,030 MBq (15 to 190 mCi). Responses of 13- to 45-month duration were observed in the progressive patients. Disease stabilization was observed in the five newly diagnosed low-grade glioma patients who received radiolabeled peptide therapy following resection. Side effects included increased seizure frequency but this was transient.
FUTURE DIRECTIONS IN RADIOIMMUNOTHERAPY
Despite the use of multimodality treatment, the prognosis of high-grade gliomas (WHO grade III and IV) remains poor, as these tumors are highly resistant to currently available therapies. There are encouraging results of many clinical trials studying targeted radiolabeled monoclonal antibody therapy of these aggressive tumor types.104–107,112,113 Radioimmunotherapy, both systemic and locoregional, could be used as part of a combined modality approach in combination with surgery, radiotherapy, and chemotherapy. It has been demonstrated that radiolabeled MoAb introduced directly into surgically created resection cavities provides a significant survival advantage with less toxicity in patients with high-grade glioma compared to standard EBRT combined with chemotherapy.115
More comparative studies are needed to evaluate and compare the protocols of multiple cycles of targeted radioimmunotherapy versus single-dose protocol. To assess the efficacy, it is necessary to study safety, timing of the radioimmunotherapy intervention following first debulking surgery versus following surgery for recurrent disease, and the type of radioactive material (i.e., 90Y versus 131I) used for labeling the MoAb. Adjusting the amount of radioactivity that will be used for labeling the MoAb according to the tumor size and/or surgical resection cavity size is another topic that requires further investigation as well as methods to improve delivery of targeted radioimmunotherapy to tumor cells distant from the primary lesion, given the infiltrative nature of gliomas. The work to date with highly cytotoxic α-emitters and highly diffusible peptides is encouraging in this regard. Use of microinfusion techniques such as those being used to treat gliomas with immunotoxins120 may also play an important role.
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