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Abstract: Glioblastoma (GB) is the most malignant and the most common type of glioma in adults, accounting for 60–70% of all malignant gliomas. Despite the current therapy, the clinical course of GB is usually rapid, with a mean survival time of approximately 1 year. For therapy response assessment in GB, magnetic resonance imaging (MRI) is the method of choice. In 2010, the Response Assessment in Neuro-Oncology (RANO) was introduced, including the tumor size (in 2D) as measured on T2-weighted and Fluid Attenuated Inversion Recovery (FLAIR)-weighted images, in addition to the contrast-enhancing tumor part. Although the RANO criteria addressed some of the limitations of the previous MacDonald criteria for therapy evaluation in high-grade glioma, treatment-related side effects hamper correct response assessment. To address the above-mentioned drawbacks in the follow-up of GB, incorporating changes in tumor biology measured by advanced MRI and positron emission tomography (PET) imaging, which may precede anatomical changes of the tumor volume, is promising. Imaging biomarkers capable of predicting response at an early time point after treatment initiation are the premise of personalized treatment enabling change or discontinuation of therapy to prevent ineffective treatment or adverse events of treatment. In this chapter, an overview of applicable PET tracers for the therapy response assessment in GB and the determination of tumor recurrence versus treatment-related effects is given.

Keywords: Glioblastoma; MRI; PET; Radiation necrosis; Therapy response

Introduction

Gliomas are the most common primary brain tumors with a peak incidence in the fifth and sixth decade of life (1, 2). The highest grade of gliomas (WHO grade IV) are called glioblastoma (GB). GBs account for more than half of all glial tumors, are a highly invasive solid tumor type, and are most often found in cerebral hemispheres, particularly in frontal, parietal, and temporal lobes, although they can be situated in any lobe. They can arise de novo (primary GB) or after progression of a low-grade glioma (secondary GB) (2–4). Usually, GBs are poorly delineated, heterogeneous tumors with necrosis, hemorrhage, and increased vascularity. Central necrosis is the hallmark of GBs and may occupy as much as 80% of total tumor mass (2). GB cell infiltration into the surrounding brain parenchyma renders a complete surgical resection mostly impossible without producing significant neurological injury. Residual glioma cells at the tumor margins frequently lead to tumor recurrence (3). In patients with suspected brain tumor, after medical history taking and clinical examination, the most important diagnostic procedure is magnetic resonance imaging (MRI) of the brain with a contrast-enhancing agent. However, the diagnosis should be confirmed via a stereotactic biopsy or, when appropriate, via resection. Functional and molecular imaging has gained a lot of attention in the last decade. Before confirmation of the diagnosis via tissue analysis, MR spectroscopy (MRS), perfusion weighted MRI (PWI), and positron emission tomography (PET) imaging can be helpful. After the diagnosis has been confirmed pathologically, these imaging modalities can be even more valuable. In particular, they may be useful for planning of radiation therapy (RT) and even more established in clinical practice for the monitoring during therapy, post-treatment surveillance, and prognostication (5, 6).

Treatment of Glioblastoma

Surgical resection remains one of the most effective treatments for cerebral gliomas (7, 8). It has been shown that patients who had a gross total resection also have a better response to subsequent adjuvant treatments than those who had only a partial resection or biopsy (7). However, in about half of the patients, (total) resection is not possible (9). The current standard of care for patients with GB has slowly evolved over the course of several decades. In the early 1960s, systemic corticosteroids were shown to have a beneficial impact on patients’ quality of life by reducing peritumoral edema. Shortly thereafter, whole brain radiation therapy (WBRT) became recognized as an effective adjuvant therapy. However, the dose was limited by potential toxicity to the surrounding normal brain (3). New developments in RT enabled to shape the radiation dose conform to the tumor target, limiting the dose to normal tissues, resulting in so-called conformal RT. Intensity-modulated radiation therapy (IMRT) allows even greater control over the shape of the dose distribution using variable intensities of the radiation beam (10, 11). In an effort to complement the beneficial effects of corticosteroids and RT, systemic chemotherapeutic agents were also studied (3). In 2005, Stupp et al. established the superiority of surgery and combined chemoradiation therapy with temozolomide (TMZ) over surgery and RT alone. As a result, for newly diagnosed GB patients with a good performance status, the standard of care now includes maximal surgical resection followed by combined external beam RT (60 Gy in 30 fractions) and TMZ, followed by maintenance TMZ (12–14). TMZ is an oral deoxyribonucleic acid (DNA) alkylating agent with good blood brain barrier (BBB) penetration. It is usually well tolerated with thrombocytopenia as its main and dose-limiting toxicity. In contrast to TMZ, nitrosoureas such as lomustine (CCNU), carmustine (BCNU), nimustine (ACNU), or fotemustine can induce prolonged leukopenia and thrombocytopenia, requiring dose reductions for the subsequent cycles, or a change of regimen. Nitrosoureas are now second-choice agents relative to TMZ for glioma treatment. In high-risk, low-grade gliomas, RT followed by procarbazine, CCNU, and vincristine (PCV) constitutes a new standard of care due to prolonged survival reported in the RTOG 9802 trial (15). The most recent development with respect to novel therapies for GB involves the use of angiogenesis inhibitors, such as bevacizumab, which improve the quality of life of patients due to their capacity to reduce vessel leakiness, resulting in diminished intracranial edema (16). Despite the current therapy for GB, the clinical course of GB tumors is usually rapid, with a mean survival time between 6 and 12 months (2).

THERAPY RESPONSE ASSESSMENT OF GLIOBLASTOMA

Several prognostic factors have been identified in patients with GB, such as age, Karnofsky performance status, neurological status, WHO tumor grade, tumor location, extent of surgery, genetic and molecular biomarker status, and concomitant TMZ (17, 18). For therapy response assessment in GB, MRI is the method of choice. Until 2010, mainly MacDonald criteria were used for assessing response to therapy in high-grade glioma (HGG). Although the MacDonald criteria were developed primarily for computed tomography (CT) scans, they have been extrapolated to MRI. The criteria are based on two-dimensional (2D) tumor measurements on CT or MRI, in addition to a clinical assessment and corticosteroid use and dose (19). In the MacDonald criteria, a significant increase (≥25%) in the contrast-enhancing lesion is used as a reliable marker for tumor progression. However, contrast enhancement after the administration of gadolinium is nonspecific and primarily reflects the passage of contrast material across a disrupted BBB. Furthermore, in 20–30% of patients, pathological contrast enhancement on MRI subsiding without any change in therapy is shown on the first post-irradiation MRI. This phenomenon, known as pseudoprogression, likely results from a combination of transiently increased permeability of the tumor vasculature from irradiation, treatment-induced necrosis, and post-operative infarcts, and should always be considered in the first 3 months after concurrent chemoradiation for gliomas (19–21). In addition, it is worth mentioning that pseudoprogression may be reinforced by chemotherapy with TMZ (9, 19, 22). This treatment-related effect complicates the determination of tumor progression immediately after the completion of RT and may result in premature discontinuation of effective adjuvant therapy (19, 22). Furthermore, since the introduction of antiangiogenic agents, another phenomenon known as “pseudoresponse” occurred. These agents can produce a marked decrease in contrast enhancement as early as 1–2 days after initiation of therapy, which may be partly a result of normalization of abnormally permeable tumor vessels and not a true anti-glioma effect as a nonenhancing tumor may continue to grow (19, 20). This normalization of BBB disruption is often combined with a regression of perifocal edema followed by an improvement of neurological symptoms and consequently a reduction of corticosteroid use (22). In an attempt to more accurately assess treatment response, new criteria for Response Assessment in Neuro-Oncology (RANO) were introduced in 2010, including the tumor size (in 2D) as measured on T2-weighted and Fluid Attenuated Inversion Recovery (FLAIR)-weighted images, in addition to the contrast-enhancing tumor part. Although the RANO criteria addressed some of the limitations of the MacDonald criteria for evaluation of therapy in HGG, the abovementioned treatment-related side effects hamper correct response assessment. The proposed new response criteria suggest that within the first 3 months after completion of RT, progression can only be determined if the majority of the new enhancement is outside of the radiation field or if there is pathologic confirmation of progressive disease. This means that response assessment shortly after the end of RT is not accepted (22). Furthermore, increased enhancement and FLAIR/T2 hyperintense signal abnormalities can also occur due to treatment-related inflammation, postsurgical changes, subacute irradiation effects, and radiation necrosis (RN) (19). As such, tumor recurrence cannot be accurately distinguished from treatment effects on CT or conventional MRI (9).

DIFFERENTIATION BETWEEN TREATMENT-RELATED EFFECTS AND GLIOBLASTOMA RECURRENCE

Early and late therapy-related effects on brain tissues are an unwanted but unavoidable consequences of RT (7). The incidence is increasing with more frequent use of stereotactic radiosurgery and combined modality therapy for brain tumors. These therapy-related effects on the brain, such as radiation injury, also add to the complexity of imaging response and recurrence patterns, which is particularly important in patients with HGG in whom recurrence is commonly seen (20, 21). Radiation injury is known to potentially target glial cells and vascular endothelial cells and has been divided into acute, early-delayed, and late-delayed reactions (20, 23). Acute RN (during RT to 3 months after completion of RT) is a consequence of injury to the vasculature, more specifically radiation-induced endothelial cell apoptosis, leading to capillary leakiness and edema. Up to 12 weeks following RT, early-delayed injury can occur due to a delay in myelin synthesis (injury to oligodendrocytes). However, pseudoprogression must be considered. Late vascular changes include vessel wall thickening, with resulting occlusive vasculopathy, perivascular parenchymal coagulative necrosis, and inflammation. Late delayed reactions are reported to occur in 3–24% of patients from 3 months to 13 years after the completion of RT (23–26). The risk increases with increasing radiation dose, fraction size, irradiated volume, and the (concomitant) administration of chemotherapy (24). The pattern of radiation injury may vary from diffuse periventricular white matter lesions to focal or multifocal lesions and may occur even distant from the original site of treatment (27). Differentiation between RN and recurrent brain tumor presents a diagnostic dilemma as both entities frequently develop at the resection site and often have a similar appearance on conventional MRI (20, 21). Both types of lesions can have similar clinical presentations, such as seizures, focal neurologic deficits, and increased intracranial pressure (25). Obviously, a correct diagnosis is important for further patient management. RN may require the administration of steroids, whereas tumor recurrence necessitates second-line treatment (20, 28). A definite diagnosis requires a biopsy. Unfortunately, a biopsy is subject to sampling error, is invasive, and can lead to potential complications such as brain hemorrhage (21).

To address the abovementioned drawbacks in the follow-up of GB, incorporating changes in tumor biology measured by advanced MRI and PET imaging, which may precede anatomical changes of the tumor volume, is promising (9, 29, 30). Imaging biomarkers able to predict response at an early time point after treatment initiation are the premise of personalized treatment enabling change or discontinuation of therapy to prevent ineffective treatment or adverse events of treatment. Moreover, identification of treatment failure may help reduce costs. This is highly relevant because the expense of newer systemic treatment options (e.g., bevacizumab) is considerably higher than conventional alkylating chemotherapy (e.g., lomustine) (31). Currently, MRI techniques that interrogate the vascular density and permeability of tumor vasculature, such as dynamic contrast-enhanced MRI (DCE-MRI), diffusion-weighted MRI (DWI), perfusion-weighted MRI (PWI), and metabolite concentrations using MRS, are being evaluated as imaging biomarkers of tumor response in treatment trials (9). Using DWI, higher apparent diffusion coefficients (ADCs) were found in RN compared to tumor recurrence due to an increase in water in the interstitial spaces resulting from cell necrosis (32). Choline/creatine and choline/N-acetylaspartate ratios as measured by MRS may also add valuable information in differentiating recurrent tumor from RN, and even a higher diagnostic accuracy was achieved when combining DWI with MRS (32, 33). PWI, such as dynamic susceptibility contrast-enhanced MRI (DSC-MRI), was found to distinguish tumor recurrence from RN by using cerebral blood volume (CBV) maps (9, 34–36). Furthermore, the use of the amide proton transfer MRI signal of endogenous cellular proteins and peptides as an imaging biomarker has been shown to be able to differentiate viable glioma from RN in rats (37). Although advanced MRI techniques may yield promising results, a major disadvantage is the current lack of standardization and validation, which hampers the translation into the clinic. In the remainder of this chapter, the focus is on the use of PET for therapy response assessment in GB. In the future, incorporation of these advanced imaging techniques into the RANO criteria is necessary, but it needs standardization and requires rigorous clinical validation before they can be recommended and incorporated into response criteria (19). Currently, the decision tree given in Figure 1 can be proposed for the follow-up of HGG (38).

Figure 1 Decision tree for post-treatment follow-up in high-grade gliomas. (Adapted from Ref. (38).)

PET for Therapy Response Assessment in GB

In the past decades, a variety of molecular targets have been addressed by specific PET tracers in neuro-oncology and could be used for therapy response evaluation in HGG, see Figure 2 (39–44).

Figure 2 Contrast-enhanced MRI (top row) and multiple PET tracers (bottom row) in glioblastoma. (a) ¹⁸F-Fluorodeoxyglucose (¹⁸F-FDG), (b) ¹⁸F-fluoroethyltyrosine (¹⁸F-FET), (c) ¹⁸F-Fluoromethylcholine (¹⁸F-FCho), (d) ¹⁸F-fluoromisonidazole (¹⁸F-FMISO) (43) PET in human GB, (e) ¹⁸F-fluoroazomycin arabinoside (¹⁸F-FAZA) PET of the rat F98 model, (f) ¹⁸F-fluorothymidine (¹⁸F-FLT) (9) PET, and (g) ¹⁸F-AIF-NOTA-PRGD2 (¹⁸F-RGD) PET/CT in human GB. (Adapted from Ref. (44).)

¹⁸F-FLUORODEOXYGLUCOSE (¹⁸F-FDG) PET

¹⁸F-Fluorodeoxyglucose (¹⁸F-FDG) is the most common clinically utilized PET tracer due to its high potential to detect tumors in the body based on increased energy demand of malignant tumors. ¹⁸F-FDG PET measures cellular glucose metabolism as a function of the enzyme hexokinase (40, 41, 45). ¹⁸F-FDG-6-PO₄ accumulates in cells over time, leading to signal amplification and making this imaging agent a suitable indicator of hexokinase-II activity as well as a cell’s need for glucose (45). In the brain, ¹⁸F-FDG exhibits high uptake in normal gray matter, reflecting the metabolic demands of neurons and glia. This high uptake in normal brain parenchyma often makes the localization and the delineation of brain tumors difficult and only co-registration of ¹⁸F-FDG PET with MRI allows the rating of glucose metabolism in specific areas of a tumor, see Figure 2A (40, 41). Several studies investigating the potential of ¹⁸F-FDG in discriminating tumor recurrence and RN have been performed. However, equivocal results with sensitivities and specificities ranging from 40 to 100% were published (21, 28, 34, 46–48). Besides the high and variable uptake by the normal cortex, radiation injury can activate repair mechanisms or lead to inflammation, which can lead to false-positive results (20).

Our research group compared the uptake of ¹⁸F-FDG, ¹⁸F-fluoromethylcholine (¹⁸F-FCho), and ¹⁸F-fluoroethyltyrosine (¹⁸F-FET) in GB and RN in rats, see Figure 3 (49, 50). We found significantly higher values for the maximum and mean standard uptake value (SUV_max and SUV_mean) and the maximum and mean lesion to normal tissue ratio (LNR_max and LNR_mean) on ¹⁸F-FDG PET in GB compared to RN. Uptake of ¹⁸F-FDG in GB was high, which means that the uptake was higher than that in the cortex. The latter was not shown in RN (51, 52). In the literature, ¹⁸F-FDG PET has been found to be of only moderate additional value to MRI for differentiation between glioma recurrence and RN, especially due to low specificity (6, 21, 28, 30, 48, 53, 54). A potentially useful approach for ¹⁸F-FDG PET is dual-phase imaging. It was shown previously that delayed ¹⁸F-FDG imaging 3–8 h after injection improves the distinction between tumor and normal gray matter because the outflow of glucose was hypothesized to be higher from normal brain tissue than from the tumor. This was confirmed using kinetic modeling (KM) showing that the dephosphorylation rate of FDG-6 phosphate values were not significantly different between tumor and normal brain tissue at early imaging times but was lower in tumor than in normal brain tissue at delayed imaging times (55–58). Applying conventional and delayed ¹⁸F-FDG PET, Horky et al. found that early and late SUVs of the lesion alone did not differentiate between tumor and necrosis. However, the change of LNR_max between early and late ¹⁸F-FDG images was 95% sensitive, 100% specific, and 96% accurate (58). In our study, we found that differences in LNR_mean and LNR_max between GB and RN were higher on the delayed PET images compared to the conventional ¹⁸F-FDG PET. A plausible explanation is that, like normal brain tissue, necrotic tissue shows increased ¹⁸F-FDG excretion at delayed times when compared with tumor (56). Consequently, the LNR increases over time for tumor but remained stable or even decreased for RN (58).

Figure 3 Contrast-enhanced MRI (A and F) and PET of glioblastoma (top row) and radiation necrosis (bottom row). For clarity, the rat brain is contoured in white. ¹⁸F-FDG PET 40-60 min post-injection (B,G) and 240 min post-injection (C,H), ¹⁸F-FCho PET 10-20 min post-injection (D,I), ¹⁸F-FET PET 35-55 min post-injection (E,J) (49).

AMINO-ACID PET

Radiolabeled amino acids are the most commonly used PET tracers for imaging brain tumors. An advantage over ¹⁸F-FDG is the relatively low uptake of amino acids by normal brain tissue. Therefore, cerebral gliomas can be distinguished from the surrounding normal tissue with higher contrast, see Figure 2B (40, 41). Labeled amino acid tracers developed so far for PET imaging are divided into two categories: tracers actively incorporated into the proteins, such as ¹¹C-Methionine (¹¹C-MET), potentially allowing investigating protein synthesis, and tracers not integrated into proteins, such as ¹⁸F-fluoroethyltyrosine (¹⁸F-FET) and 3,4-dihydroxy-6-¹⁸F-fluoro-l-phenylalanine (¹⁸F-FDOPA), which are valuable tools to evaluate amino acid transport (59). The increased uptake of ¹⁸F-FET and ¹⁸F-FDOPA by cerebral glioma tissue appears to be caused mainly by increased transport via sodium-independent amino acid transport system L for large neutral amino acids (LATs) and Na⁺-dependent general amino acid transporters B^0,+ and B⁰, with a disruption of the BBB not being a prerequisite for intratumoral accumulation (20, 60–62). Most PET studies of cerebral gliomas have been performed with ¹¹C-MET, although the short half-life of ¹¹C (20 min) limits the use of this tracer to the few centers that are equipped with an on-site cyclotron facility. Results with ¹⁸F-FET PET are similar to those with ¹¹C-MET (63), and due to its longer half-life (109 min) and lack of (or minimal) uptake in macrophages and inflammatory cells, ¹⁸F-FET PET is preferred for clinical use (56, 59, 61, 64–67). The diagnostic potential of ¹⁸F-FET PET in brain tumors is well documented, for example, a superior delineation of human gliomas by ¹⁸F-FET PET compared with MRI and a high specificity for the detection of gliomas and biopsy site planning (31, 64, 68). Among WHO grades III and IV gliomas, the vast majority (>95%) shows increased ¹⁸F-FET uptake. However, a lack of ¹⁸F-FET uptake does not exclude a glioma, as approximately one-third of WHO grade II gliomas and most dysembryoplastic neuroepithelial tumors (WHO grade I) are ¹⁸F-FET negative (6). Several studies have also indicated that time–activity curves of ¹⁸F-FET uptake contain biological information beyond that of static images, and these data may be helpful for glioma grading (31). In HGGs, uptake patterns of ¹⁸F-FDOPA are not significantly different from ¹⁸F-FET, but both SUV_mean and LNRs were 10–15% higher for ¹⁸F-FET than ¹⁸F-FDOPA (69).

Current amino acid PET data suggest that deactivation of amino acid transport and/or decrease of the metabolically active tumor volume is a sign of treatment response associated with long-term outcome (6, 70–73). Treatment response and outcome in bevacizumab therapy has been suggested to be better assessed by ¹⁸F-FET and ¹⁸F-FDOPA, compared to MRI (6, 74–77). Also, reliable monitoring of TMZ and nitrosourea-based chemotherapy effects has been demonstrated in patients with recurrent HGG (9, 31, 64, 66, 70, 71). In a study by Rachinger et al., ¹⁸F-FET PET was able to distinguish tumor progression from stable disease with 93% specificity and 100% sensitivity, while the specificity of conventional MRI alone was 50% (78). ¹⁸F-FET PET responders, based on a decrease of more than 10% of LNR after completion of therapy, also showed a significant longer overall survival than nonresponders (60). The biological tumor volume on ¹⁸F-FET PET prior to chemoradiotherapy and as early as 7–10 days after the completion of treatment in GB was also found to be highly prognostic. Remarkably, the time-to-peak and the shape of the ¹⁸F-FET time–activity curve, derived from dynamic PET acquisitions, were shown to have value in therapy response assessment (6, 60, 70, 79, 80).

A promising role of amino acid PET for the distinction between tumor recurrence and benign post-therapeutic changes has also been suggested. The LNR of ¹¹C-MET PET revealed a sensitivity and specificity of 70–80% for the differentiation of brain metastasis recurrence from radiation-related effects (31). A higher diagnostic accuracy was shown by Grosu et al., with ¹¹C-MET able to differentiate tumor tissue from treatment-related changes with a sensitivity of 91% and a specificity of 100% (63). Using ¹⁸F-FET PET, the detection of tumor recurrence/progression was even more accurate, with a sensitivity and specificity of 100% and 93%, respectively, compared with 93- and 50% for MRI alone (73, 78). Pöpperl et al. were able to distinguish recurrent tumor and RN with 100% accuracy, applying a threshold of 2.0 for LNR_max, and Galldiks et al. suggested that the combined evaluation of the LNR_mean of ¹⁸F-FET uptake and the pattern of the time–activity curve can differentiate brain metastasis recurrence from RN with high accuracy (70, 73). The lower specificity of ¹¹C-MET may be explained by its higher affinity for macrophages compared with ¹⁸F-FET as demonstrated in animal experiments (81, 82). In our study, ¹⁸F-FET uptake in GB was more intense and more heterogeneous compared to RN, see Figure 3E. It was already mentioned that focal and high ¹⁸F-FET uptake was suspicious for tumor recurrence, whereas low and homogeneous uptake around the resection cavity was considered benign due to post-treatment alterations of the BBB (73). Furthermore, amino acid PET was assumed to be superior to both ¹⁸F-FCho PET and ¹⁸F-FDG PET for diagnostic accuracy in distinguishing glioma recurrence from RN (6, 49, 50, 83). Using ¹⁸F-FDOPA PET, a sensitivity and specificity of more than 80% to distinguish recurrent GB or recurrent brain metastasis and radiation-related effects was shown (25, 84). However, the lack of physiological ¹⁸F-FET uptake in the basal ganglia when compared with ¹⁸F-FDOPA PET makes ¹⁸F-FET the most promising amino acid tracer for PET imaging in brain tumor patients (31). However, it should be kept in mind that (moderately) increased ¹⁸F-FET uptake can also be seen in acute inflammatory lesions such as active multiple sclerosis and brain abscesses (6).

¹⁸F-FLUOROMETHYLCHOLINE (¹⁸F-FCHO)

Positron-labeled choline analogues appear to be successful as oncological PET probes because a major hallmark of cancer cells is increased lipogenesis (85, 86). Phosphorylation by choline kinase (CK) constitutes an important step in the incorporation of choline into phospholipids, which is an essential component of all cell membranes. In cancer, there is often an increase in the cellular transport and phosphorylation of choline, as well as an increase in the expression of CK, increasing the uptake of radiolabeled choline (87–89). Choline can be labeled with either ¹¹C or ¹⁸F. As a tracer, ¹¹C-Cho is biochemically indistinguishable from natural choline; however, the short half-life of ¹¹C has led to the development of ¹⁸F-labeled derivatives, such as ¹⁸F-Fluoromethylcholine (¹⁸F-FCho) (90, 91). Previous in vitro studies have clearly documented that these fluorinated choline analogues are suitable substrates for the enzyme CK (90, 92), although the rate of their incorporation in phospholipids may be slower than that of endogenous choline (93). ¹⁸F-labeled choline analogues have been investigated as oncological PET probes for the detection of (recurrent) local prostate cancer, but seem to have limited value for tumor and nodal staging. Rapidly proliferating GB cells have increased membrane/fatty acid requirements, which result in a higher ¹⁸F-FCho uptake than in healthy brain tissue (86). Kwee et al. showed promising results for ¹⁸F-FCho in brain tumor PET imaging with a differential uptake in HGG, brain metastases, and benign lesions (87). One of the assets of this tracer is the very low uptake in normal brain, increasing distinctively the contrast between GB and healthy brain, see Figure 2C. Changes in ¹⁸F-FCho uptake may also precede post-treatment anatomical changes on conventional MRI (86). However, only a few studies investigated the potential of ¹⁸F-FCho for therapy response assessment in gliomas. Li et al. reported that, for ¹¹C-Choline PET, an LNR≤1.4 might predict a longer overall survival in patients with suspected recurrent glioma after treatment (94). Parashar et al. suggested that there was a good correlation between a change in SUV_max of the tumor during RT and response (95). However, in the latter study, only one patient with a malignant glioma was included. Our research group recently investigated the potential of ¹⁸F-FCho PET for early therapy response assessment in GB patients; see Figure 4 (96). Based on our results, ¹⁸F-FCho SUV values pre-RT, during RT, and 1 month post-RT did not predict response. Physiological phenomena, such as therapy-induced perfusion changes due to alteration of BBB, cell repair mechanisms obscuring assessment of true cell death, and aspecific uptake of PET tracers due to infiltrating macrophages, may complicate response assessment. It should also be kept in mind that GBs are very heterogeneous tumors, containing clusters of tumor and normal cells, vascular structures, and necrotic tissues (29), which are not fully captured when using SUV_max or SUV_mean values. Based on our results, we also noted that in some nonresponders, absolute SUV values decreased during the course of the treatment while the metabolic tumor volume (MTV) increased, indicating that MTV is an important parameter. As such, we found that the ¹⁸F-FCho PET-derived parameter, MTV x SUV_mean, allowed prediction of therapy response as early as 1 month after the completion of RT. Interestingly, the tumor volume derived from contrast-enhanced MRI was able to predict response earlier, that is, at week 6 during RT. However, due to the possibility of pseudoprogression, inclusion of PET in the RANO criteria might be helpful for early therapy response prediction in HGG.

Figure 4 ¹⁸F-Fluoromethylcholine (¹⁸F-FCho) PET and contrast-enhanced T1-weighted MR images in 3 GB patients (a,b,c). (a) A 47-year old female patient diagnosed with GB in the right frontal and temporal lobe. According to the RANO criteria the patient is categorized as a partial responder. A 60 % decrease in SUV_max and SUV_mean is observed from pre-RT to 1 month post-RT. (b) A 71-year old male patient diagnosed with a bifrontal GB. According to the RANO criteria, the patient was categorized as stable disease. From pre-RT to 1 month post-RT, SUV_max decreased 17 % while SUV_mean remained more or less stable. (c) A 66-year old male patient diagnosed with multifocal GB. A new lesion was visible on follow-up MRI, categorizing the patient as progressive disease. From pre-RT to 1 month post-RT SUV_max and SUV_mean decreased 52 % and 59 % respectively, while MTV increased with > 300 % (96).

Finally, ¹⁸F-FCho PET was assumed to be promising in differentiating GB from RN (47, 52, 97). ¹⁸F-FCho PET was studied in patients with solitary brain lesions and correctly identified patients with RN based on LNR (87). Tan et al. showed higher sensitivity and specificity for ¹¹C-Cho PET compared to MRI and ¹⁸F-FDG, and Spaeth et al. noted a higher ¹⁸F-FCho uptake in HGG compared to acute radiation injury (52, 97). Although promising results for the differentiation of RN and tumor recurrence in gliomas were reported, in our in vivo animal experiment, ¹⁸F-FCho was not able to differentiate “pure” GB from “pure” RN; see Figure 3D (87, 97). Using KM and graphical analysis, we tried to interpret these results. However, we could not confirm an increased choline transporter-like protein-mediated transport, nor a higher expression of CK in GBs compared to RN. The immediate metabolization of choline raises the question if ¹⁸F-Fluorobetaine attributes to the detected choline signal, and the uptake in RN is influenced by leakage through the damaged BBB and inflammation (93, 98–101). As such, correlative imaging with MRI is of utmost importance (85). Also, it should be kept in mind that the metabolism of choline tracers in humans is slower than in rodents.

HYPOXIA-PET

Hypoxia is a pathological condition arising in living tissues when oxygen supply does not adequately cover the cellular metabolic demand. Detection of this phenomenon in tumors is of utmost clinical relevance because tumor aggressiveness, metastatic spread, failure to achieve local tumor control, increased rate of recurrence, and ultimate poor outcome are all associated with hypoxia (39, 102, 103). A number of hypoxia tracers are available for PET. The first introduced hypoxia tracer is called ¹⁸F-fluoromisonidazole (¹⁸F-FMISO). After passive diffusion through the membrane and in the presence of reduced pO₂, ¹⁸F-FMISO undergoes progressive reduction by the nitroreductase enzyme (NTR). This process is reversible in the presence of sufficient O₂. Conversely, in hypoxic conditions, the reduced ¹⁸F-FMISO is covalently bound to the intracellular proteins, resulting in tracer accumulation within the hypoxic cell (39, 40, 45, 88). To date, ¹⁸F-FMISO has predominantly been used in a preclinical setting (79, 104). Concerning its use in therapy response assessment, the volume and intensity of hypoxia on ¹⁸F-FMISO PET in GB before radiotherapy was strongly associated with poorer time to progression and survival (57). However, the slow uptake of ¹⁸F-FMISO in target tissue and slow clearance of unbound ¹⁸F-FMISO from nonhypoxic areas stimulated the development of ¹⁸F-fluoroazomycin arabinoside (¹⁸F-FAZA) with improved pharmacokinetics (39). A highly increased uptake of ¹⁸F-FAZA was observed in all glioma types, with a LNR ranging between 2 and 16 due to low uptake in normal brain tissue (105). Also, in the F98 GB rat model, we observed a high LNR on ¹⁸F-FAZA PET; see Figure 2D. Further prospective studies are however needed before incorporating hypoxia PET in glioma in the clinic. Another promising role for hypoxia PET lies in the era of PET-guided RT in GB.

¹⁸F-FLUOROTHYMIDINE

DNA synthesis is required for cell growth and proliferation. Nucleotides of the four bases (cytosine, guanine, adenine, and thymidine) are required for DNA synthesis. Of these four nucleosides, thymidine is the only one incorporated exclusively into DNA, and not ribonucleic acid (RNA), providing a measure of DNA synthesis (106). ¹⁸F-fluorothymidine (¹⁸F-FLT) has been proposed to directly assess DNA synthesis to estimate tumor cell proliferation and has been proposed for therapy monitoring, based on the concept that change in DNA synthesis should be the most direct index of therapeutic effects on tumor proliferation (59). A direct correlation between ¹⁸F-FLT uptake and Ki67 expression in tumor cells has been documented (56), leading to the use of this tracer in many tumor types as a surrogate for aggressiveness and an early marker of response (39, 56, 107–111). Obviously, tumor size is an important prognostic indicator, and tumor volume determined by ¹⁸F-FLT was assumed to be a better predictor of overall survival than the intensity of uptake (112). In preclinical GB models, early therapy response to chemotherapeutic and/or antiangiogenic therapy could be predicted via ¹⁸F-FLT PET (113–115). This was confirmed in recurrent glioma patients treated with bevacizumab and irinotecan showing that ¹⁸F-FLT is able to predict overall survival and would allow differentiation between recurrent glioma and RN (56, 116, 117). A high LNR of a GB tumor on ¹⁸F-FLT PET is visible in Figure 2F (9). However, the sensitivity for the detection of HGG might be lower than required for clinical application, and dependence of ¹⁸F-FLT uptake on BBB disruption raises the question of its specificity (59).

NOVEL PET TRACERS

Currently, novel promising glioma PET tracers are under investigation. The value of new amino acid PET tracers, such as α-¹¹C-methyl-tryptophan and ¹⁸F-Fluciclovine as well as glutamine-based amino acid PET tracers has been evaluated with promising results in glioma patients in terms of tumor delineation, prognostication, and the differentiation of tumor recurrence from radiation injury (31, 118–122). Another interesting new PET target is the translocator protein (TSPO), a mitochondrial membrane protein highly expressed in activated microglia, macrophages, and neoplastic cells. Imaging with the TSPO ligand ¹¹C-(R)PK11195 demonstrates increased binding in HGG compared to low-grade gliomas and normal brain parenchyma (123, 124). More recently, the TSPO ligand ¹⁸F-DPA-714 has been evaluated in glioma animal models, but results in human glioma patients are pending (31, 125, 126). A novel labeled integrin α_vβ₃-targeting ¹⁸F-AIF-NOTA-PRGD2 (¹⁸F-RGD) tracer showed positive results in assessing sensitivity to concurrent chemoradiotherapy in GB. An example is given in Figure 2G (44, 26). Another approach was published by Oborski et al., suggesting the ability to image therapy-induced tumor cellular apoptosis using ¹⁸F-2-(5-fluoro-pentyl)-2-methyl-malonic acid (¹⁸F-ML-10) for early therapy response assessment of a newly diagnosed GB patient (127).

Conclusion

The identification of new MRI and PET biomarkers and their inclusion in the RANO criteria may be helpful for early therapy response prediction in HGG. However, it is difficult to compare results of individual studies because of methodological differences and varying clinical endpoints (128). As such, standardization and validation are needed first.

Acknowledgment: The authors would like to thank Stichting Luka Hemelaere and Soroptimist International for supporting this work.

Conflict of interest: The authors declare no potential conflicts of interest with respect to research, authorship, and/or publication of this manuscript.

Copyright and permission statement: To the best of our knowledge, the materials included in this chapter do not violate copyright laws. All original sources have been appropriately acknowledged and/or referenced. Where relevant, appropriate permissions have been obtained from the original copyright holder(s).

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