There are approximately 16,900 new cases of primary central nervous system tumors diagnosed in the United States each year. The incidence of these tumors has increased significantly in the last decades.1 About 50% of these lesions are supratentorial high-grade gliomas. Anaplastic astrocytoma (World Health Organization grade 3) and glioblastoma multiforme (GBM) (World Health Organization grade 4) are the most common glial primary brain tumors.2,3 Patients with newly diagnosed malignant gliomas are usually treated with surgical debulking or resection, followed by radiation therapy and/or chemotherapy, depending on their functional status. With recent advances in chemotherapy, such as temozolomide and combined modality treatment for glial brain tumors, the proportion of long-term survivors has increased from less than 5% to between 15% and 20%.4 However, overall survival for GBM remains poor even with the addition of temozolomide drug therapy. A recent study showed a median survival of 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone.5
A particularly problematic aspect of the management of patients with brain tumors is the development of a new enhancing lesion on a gadolinium-enhanced MRI (Gd-MRI) within the radiation field, which could indicate either recurrent tumor or radiation necrosis. The distinction between these 2 entities is difficult by conventional imaging techniques alone and typically requires either biopsy or longitudinal observation, which complicates and greatly affects short-term patient management.
18F-FDG PET has been used to differentiate recurrent tumor from radiation necrosis for nearly 30 years.6 The literature reveals disparity in the performance of 18F-FDG PET for this application. Typical sensitivities are reported between 81% and 86%, although some results are reported to be greater, up to 100%.7–11 Sensitivity may be complicated by high metabolic activity in adjacent cortex and partial volume effects because of small lesions. Estimates of specificity are lower, ranging from 22% to 92%. Specificity may be compromised by metabolic activity in areas of posttreatment inflammatory change.
18F-fluorothymidine (FLT) is a radiopharmaceutical that has been shown to directly assess tumor proliferation using PET.12–16 18F-FLT PET has been shown to be a marker of tumor aggressiveness and overall therapeutic response.14–17 18F-FLT does not localize to normal brain because of low proliferative activity and because it does not cross an intact blood-brain barrier. Methods have been developed and validated to model the kinetic features of 18F-FLT PET by tumors, and the necessity for this kinetic modeling is thought to be critical in distinguishing nonspecific uptake of FLT from that pertaining to new DNA synthesis and cell proliferation.15,18–20 Several studies have shown significant 18F-FLT uptake in higher-grade primary brain tumors.21–23 To date, only 1 preliminary published comparison has been made between 18F-FLT PET and 18F-FDG PET in distinguishing recurrent glioma from radiation necrosis, and this report showed a significantly poorer performance of 18F-FDG PET than typically reported elsewhere.24 The primary objective of the current study was to compare the efficacy of quantitative and visual assessments of 18F-FDG and 18F-FLT PET in differentiating radiation necrosis from recurrent moderate to high-grade gliomas (≥grade 2).
MATERIALS AND METHODS
All studies were performed with approval from the institutional review board and the provision of signed informed consent by each patient. Enrolled subjects included 15 evaluable adult patients (9 men and 6 women aged 22–75 years) with histologically proven grade 2 or worse glial-based primary brain tumors. All patients had been treated with radiation, with or without chemotherapy. Radiation therapy had been completed a minimum of 4 months before study entry. All subjects had a new enhancing lesion within the radiation field demonstrated by a clinical Gd-MRI. This lesion was interpreted as consistent with either radiation necrosis or recurrent tumor. All subjects had also undergone a clinical 18F-FDG PET of the brain within 1 month of the Gd-MRI for the purpose of differentiating radiation necrosis from tumor recurrence. Enrolled subjects consented to undergo an additional PET scan with 18F-FLT, which, in all cases, was performed within 3 weeks of the clinical 18F-FDG PET.
Exclusion criteria were pregnancy or lactation (a negative pregnancy test was required for premenopausal women), clinically significant signs of uncal herniation (such as acute pupillary enlargement, rapidly developing motor changes, or rapidly decreasing level of consciousness), known allergic or hypersensitivity reactions to previously administered radiopharmaceuticals, and the requirement of monitored anesthesia for PET scanning.
All Gd-MRI scans were performed according to clinical protocols on Siemens 1.5- or 3-T systems (Erlangen, Germany) with the following parameters: sagittal T1 fast spin echo (FSE), axial T1 FSE, axial T2 FSE, axial FLAIR inversion-recovery, axial gradient recalled echo, axial diffusion tensor imaging, or diffusion-weighted imaging, as well as axial and coronal T1-weighted images after the administration of IV gadolinium (Gd-DTPA). The presence of a new or enlarging area of enhancement within the radiation port and follow-up assessment of progression, stability, or regression of this specific lesion were characterized by an experienced neuroradiologist (L.Z.), independent of a separate clinical report.
All 18F-FDG PET scans were performed according to clinical protocol. Patient preparation included 6 hours without caloric intake or insulin administration. Then, 370 MBq (10 mCi) of 18F-FDG was given intravenously through a peripheral vein. Patients rested quietly in a recliner during the uptake interval (45 minutes), without physical activity and with minimal vocalization. A 18F-FDG PET scan was performed for 30 minutes over a single bed position using a GE Advance PET scanner (Milwaukee, Wis) in 3-dimensional mode, with transmission attenuation correction performed for 5 minutes using a rotating 68Ge rod source. Images were reconstructed using the 3-dimensional reprojection algorithm.
The 18F-FLT studies were investigational and conducted under an investigational new drug (IND) for FLT. The 18F-FLT was synthesized by methods previously reported,25,26 FLT average specific activity was 7368 Ci/mmol (5170–11,669 Ci/mmol). After positioning for a dynamic brain scan, 18F-FLT was infused for 1 minute via an infusion pump or by slow bolus, followed by a saline flush. An injected dose of approximately 370 MBq or (10 mCi) maximum was administered. A 70-minute dynamic brain imaging was then performed. The plasma input function was sampled using either a catheter placed in a radial artery or an arterialized venous blood using the heated hand methodology.27,28 Twelve blood samples were rapidly drawn during the first 120 seconds after injection, with additional samples obtained at 3, 4, 5, 7, 10, 15, 20, 30, 45, and 60 minutes after injection. All blood samples were corrected for radiolabeled metabolites by the simplified column chromatography method of Shields et al,29 and the activity concentration of unmetabolized 18F-FLT in plasma was calculated as a function of time. The 18F-FLT PET images were reconstructed using 3 iterations ordered-subsets expectation-maximization with 32 subsets, and a 2.79-mm postreconstruction Gaussian smoothing filter was applied. Static images for SUV calculation were computed by combining dynamic time frames from 60 to 70 minutes after injection. Patlak graphical analysis was applied using the metabolite-corrected plasma input function to obtain voxel-wise estimates of the FLT metabolic influx parameter Kimax, also commonly referred to as KFLT or FLT KFLUX .15,18–20
18F-FDG PET Imaging
18F-FDG PET images were fused with the most recent prior Gd-MRI T1 postcontrast images for target lesion confirmation. Visual (qualitative) assessment of 18F-FDG PET and 18F-FLT PET was performed, and the deidentified scans were independently scored in random order by 2 experienced PET readers (J.H. and K.M.), based on a 5-point receiver operating curve (ROC) scale as to confidence of tumor recurrence: 1 = definitely recurrence, 2 = probably recurrence, 3 = unable to differentiate recurrence from necrosis, 4 = probably necrosis, and 5 = definitely necrosis. The presence of tumor was defined as a value of 1, 2, or 3, and radiation necrosis was defined as a value of 4 or 5. Although the value of 3 indicated an indeterminate lesion, these cases were scored as positive for tumor in the dichotomous paradigm. This designation was made based on similar situations that arise in the clinical setting, where an indeterminate lesion is treated as tumor if not clearly identifiable as necrosis.
For 18F-FDG PET, the SUVmax with correction for body weight was measured at suspicious area of enhancement on Gd-MRI. SUVmean and SUVpeak were not recorded because many of the lesions were small and irregular, making such measures subjective and sensitive to user variability in region-of-interest definition and partial volume effect errors. The ratio of 18F-FDG SUVmax of the suspicious lesion to that of the SUVmean of a 1-cm-diameter region of normal (based on 18F-FDG PET and Gd-MRI) contralateral white matter was measured.
18F-FLT PET Imaging
Visual confidence scoring based on a 5-point ROC scale was performed in the same fashion as for 18F-FDG PET scans. Similarly, the FLT SUVmax and Kimax were recorded at the site of the suspicious target lesion on Gd-MRI.
On the basis of 2 to 33 months of observation, and established by review of the clinical reports with independent agreement by an additional neuroradiologist (L.Z.), confirmation of recurrent tumor was defined as a definitive increase in size of the lesion by Gd-MRI. Radiation necrosis was defined as stability or regression of this specific lesion over time, even in the face of advancing disease in noncontiguous sites. ROC analysis was performed for both quantitative and visually scored data. Approximate sensitivities and specificities were derived from optimized cutoff values. Differences between recurrent tumor and radiation necrosis for the means of individual quantitative parameters were assessed by the Kruskal-Wallis 1-way analysis of variance, with significance defined as P ≤ 0.05.
No adverse events were noted with the use of the investigational imaging agent 18F-FLT. The tumor features, tabulated imaging data, and lesion-specific outcome for each subject are shown in Table 1. Table 2 summarizes the ROC analysis of the continuous (quantitative data). Table 3 summarizes the ROC analysis for the visual confidence scores of the 18F-FDG PET and 18F-FLT PET scans. Figures 1 to 3 provide illustrative examples of individual cases. Among the 15 patients enrolled, 10 had glioblastoma multiforme, 3 had grade 2 oligodendroglioma, 1 had grade 2 astrocytoma, and 1 had oligoastrocytoma. On the basis of longitudinal observation by Gd-MRI at the specific site of interest, of all 15 patients, 11 proved to have lesion-specific recurrent tumor and 4 had radiation necrosis. Those with radiation necrosis included 3 patients with glioblastoma multiforme and 1 patient with grade 2 astrocytoma.
On the basis of the Kruskal-Wallis 1-way analysis of variance for nonparametric data, there was a statistically significant difference (P = 0.019) between the 18F-FDG SUVmax for tumor (mean, 8.19; range, 5.3–12.1) compared with that for radiation necrosis (mean, 5.45; range, 4.3–6.5). There was also a significant difference (P = 0.006) between the 18F-FDG ratio lesion–contralateral white matter (mean, 2.83; range, 1.83–3.96) compared with that for radiation necrosis (mean, 1.47; range, 1.13–2.03). There was a significant difference (P = 0.026) between the 18F-FLT Kimax for tumor (mean, 0.0225; range, 0.0127–0.0294) compared with that for radiation necrosis (mean, 0.0109; range, 0.0027–0.1233). However, there was no significant difference (P = 0.068) between the 18F-FLT SUVmax (mean, 1.54; range, 1.13–2.02) for tumor compared with that for radiation necrosis (mean, 0.881; range, 0.226–1.44).
As summarized in Table 2, ROC analysis was performed for the continuous-variable quantitative data (18F-FDG SUVmax, 18F-FDG ratio lesion–contralateral white matter, 18F-FLT SUVmax, and 18F-FLT Kimax). The relative ranking of test performance [area under the curve (AUC), confidence interval (CI)] was as follows: FDG ratio lesion–contralateral white matter > (AUC, 0.98; CI, 0.91–1.00) > 18F-FDG SUVmax (AUC, 0.91; CI, 0.75–1.00) > 18F-FLT Kimax (AUC, 0.89; CI, 0.69–1.00) > 18F-FLT SUVmax (AUC, 0.82; CI, 0.56–1.00). Within these test (“training”) groups, individual data points were examined, and putative optimized cutoff values for quantitative parameters were identified, which resulted in the best sensitivities and specificities. For 18F-FDG PET, recurrent tumor was best identified with a ratio of 18F-FDG lesion–contralateral white matter ≥ 1.83 (sensitivity, 100%; specificity, 75%) and an FDG SUVmax ≥ 6.20 (sensitivity, 90.9%; specificity, 75%). For 18F-FLT PET, recurrent tumor was best identified by an 18F-FLT Kimax ≥ 0.0165 (sensitivity, 91%; specificity, 75%) and an 18F-FLT SUVmax ≥ 1.34 (sensitivity, 73%; specificity, 75%).
As summarized in Table 3, ROC analysis was also performed for visually scored data for 18F-FDG PET and 18F-FLT PET by 2 experienced nuclear medicine physicians. The area under the ROC curve for 18F-FDG PET was 0.93 (CI, 0.80–1.00). The area under the ROC curve for 18F-FLT PET was 0.86 (CI, 0.67–1.00). On the basis of a predetermined cutoff value of tumor of 3 or lower for the visual confidence score, the sensitivity and specificity values were as follows: 91% and 50% for 18F-FDG PET, respectively; and 81% and 50% for 18F-FLT PET, respectively.
18F-FDG PET has been used to differentiate recurrent tumor from radiation necrosis in patients with primary brain tumors for nearly 30 years with a broad range of reported sensitivities and specificities.6–11 Recurrent tumor is typically identified by visually appreciable increased metabolic activity in the lesion of interest compared with normal white matter. No specific quantitative parameters have been broadly adopted in the distinction of recurrent tumor from radiation necrosis.
Alternative imaging methods have also been used to distinguish recurrent tumor from radiation necrosis, including magnetic resonance spectroscopy (MRS), which is limited by lack of reimbursement and technical challenges.30,31 Newer MRI techniques, such as arterial spin labeled, and dynamic susceptibility and contrast methods show promise but require validation.32–34 11C-methionine and 13N-ammonia PET also show potential.35–39
A number of studies have suggested that dynamic kinetic modeling is necessary to ensure that 18F-FLT uptake is due to specific mechanisms.15,18–20 Dynamic kinetic modeling requires extended dynamic imaging in a single bed position, limiting analysis to a specific target field of view. It is also necessary to draw 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 the 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 adopted in clinical practice because of the complexity of the procedure. To assess the necessity for dynamic 18F-FLT imaging, we compared both 18F-FLT SUVmax derived from the interval from 60 to 70 minutes after injection to the metabolite-corrected Patlak Kimax derived from the plasma input function. There was a significant difference between recurrent tumor and radiation necrosis for 18F-FLT Kimax but not for 18F-FLT SUVmax. Although a larger sample size may show a significant difference between recurrent glioma and radiation necrosis for 18F-FLT SUVmax, these data support numerous previous reports that dynamic kinetic modeling of 18F-FLT PET is necessary to ensure optimal results.19,20,24
For 18F-FDG SUVmax, 18F-FDG ratio lesion–contralateral white matter, and 18F-FLT Kimax, there was a significant difference between mean values for recurrent tumor and radiation necrosis. The overall ranking of the performance of all quantitative and semiquantitative tests in distinguishing recurrent tumor from radiation necrosis was as follows: 18F-FDG ratio lesion–contralateral white matter > 18F-FDG SUVmax > 18F-FLT Kimax > 18F-FLT SUVmax. Each of these parameters showed an equal specificity (75%). Although this would require independent confirmation in a separately validated study, an optimized cutoff lesion–contralateral white matter 18F-FDG ratio of 1.83 or higher for recurrent tumor in this series resulted in the highest sensitivity (100%) in distinguishing recurrent glioma from radiation necrosis.
The visual assessment of the likelihood of tumor by 2 experienced readers also performed well in distinguishing recurrent tumor from radiation necrosis. However, 18% of the subjects (2/11) with recurrent tumor and a confidence score of 1 or 2 by 18F-FDG PET had little or no uptake of 18F-FLT in the region of tumor (score of 4 or 5). Of all patients with radiation necrosis, 50% (2/4) had mild 18F-FLT accumulation at the site of radiation necrosis (scored as 3 on the ROC visual confidence score), presumably because of a nonspecific leakage of 18F-FLT across a disrupted blood-brain barrier. Visual assessment would be expected to vary as a function of reader experience. In clinical practice, where a broad range of reader expertise would be expected, semiquantitative assessment of 18F-FDG uptake would likely be more reproducible that visual assessment.
Although both visual and quantitative assessments of 18F-FDG and FLT uptake on PET performed well, this study suggests that 18F-FLT PET offers no advantage over 18F-FDG PET in the distinction between recurrent tumor and radiation necrosis for moderate- and high-grade gliomas (≥grade 2). In this series, a ratio of 1.83 or higher of 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%), but this requires independent validation.
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