Differentiation of tumor recurrence from radiation necrosis in high-grade gliomas using 201Tl-SPECT

Available online at www.sciencedirect.com

Journal of Clinical Neuroscience 15 (2008) 1327–1334 www.elsevier.com/locate/jocn

Clinical Study

Differentiation of tumor recurrence from radiation necrosis in high-grade gliomas using 201Tl-SPECT Jeanne Tie a,*, Dishan H. Gunawardana a,b, Mark A. Rosenthal a a

Department of Medical Oncology, Royal Melbourne Hospital, Grattan Street, Parkville, Victoria 3050, Australia b Department of Nuclear Medicine, Royal Melbourne Hospital, Parkville, Victoria, Australia Received 2 December 2007; accepted 17 December 2007

Abstract MRI is routinely performed to detect recurrence in patients with primary brain tumors, but it may not differentiate recurrent tumor from radiation-induced necrosis reliably. Thallium-201 single-photon emission computed tomography (201Tl-SPECT) might be useful in distinguishing between these two clinical entities. In a retrospective study 201Tl-SPECT studies with corresponding MRI studies in 19 patients with clinical or radiological suspicion of high-grade tumor recurrence were reviewed. The diagnostic accuracies of both modalities were based on the subsequent histology or clinical course where biopsy was not performed. Post-scan histology was available in nine patients (43%) who underwent re-resection. The SPECT result determined management in six patients (29%). Post-SPECT survival was significantly better in patients with negative 201Tl-SPECT studies compared to patients with positive studies (median survival 15 + vs. 6 months) (p = 0.04, log-rank test). The sensitivity and specificity of 201Tl-SPECT in diagnosing tumor recurrence were 83% and 100%, respectively. 201Tl-SPECT can accurately differentiate tumor recurrence from radiation necrosis in patients with high-grade gliomas and abnormal MRI findings post irradiation. This is reflected in a significantly longer post-scan survival time in patients with a negative 201 Tl-SPECT result. Ó 2008 Elsevier Ltd. All rights reserved. Keywords:

201

Tl-SPECT; Radiation necrosis; High-grade gliomas

1. Introduction Management of high-grade gliomas remains one of the greatest challenges in oncology, requiring a multidisciplinary approach, which consists of cytoreductive surgery, radiation therapy and chemotherapy. Nonetheless, these tumors recur almost invariably, with a median survival of 14.6 months in patients with glioblastoma multiforme treated with concurrent radiotherapy and temozolomide followed by 6 months of adjuvant temozolomide.1 Serial MRI is routinely performed in these patients after primary treatment to detect tumor recurrence. However, conventional contrast-enhanced CT scans or MRI cannot reliably distinguish radiation necrosis from recurrent *

Corresponding author. Tel.: +61 3 93413155; fax: +61 3 93413104. E-mail address: [email protected] (J. Tie).

0967-5868/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2007.12.008

tumor. Both entities can cause extensive edema and blood–brain barrier disruption that result in mass effect and abnormal contrast enhancement.2,3 Radiation-induced necrosis often occurs within 2 years after radiation therapy, the same time frame during which tumor recurrence is most frequent.4 Differentiation between tumor progression and radiation necrosis carries obvious prognostic and therapeutic implications. To overcome this problem, several functional and physiological imaging techniques, such as MR spectroscopy (MRS), perfusion-weighted MRI, positron emission tomography (PET), and thallium-201 single-photon emission computed tomography (201Tl-SPECT) have been examined for clinical use.5–12 Radiothallium (201Tl) is a monovalent cationic radioisotope with biological properties similar to potassium.13 Experimental evidence suggests that the ionic movement of thallium and potassium are

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related to active transport through an adenosine triphosphate (ATP) cell membrane pump, and that 201Tl uptake is related to cell growth rates.14 Previous studies showed substantial 201Tl uptake in brain tumors with little uptake in normal brain.15,16 In the mid-1980s, noting the disparity between clinical status and CT scan results in patients with gliomas, Kaplan et al. found 201Tl to be superior to CT scans, gallium-67 citrate and technetium-99m gluceptate in identifying viable tumors.11 Subsequently, other studies suggest that 201Tl-SPECT may be a useful method to differentiate between tumor recurrence and radiation necrosis.12,17–20 We use 201Tl-SPECT in our centre to clarify equivocal MRI findings in patients with post-irradiated brain tumors. Although previous studies have examined the accuracy of 201 Tl-SPECT in differentiating radiation necrosis from recurrent tumor, its impact on clinical decision making has not been explored. The aim of this study was to establish the value of 201Tl-SPECT in differentiating radiation necrosis from recurrent tumor, and its influence on therapeutic decision making in a cohort of patients with postirradiated high-grade gliomas and abnormal MRI findings.

progressive disease, radiation necrosis or equivocal. MRI findings were considered equivocal if the reporting radiologist believed that the area of abnormality could be due to either tumor recurrence or radiation damage.

2. Patients and methods

2.4. Clinicopathologic follow-up

2.1. Patients

We made the final differentiation between recurrent tumor and radiation necrosis based on subsequent histological or, in cases where biopsies were not available, on subsequent clinical and/or radiological findings. Histological confirmation within 4 months of the 201Tl-SPECT was available in 9 cases. In the remaining patients, a clinical diagnosis of tumor recurrence or radiation necrosis was made on the basis of the patient’s clinical course 6 months after the 201Tl-SPECT. Tumor recurrence was defined by progressive clinical deterioration or an increase in size of the suspicious brain lesion on serial MRI. Radiation necrosis was defined by stabilization or improvement in both the clinical condition and the abnormal finding on MRI.

We identified 19 consecutive patients with primary brain tumors who underwent 201Tl-SPECT at the Royal Melbourne Hospital between March 2004 and May 2007. Two patients had two 201Tl-SPECTs during this time. Therefore, a total of 21 SPECT scans from 19 patients were included in this retrospective analysis. MRIs were performed as routine follow-up evaluation of treated brain tumors, or when there was clinical suspicion of disease recurrence. In all patients, 201 Tl-SPECT was prompted either by an inconclusive MRI finding showing abnormality compatible with tumor progression and radiation necrosis, or if the treating neuro-oncologist wished to confirm the MRI findings. All patient characteristics, treatment history, clinical status at the time of scan, MRI and 201Tl-SPECT reports, post-scan histology, post-scan clinical course and survival data were extracted from clinical records. 2.2. Imaging 2.2.1. MRI MRIs were performed with a 1.5-T imaging system (Signa Echospeed Plus or Signa Horizon; GE Medical Systems, Milwaukee, WI, USA) at our institution, using a standard protocol including multisequence, multiplanar transverse T2-weighted and T1-weighted images before and after administration of 15 mL of gadolinium (Magnevist, Bayer HealthCare, Pymble, NSW, Australia). Axial fluid-attenuated inversion-recovery (FLAIR) images were also obtained. MRI interpretations were based on our radiologists’ reports and were classified into 3 categories:

2.3. SPECT Thallium-201 at a dose of 125 MBq was administered intravenously and SPECT imaging was performed 15 minutes later. Triple head (MultiSPECT, Siemens, Munich, Germany) or dual head (Symbia T2, Siemens, Munich, Germany) gamma cameras were used for image acquisition. Projection data were acquired with a 128  128 matrix, 40 s per projection. Iterative reconstruction without attenuation correction was performed. SPECT-CT studies were acquired in a few patients, with low dose non-contrast CT scan (130 kV, 120 mAs, 3 mm slice thickness) performed on the Symbia camera for the purposes of anatomical correlation. The nuclear medicine specialist reported SPECT studies as positive or negative based on a qualitative assessment of uptake in the area of interest compared to background brain uptake.

2.5. Influence on management 201

Tl-SPECT was said to have correctly determined management if the 201Tl-SPECT finding was consistent with the final outcome of tumor recurrence or radiation necrosis but was inconsistent with the MRI report. 201TlSPECT was considered to have assisted management when both the imaging findings were consistent with the final outcome. 2.6. Statistical methods Follow-up was complete through to June 2007. Sensitivities, specificities, positive and negative predictive values, and accuracies were calculated for 201Tl-SPECT and MRI. For the purpose of calculating diagnostic accuracies and post-scan survival, both ‘‘equivocal” and ‘‘radiation necrosis” MRI reports were considered negative for tumor

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recurrence. The post-scan survival was calculated from the day of the 201Tl-SPECT to the date of death or the last follow-up. Post-scan survival for positive and negative 201TlSPECT results, and for the MRI reports were estimated by the Kaplan–Meier method. The log-rank test was used to compare the survival curves. Statistical analysis was carried out using GraphPad Prism statistical software (version 4.00.169 17 July 2002, San Diego, CA, USA). 3. Results 3.1. Demographics Patient characteristics and treatment history of the 19 patients in this study are shown in Table 1. Median age

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for all patients was 51 (range, 25–78 years), with three patients above 70 years. All patients had histologically confirmed high-grade gliomas. Seven patients had glioblastoma multiforme, seven had anaplastic astrocytoma, and five had anaplastic oligoastrocytoma. Most patients (89%) had undergone either a complete or partial resection of their gliomas, while the remaining two patients had biopsy only. Twelve patients (63%) received previous chemotherapy (9 temozolomide, and 3 carmustine). Seven MRI reports (33%) were considered equivocal for tumor recurrence or radiation necrosis, 57% suggested progressive disease, and 10% were reported to have stable disease. The median time interval between the end of radiotherapy and the 201Tl-SPECT scans was 15 months (range, 1–204 months). Fusion SPECT-CT scans were performed on three patients.

Table 1 Patient characteristics and treatment history (n = 19)

3.2. Histological confirmation

Sex Male Female

12 7

Age, years Median Range

51 25–78

Histology GBM AA OA

7 7 5

Post-scan histological confirmation was available in nine patients, all of which had evidence of tumor recurrence. The histological diagnosis was the same as at initial surgery in all patients. 201Tl-SPECTs were positive in seven patients and negative in two (Table 2). The sensitivity of 201TlSPECT in detecting tumor recurrence based on histology was 78%. Specificity could not be determined as none of the patients had radiation necrosis only on histology. MRI correctly predicted histological recurrence in six cases with three false negative studies.

Prior surgery Complete excision Partial excision Biopsy

7 10 2

Prior radiotherapy (Gy) Mean Range

59.6 36–80

Prior chemotherapy Temozolomide BCNU

9 3

Clinical status at the time of scana Stable disease Progressive disease

11 10

MRI findingsa Stable disease Progressive disease Inconclusive

2 12 7

Interval between completion of RT and Median Range

Tl-SPECT, monthsa 15 1–204

Of the 12 patients without histological confirmation, eight had evidence of disease progression within 6 months after 201Tl-SPECT. Seven of the 201Tl-SPECT results had correctly predicted tumor recurrence in these eight patients. 201 Tl-SPECT findings were negative in all four patients who continued to be stable (Table 2). The median overall survival predicated by pathology was 8.9 months for glioblastoma multiforme, 29.7 months for anaplastic astrocytoma, and 68.9 months for anaplastic oligoastrocytoma. Table 2 201 Tl-SPECT and MRI findings vs. histology or clinical outcome 201

Tl-SPECT

MRI

201

a

Steroid use at the time of scan Yes No Unknown

3.3. Clinical outcome

6 14 1

BCNU = carmustine; GBM = glioblastoma multiforme; AA = anaplastic astrocytoma; OA = anaplastic oligoastrocytoma; RT = radiation therapy; 201 Tl-SPECT = thallium-201 single-photon emission computed tomography. a These values were based on the total of 21 201Tl-SPECT scans from the 19 patients.

Positive

Negative

PD

Equiv./RN

Clinical status at time of scan Stable 5 Progression 9

6 1

5 7

6 3

Histology Tumor recurrence Radiation necrosis

2 0

6 0

3 0

1 4

5 1

3 3

7 0

Clinical status 6 months post-scan Tumor recurrence 7 Stable disease 0

PD = progressive disease; RN = radiation necrosis; 201Tl-SPECT = thallium-201 single-photon emission computed tomography.

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Table 3 Patients for whom

201

Tl-SPECT correctly determined management

Clinical status

MRI

SPECT

SD (n = 11)

PD Equiv/ RN

— +

PD (n = 10)

PD Equiv/ RN

— +

Histology

Clinical outcome

SPECTdetermined management

N/A Recurrence

RN PD

1/5 3/6

N/A Recurrence

RN PD

0/7 2/3

Total

Table 4 Diagnostic accuracy of

201

Tl-SPECT vs. MRI 201

Sensitivity Specificity Positive predictive value Negative predictive value Accuracy (%)

Tl-SPECT (%)

MRI (%)

84 100 100 57 86

65 75 92 33 67

201

Tl-SPECT = thallium-201 single-photon emission computed tomography.

6/21 (29%)

SD = Stable disease; PD = progressive disease; Equiv. = equivocal; RN = radiation necrosis; N/A = not available; 201Tl-SPECT = thallium201 single-photon emission computed tomography.

3.4. Outcome of ‘‘equivocal’’ MRIs The outcome of the seven ‘‘equivocal” MRI reports are shown in Table 3. There were four positive and three negative 201Tl-SPECT studies. In this subgroup, 201Tl-SPECT correctly predicted the final outcome of either tumor recurrence or radiation necrosis in all but one case. 3.5. Diagnostic accuracies The diagnostic accuracies of 201Tl-SPECT and MRI in predicting tumor recurrence are shown in Table 4. The sensitivity, specificity, and positive and negative values were comparatively better with 201Tl-SPECT than with MRI. Overall, 201Tl-SPECT and MRI correctly predicted final

outcome in 18 of 21 cases and 14 of 21 cases, respectively (diagnostic accuracy of 86% vs. 67%). All three false negative 201Tl-SPECT scans were in patients who had World Health Organization (WHO) grade III gliomas (two anaplastic oligoastrocytoma, and one anaplastic astrocytoma). All three patients received prior chemotherapy and none were using steroid at the time of their scans. Examples of a positive 201Tl-SPECT and a negative 201 Tl-SPECT study, with their corresponding MRIs, are shown in Figs. 1 and 2, respectively. 3.6. Post-scan management Of the 14 patients with positive 201Tl-SPECT results, 12 received subsequent active treatment for tumor recurrence (six surgery, and six chemotherapy). The remaining two patients deteriorated rapidly and both died within 2 months of their scans. All seven patients with negative 201 Tl-SPECTs continued on routine observation or their pre-scan chemotherapy.

Fig. 1. A 46-year-old woman who had a complete excision of a right frontal glioblastoma multiforme followed by cranial radiotherapy and adjuvant carmustine chemotherapy 18 months earlier. (A) A fluid-attenuated inversion-recovery (FLAIR) MRI showed extensive oedema with mass effect within the right frontal lobe anterior to the surgical defect, associated with enhancement on contrast-enhanced T1-weighted MRI (not shown). The appearance was ascribed to radiation or chemotherapy-related necrosis. (B) Thallium-201 single-photon emission computed tomography (201Tl-SPECT) scan demonstrated intense increase in thallium uptake in the right frontal lobe consistent with tumor recurrence. Histology from re-excision confirmed tumor recurrence and the patient died 2 months later.

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Fig. 2. A 47-year-old man with anaplastic astrocytoma of the left frontal lobe treated with macroscopic complete excision followed by adjuvant cranial radiotherapy 12 months earlier. (A) A fluid-attenuated inversion-recovery (FLAIR) MRI showed white matter changes inferior to the surgical resection site suspicious for tumor recurrence. (B) There was no thallium uptake in the left frontal lobe on thallium-201 single-photon emission computed tomography (201Tl-SPECT). An MRI 3 months later demonstrated reduction in the extent of the white matter signal abnormality, which suggested resolution of the post-radiation effect.

3.7. Influence of

201

T-SPECT on management 201

The number of patients where Tl-SPECT correctly determined management is summarised (Table 5). Eleven 201 Tl-SPECT scans were performed when the patients were clinically stable, while the remaining ten scans were performed on patients with evidence of neurological deterioration. Of the 11 stable patients, five had evidence of tumor recurrence on MRI, and six had either ‘‘radiation necrosis” or ‘‘equivocal” MRI reports. 201Tl-SPECT correctly determined subsequent clinical management in four of these 11 stable patients. In the remaining ten patients with symptomatic progression, seven had evidence of tumor recurrence on MRI, and three had either ‘‘equivocal” or ‘‘radiation necrosis” reports. 201Tl-SPECT correctly influenced management in two of these ten patients. Overall, the 201Tl-SPECT result was considered to have correctly determined management in six patients (29%). 201Tl-SPECT assisted management in a further ten cases (48%) where both the 201Tl-SPECT findings and MRI reports were consistent with the final outcome.

Table 5 Outcome of ‘‘equivocal” MRIs (n = 7) 201

Tl-SPECT

Positive

Negative

Histology Tumor recurrence Radiation necrosis

1 0

1 0

Clinical Tumor recurrence Stable disease

3 0

0 2

3.8. Post-scan survival At the time of analysis, 16 of the 19 patients had shown evidence of disease progression, with nine patients still alive after a median follow-up time of 33 months (range, 6–191 months). Kaplan–Meier estimates of the post-scan survival curves, based on the 201Tl-SPECT and MRI results, are shown in Figs. 3a and 3b, respectively. Patients with negative uptake as shown on 201Tl-SPECT had a significantly better survival compared to patients with positive uptake,

Fig. 3a. Kaplan–Meier post-scan survival curves for patients reported to be negative (–) or positive (- - -) on thallium-201 single-photon emission computed tomography (201Tl-SPECT). Median survivals for 201Tl-SPECT positive and negative patients were 6 months and 15+ months (not reached), respectively (p = 0.04).

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Fig. 3b. Kaplan–Meier post-scan survival curves for patients reported to have tumor recurrence (- - -) or radiation necrosis/equivocal (–) on MRI. Median post-scan survival were not statistically different (7 months vs. 13 months, p = 0.6).

with the median survival not reached (15 + months) in the negative group compared to median survival of 7 months in the positive group (p = 0.04). In contrast to the 201TlSPECT results, there was no significant difference in overall survival between patients with ‘‘progressive disease” and ‘‘equivocal” or ‘‘radiation necrosis” MRI reports (p = 0.6). 4. Discussion Ionizing radiation applied to the central nervous system can result in a localized area of necrosis in the brain. The most common MRI characteristics of radiation necrosis consist of an enhancing mass with a central area of necrosis, which mimics tumor recurrence. The incidence of pure radiation necrosis was 14% in a series of 148 patients with treated malignant gliomas, with another 11% of patients with a mixture of predominantly radiation necrosis intermingled with limited residual and/or recurrent tumor.21 The lack of specificity of conventional CT or MRI in distinguishing radiation necrosis and tumor recurrence, coupled with the relatively high incidence of radiation necrosis, poses a significant problem for clinicians in the follow-up of irradiated brain tumors. The prospect of non-invasively differentiating these two entities spurred on further studies examining the utility of functional imaging methods to directly estimate tumor activity based on metabolic markers. MRS uses the presence and/or ratio of tissue metabolites to further characterize changes on a routine MRI.22 The major limitation of this technique is its low accuracy where patients have coexisting necrosis and tumor. Although early work with 18fluorodeoxyglucose (FDG) PET was promising, more recent studies have challenged the usefulness of PET for this purpose, with specificity as low as 40%.7,23,24 Apart from its high cost and limited availability, other drawbacks of this imaging modality are the background levels of cortical glucose, and false positive scans from non-malignant inflammatory process and subclinical seizure activity.9,25,26

Perfusion MRI is a promising tool that measures tumor angiogenesis and capillary permeability, both of which are biological markers of malignancy.7 Although first-pass perfusion MRI is more accurate than conventional MRI for differentiating between radiation necrosis and tumor recurrence, it is by no means the perfect test. Sugahara et al. found a significant degree of overlap in relative cerebral blood volume (rCBV) between these two entities.27 Results from studies using more delayed, T1-weighted MRI permeability methods were more encouraging.28 The uptake of 201thallium into tumor cells may be related to the alterations in the blood brain barrier, regional blood flow, cellular metabolic activity, and the variability in Na+-K+-ATPase (adenosine triphophatase) activity.13,19 Further studies examined the clinical utility of 201Tl-SPECT in the detection and differential diagnosis of various brain tumors,29 in predicting histologic grades of brain tumors,14,16,30 in detecting residual brain tumors post-operatively,16 the correlation of 201Tl uptake indices with cell proliferating indices,31 the prognostic value of pre-operative 201Tl-SPECT as a predictor of survival outcome,30,32 and its role in predicting response to chemotherapy in recurrent glioma.33,34 The results from this present study partly correspond to results from previous studies that explored the accuracy of 201 Tl-SPECT as a non-invasive tool in distinguishing postirradiated brain tumor recurrence from radiation necrosis. Other studies included a mixture of patients with low- and high-grade gliomas, malignant meningiomas, metastatic tumors and lymphomas.12,19,20 However, our study specifically examined patients with high-grade glioma and abnormal MRI findings. Interpretation of 201Tl-SPECT images was based on visual inspection of intensity of uptake rather than quantitative measurement using tumor–scalp ratio or early-delayed ratio.12,19 In this study, the diagnostic accuracies of 201Tl-SPECT were superior to conventional MRI. We also found 201TlSPECT to be a potential prognostic tool as indicated by the significantly better post-scan survival in the group of patients with negative 201Tl-SPECT uptake compared to patients with positive 201Tl-SPECT uptake. In contrast, the post-scan survival based on the patient’s MRI report was not significantly different. More importantly, our study highlighted the impact of 201 Tl-SPECT findings on therapeutic management. The 201 Tl-SPECT results accurately affected management decisions in 29% of the cases, and assisted management in a further 48% of patients. The confirmation of tumor recurrence by 201Tl-SPECT led to subsequent active treatment for recurrence with either re-resection or chemotherapy in most patients. All patients with negative 201Tl-SPECT study were maintained on routine observation. To date, there is a paucity of data in the literature on the influence of 201Tl-SPECT on the clinical management of patients with post-irradiated high-grade gliomas. The sensitivity of 201Tl-SPECT in our study is in concordance with several other studies with sensitivities ranging

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from 83% to 95%.12,19,20 Datta et al.20 performed a comparative study of 201Tl-SPECT and CT scans in 35 patients with irradiated brain tumors. Similar to our study, 201Tl uptake was evaluated qualitatively by visual inspection of images. Histopathological confirmation at the time of relapse was obtained in only three patients. They found a sensitivity and specificity of 83% and 83% for 201TlSPECT, compared to 59% and 67%, respectively, for the CT scans. Post-scan progression-free survival was significantly better in patients with negative 201Tl-SPECT uptake compared to patients with positive uptake (33 months vs. 4 months, p = 0.003). Other studies have also confirmed the strength of 201Tl-SPECT findings as a predictor of outcome in the follow-up of patients with post-irradiated brain tumor.34,35 There were no false positive scans in our study, resulting in the 100% specificity. This contrasts with previous studies with lower specificity values that range from 60% to 83%.12,19,20 This discrepancy may be partially attributed to the few patients in our study who had no tumor recurrence (n = 4). There were three false negative 201Tl-SPECT scans in our study. Interestingly, all three cases were in patients with WHO grade III glioma. Two of the negative 201TlSPECTs had faint uptake of thallium in the area of interest but this was interpreted as a negative scan. Previous work using semi-quantitative analysis found a strong correlation between 201Tl-uptake index and glioma tumor grade.14,16,36 It may be that the false negative cases represent tumors that are less aggressive biologically. This study is limited by the few patients and the retrospective design with its inherent selection and incorporation bias. Post-scan histological confirmation was available in only under half of the patients. Although histology remains the gold standard for the final distinction between tumor recurrence and radiation necrosis, this may not always be feasible in routine clinical practice due to rapid worsening of clinical status, the resectability of the lesion, or patient’s refusal. The main diagnostic pitfall of 201Tl-SPECT is its low spatial resolution and poor anatomical localization, which could lead to confusion between physiological and pathological uptake.37 This problem potentially can be overcome by the recent advances in SPECT-CT fusion imaging,38 which has become available recently in our institution. However, the numbers of SPECTCT studies acquired are too small to make any meaningful analysis. In conclusion, our study demonstrated the usefulness of 201 Tl-SPECT as an adjunct to MRI in the follow-up of patients with post-irradiated high-grade glioma. This functional imaging modality provided additional diagnostic and prognostic information not obtainable with traditional anatomic imaging such as CT scans or MRI. It is relatively inexpensive compared to FDG PET and can be performed in any nuclear medicine department equipped with a basic SPECT camera.

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