First published online November 22, 2006
British Journal of Radiology (2007) 80, 274-278
© 2007 British Institute of Radiology
doi: 10.1259/bjr/28164599
123I-IMT SPECT for evaluation of the response to radiation therapy in high grade gliomas: a feasibility study
D Kuczer, MD
2
A Feußner , MD
2
R Wurm, MD
2
P Wust, PhD
2
R Michel, PhD
2
F Stockhammer
3
T Denecke, MD
1
H Amthauer, MD
1
R Felix, MD, PhD
1 and
M Plotkin, MD
1
1 Department of Radiology, Nuclear Medicine and Radiooncology, Campus Virchow-Klinikum, 2 Department of Radiation Therapy, Campus Mitte, 3 Department of Neurosurgery, Campus Virchow-Klinikum, University Clinic Charité, Berlin, Germany
Correspondence: Dr Michail Plotkin, Senior Physician, Klinik für Strahlenheilkunde, Universitätsklinik Charité, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail: michail.plotkin{at}charite.de
 |
Abstract
|
|---|
Assessing response to radiation therapy in patients with high grade gliomas is needed upon making decisions toward further therapy strategies. Currently used standard imaging tools such as CT and MRI are not sensitive enough to detect early therapy effects. We prospectively investigated if single photon emission computed tomography (SPECT) using radiolabelled amino acid derivate 123I-methyltyrosine (IMT) would be useful for this aim. 10 patients with histologically proven high grade gliomas, who were candidates for radiation therapy, were enrolled in this investigation. All patients were examined by IMT SPECT before radiation therapy and 4 weeks after the initiation of the hypofractionated application of 40 Gy. Patients were followed up for 39 months; the tumours to background ratios (T/B) for IMT under/before radiation therapy were correlated to survival times. Initially, SPECT depicted an abnormal intratumoural IMT uptake in all patients (mean T/B ratios 1.37–1.87). In four out of 10 patients, the mean T/B ratios decreased by more than 10% under radiation therapy. In six other patients, the BQ decreased by less than 10% or increased. There were no significant correlations between the degree of changes in T/B and survival (r = –0.1, p = 0.973). Serial IMT SPECT measurements allow detection of changes in amino acid accumulation in high-grade gliomas under radiation therapy. However, these changes seem to possess no prognostic value in respect to survival prediction.
|
Introduction
|
|---|
In spite of the recent advances in surgical and radiation technique as well as chemotherapy of high grade gliomas, the prognosis of these tumours remains uniformly fatal. Significant efforts are currently being undertaken to optimize the treatment strategy. In this context, an early evaluation of tumour response to radiation therapy is needed in order to enable treatment modifications. The standard imaging tools for diagnosis of brain tumours such as CT or MRI do not reliably identify the tumour response during or shortly after therapy, and thus do not allow a differentiation of radiation-induced benign tissue alterations from residual tumour [1]. Therefore, nuclear medicine imaging, which allows in vivo investigation of tumour metabolism, was proposed for monitoring the radiation therapy. Several studies addressed the value of positron emission tomography (PET) using a marker for glucose metabolism 2-18F-fluoro-2-deoxyglucose (FDG) for this task, but delivered contradictory results [2–4]. As compared with FDG, the radiolabelled amino acid tracers appear to be more promising for evaluation of tumour response to radiation therapy, because they have an advantage of more specific tumour targeting, free from contaminant non-tumoural accumulations and seem to be more sensitive than FDG for evaluation of therapy effects [5]. However, to date, little is known about the changes in amino acid metabolism in brain tumours under radiation [6–8]. Therefore, the clinical usefulness of amino acid imaging for response evaluation of radiation therapy remains unclear.
In the present pilot study, we investigated the effect of radiation on amino acid metabolism in high grade gliomas using single photon emission computed tomography (SPECT) with the radiolabelled amino acid derivate 3-123I-iodo-
-methyl-L-tyrosine (IMT). The results of serial IMT SPECT measurements were compared with survival after therapy to estimate the prognostic value.
View larger version (27K):
[in this window]
[in a new window]
|
Figure 1. A 47-year-old female patient (patient no.1) suffering from glioblastoma in the left frontal lobe presented 2 weeks after partial tumour resection. (a) The T1 weighted MR scan shows slight contrast media accumulations around the resection area. (b) Single photon emission computed tomography (SPECT) scan and (c) fused image demonstrate a high tracer uptake around the resection defect. (d) The control SPECT study following application of 40 Gy shows a reduction of the intratumoural 123I-methyltyrosine (IMT) uptake, as compared with the baseline study. The control investigation 7 months after completing the therapy (c) demonstrates no further changes of the tracer uptake in the lesion. In the follow up of 34 months, the patient was only slightly hindered by the tumour.
|
|
View larger version (9K):
[in this window]
[in a new window]
|
Figure 2. Amino acid transport under radiation therapy/at baseline in patients with high grade glioma in relation to survival. Changes in T/Bmean were not significantly correlated with survival: r (Spearman) = –0.1; p = 0.973.
|
|
Materials and methods
Patients
10 patients (three female; seven male; median age 57.4 years; range 29–72 years) with high grade gliomas, who were all candidates for radiation therapy, were enrolled in a prospective investigation. The diagnoses had been verified previously by histology in all cases. The inclusion criteria were Karnofsky performance index 
70 and the absence of any other life-threatening disease. Patient characteristics and pre-treatment data are given in Table 1.
A written informed consent was obtained from all patients for the SPECT examinations. The study was approved by the local ethics committee and by the German Radiation Protection Authorities.
SPECT imaging
All patients were examined by IMT SPECT prior to radiation therapy and after application of 40 Gy out of 75 Gy (4 weeks after therapy initiation). The patients fasted overnight before the SPECT studies were performed. In order to prevent possible uptake of free iodine, the thyroid was blocked with 400 mg of sodium perchlorate 30 min prior to tracer application. Image acquisition started 10 min after intravenous injection of 370 MBq IMT. SPECT imaging was performed using a triple-head system (Multispect 3; Siemens Medical Systems, Erlangen, Germany). For identical head positioning during the initial and the follow up study, individual thermoplastic masks were used. Images were acquired in step and shoot mode with 120 views over 360°. The matrix was set at 128x128. The energy window (20%) was centred on 159 keV. Slices were reconstructed using filtered back projection employing a Butterworth filter (cut-off frequency, 0.38; Nyquist; order, 6). First order attenuation correction was applied using the method of Chang. The reconstructed in-plane image resolution was 13 mm full width at half maximum (FWHM). The slice thickness was 3.5 mm (Figure 1
).
Data analysis
SPECT scans were automatically co-registered with individual MRI data using the MPI Tool software (ATV Inc., Kerpen, Germany). For quantification, irregular regions of interest (ROIs) were first placed on the baseline SPECT images around the IMT-accumulating tumour lesions (tumour ROIs) and on MRI around the area of normal brain (reference ROIs), respectively. The reference ROIs defined on MR scans were then transferred onto the corresponding SPECT images. In the next step, the resulting ROI set was applied to the co-registered post-therapeutic SPECT images. The spread of the IMT-accumulating tumour in the post-therapeutic SPECT outside the borders of the baseline ROI was not observed in any cases. The tumour-to-brain ratios were calculated as the relationship of the mean IMT uptake in the tumour ROI to the mean uptake in the normal tissue ROI (T/Bmean) and as the relationship of the maximal IMT uptake in the tumour to the mean uptake in the normal brain (T/Bmax). The T/B ratios at baseline and under radiation therapy were compared using the t-test for paired variables. The relation of the T/B ratios before and after the initiation of radiation therapy was compared with the individual survival by calculating the Spearman correlation coefficient. The statistics were performed using the SPSS v. 10 (Chicago, IL).
|
Results
|
|---|
The individual T/B values and their changes following radiation therapy are given in Table 2. At baseline, prior to radiation therapy, SPECT depicted an abnormal intratumoural IMT uptake in all patients (averaged T/Bmean ratio 1.55, range 1.37–1.87; averaged T/Bmax ratio 2.08, range 1.38–2.52). Under radiation therapy, the averaged T/Bmean and T/Bmax ratios decreased to 1.47 and 1.99, respectively; the differences were not statistically significant (p = 0.45 and p = 0.59). However, if analysing the changes in T/B, it should be taken into consideration that they were bi-directional. So, in four out of 10 patients, the mean T/B ratios decreased under radiation therapy by more than 10% (patient no. 1–3, 9). In six other patients, the T/Bmean ratios decreased by less than 10% (patient no. 4–7, 10) or increased (patient no. 8). A complete disappearance of the metabolic activity in the tumour was observed in no cases. The T/Bmax decreased by more than 10% in three patients, and were stable (range <10%) or increased by more than 10% in the remaining seven patients.
We found no significant correlation between the degree of the changes in T/Bmean or T/Bmax and survival (r = –0.1, p = 0.973 and r = –0.9, p = 0.448, respectively). During the follow up of 2–39 months, all studied patients died of tumour progress. The T/Bmean or T/Bmax at baseline and the IMT uptake 4 weeks after therapy initiation were also not correlated with survival (Figure 2).
|
Discussion
|
|---|
Previous studies have demonstrated the ability of SPECT imaging using synthetic amino acid tracer IMT to detect the metabolic activity of brain tumours with high sensitivity and specificity and to differentiate recurrence from radiation necrosis and peritumoural oedema [9–12]. The changes in the intratumoural IMT accumulation under chemotherapy were shown to correlate with the therapy response, as evaluated by delayed MRI or CT [13]. To the best of our knowledge, the present study is the first one that addresses the value of IMT SPECT for monitoring radiation therapy in a clinical setting.
4 weeks after beginning radiation therapy, a decrease in mean intratumoural amino acid transport of greater than 10% was observed in four out of 10 studied patients with high grade gliomas (see example in Figure 1). However, the decrease in the intratumoural amino acid accumulation was not associated with a better survival. Taking into consideration the intrinsic heterogeneity of the glioblastomas, we also analysed the changes in maximal IMT uptake, which is believed to reflect the proliferation activity of the most malignant tumour area [9], but also found no relationship between the changes in maximal IMT uptake and survival. A possible explanation for these results is that the irradiation-induced changes in tumour proliferation activity might be less important for the prognosis of patients suffering from high grade gliomas than such well-estimated prognostic factors as age, performance factor, mental status, tumour histology and previous resections [14]. Indeed, the studied patient population was heterogeneous in respect to the above-named features. However, the striking differences in the post-therapeutic IMT uptake alterations between patient no. 2 and 7 (both had a non-resectable glioblastoma and showed a short survival, Tables 1 and 2) indicate that the measurements of the amino acid transport under radiation therapy might be unhelpful for prognosis prediction. Another possible reason for the low prognostic value of IMT SPECT in our study can be related to the fact that IMT accumulates in both high grade and low grade gliomas [10]. High grade gliomas are known to include the low grade areas. Consequently, in the individual case, it seems to be difficult to define whether changes in the IMT uptake under irradiation reflect a response of the low grade or high grade tumour part. This information would, however, be relevant for estimation of prognosis. The timing of the post-treatment scans is an important factor influencing the results of nuclear medicine imaging [15]. In the current study, the control SPECT was performed after application of approximately half of the radiation dose. That might not be the optimal time point for evaluating the tumour response to therapy. The course of alterations of amino acid metabolism in gliomas under irradiation has been addressed by only a few studies, which delivered controversial data. Riemann et al recently reported an increase in IMT accumulation on the second and third day after irradiating the rat C6 glioma cells with 20 Gy [6]. Earlier, Kubota et al investigated amino acid metabolism in a rat AH109A tumour model using 14C-methionine and PET, and found, in contrast to the above-cited study, a decrease of about 50% from the baseline uptake measured on the first day after irradiation; and this further declined to background levels during the following 6 days [7].
Further investigations involving larger cohorts of patients and including scans in the hyperacute phase post radiation are needed for final evaluation of the usefulness of amino acid imaging for monitoring radiation therapy in patients with high grade gliomas.
|
Conclusion
|
|---|
Serial IMT SPECT measurements allow detection of changes in amino acid accumulation in high grade gliomas under radiation therapy. However, our data, based on a limited number of patients, indicate that these changes possess no prognostic value in respect to survival prediction.
Received for publication July 24, 2006.
Accepted for publication September 18, 2006.
|
References
|
|---|
- Dooms GC, Hecht S, Brant-Zawadzki M, Berthiaume Y, Norman D, Newton TH. Brain radiation lesions: MR imaging. Radiology 1986;158:149–55.[Abstract/Free Full Text]
- Mineura K, Yasuda T, Kowada M, Ogawa T, Shishido F, Uemura K. Positron emission tomographic evaluation of radiochemotherapeutic effect on regional cerebral hemocirculation and metabolism in patients with gliomas. J Neurooncol 1987;5:277–85.[CrossRef][Medline]
- Spence AM, Muzi M, Graham MM, O'Sullivan F, Link JM, Lewellen TK, et al. 2-[18F]Fluoro-2-deoxyglucose and glucose uptake in malignant gliomas before and after radiotherapy: correlation with outcome. Clin Cancer Res 2002;8:971–9.[Abstract/Free Full Text]
- Maruyama I, Sadato N, Waki A, Tsuchida T, Yoshida M, Fujibayash Ishii Y, et al. Hyperacute changes in glucose metabolism of brain tumors after stereotactic radiosurgery: a PET study. J Nucl Med 1999;40:1085–90.[Abstract/Free Full Text]
- Voges J, Herholz K, Holzer T, Wurker M, Bauer B, Pietrzyk U, et al. 11C-methionine and 18F-2-fluorodeoxyglucose positron emission tomography: a tool for diagnosis of cerebral glioma and monitoring after brachytherapy with 125I seeds. Stereotakt Funct Neurosurg 1997;69:129–35.[CrossRef]
- Riemann B, Könemann S, Pöppling , Kopka K, Weckesser M, Willig N, et al. Early effects of irradiation on [123I]-IMT and [18F]-FDG uptake in rat C6 glioma cells. Strahlenther Onkol 2004;180:434–44.[Medline]
- Kubota K, Matsuzawa T, Takahashi T, Fujiwara T, Kinomura S, Ido T, et al. Rapid and sensitive response of carbon-11-L-methionine tumor uptake to irradiation. J Nucl Med 1989;30:2012–16.[Abstract/Free Full Text]
- Suzuki A, Mineura K, Sasajima T, Kowada M, Ogawa T, Hatazawa J, et al. Sequential analysis of three integrated images of PET, CT and MR in malignant brain tumors before and after radiotherapy. No To Shinkei 1996;48:449–57.[Medline]
- Kuwert T, Morgenroth C, Woesler B, Matheja P, Palkovic S, Vollet B, et al. Influence of size of regions of interest on the measurement of uptake of iodine-123--methyl tyrosine by brain tumors. Nucl Med Commun 1996;17:609–15.[Medline]
- Langen KJ, Cohnen HH, Roosen N, Kling P, Muzik O, Herzog H, et al. SPECT studies of brain tumors with L-3-[123]iodo--Methyltyrosine: comparison with PET, 124IMT and first clinical results. J Nucl Med 1990;31:281–6.[Abstract/Free Full Text]
- Plotkin M, Eisenacher J, Bruhn H, Wurm R, Michel R, Stockhammer F, et al. 123I-IMT SPECT and 1H MR-spectroscopy at 3.0 Tesla in the differential diagnosis of recurrent or residual gliomas: a comparative study. J Neurooncol 2004;70:49–58.[CrossRef][Medline]
- Plotkin M, Amthauer H, Eisenacher J, Wurm R, Michel R, Wust R, et al. Value of 123I-IMT SPECT for diagnosis of recurrent non-astrocytic intracranial tumours. Neuroradiology 2005;47:18–26.[CrossRef][Medline]
- Schmidt D, Wunderlich G, Langen K-J, et al. I-123--Methyl-Tyrosine (IMT) SPECT for evaluation of chemotherapy in cerebral gliomas. J Nucl Med 1996;37:354P
- Buckner JC. Factors influencing survival in high-grade gliomas. Semin Oncol 2003;30:10–14.[Medline]
- Young H, Baum R, Cremerius U, Herhollz K, Hoekstra O, Lammertsma AA, et al. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTS recommendations. Eur J Cancer 1999;13:1773–82.
Top
Abstract
Introduction
