Clinical application of18F-FUdR in glioma patients ? PET study of nucleic acid metabolism

Journal of Neuro-Oncology 23: 53-61,1995. �9 1995 Kluwer Academic Publishers. Printed in the Netherlands.

Clinical Study

Clinical application of lSF-FUdR in glioma patients - PET study of nucleic acid metabolism

Motonobu Kameyama, Kiichi Ishiwata, 2 Yuji Tsurumi, Jun Itoh, Kiyotaka Sato, Ryuichi Katakura, Takashi Yoshimoto, Jun Hatazawa, 1 Masatoshi Ito ~ and Tatsuo Ido 2 Department of Neurosurgery, Tohoku University School of Medicine, 1 Division of Nuclear Medicine and 2 Di- vision of Radiopharmaceutical Chemistry, Cyclotron RI Center, Tohoku University, Japan

Key words: 18F-fluoro-2'-deoxyuridine, PET, brain tumor, glioma, nucleic acid metabolism

Summary

Positron emission tomography was used to investigate the metabolism of nucleic acids by 18F-fluoro-2'-deoxyuridine (lSF-FUdR) in 22 patients with gliomas. Sixteen cases of high grade glioma clearly demonstrated a region of high activity with a differential absorption rate (DAR) of 0.64 + 0.34. Six cases of low grade glioma failed to reveal a positive image of the tumor and the DAR in tumor was 0.21 + 0.042 (p < 0.01). This PET-~SF - FUdR study succeeded in differentiating high and low grade gliomas from the view point of nucleic acid metabolism.

Introduction

Despite recent advances in neurosurgical treatment and sophisticated radiochemotherapy, satisfactory results have not as yet been achieved in glioma patients [1]. To establish better treatment strategy, more must be known about the pathophysiology of the glioma. Positron emission tomography (PET) has allowed us to examine various physiological information and a number of studies of brain tumors have already been made [2-20] from the view points of blood flow, gluose, amino acids and oxygen metabolism. Since nucleic acid metabolism closely cor- relates with the proliferative potential of neoplas- mas [21], information concerning nucleic acid metabolism seems useful in the diagnosis and treatment of glioma.

For these reasons, we undertook a clinical PET study of the nucleic acid metabolism of glioma. One of the fluorinated pyrimidines labeled with a positron emitter, 18F-fluoro-2'-deoxyuridine (18F-

FUdR), was used in the present study as a tracer of nucleic acid metabolism [22-29].

Materials and method

Patients

Twenty-two histologically defined glioma cases (17 males and 5 females, ranging in age from 27 to 73 years old, with a mean age of 44.0 years old) were studied with PET using 18F-FUdR. Twelve patients were studied before radiochemotherapy (Table 1). The remaining ten patients were studied during or after radiochemotherapy (Table 2). All of the patients underwent PET examination before radical surgery with the exception of case 13, who was scanned 3 months after resection of the tumor. Hist- ological diagnosis were made from CT-guided stereotaxic biopsies (10 cases) or operative specimens (12 cases). There were 5 cases of grade IV (5 glio- blastoma), 11 cases of grade III (10 anaplastic astro-

54

Table 1. Patients scanned (PET) before treatment

Case Age Sex Histological CT DAR Ratio

grade enhancement

Tumor Contralateral

1 59 M IV + 0.84 0.17 4.9

2 33 M IV + 0.73 0.23 3.2

3 63 M III + 0.85 0.24 3.5

4 27 F III + 0.41 0.15 2.7

5 49 M III + 0.69 0.23 3.0

6 42 M III + 0.46 0.15 3.1

7 54 M III - 0.26 0.08 3.3

8 35 M III + 0.40 0.15 2.7

9 73 M III + 1.73 0.23 7.5

10 37 F II - 0.23 0.26 0.9

11 43 F II - 0.24 0.24 1.0

12 28 M II - 0.17 0.12 1.4

DAR: Differential absorption rate, contralateral: contralateral brain tissue, ratio: DAR ratio of tumor/contralateral brain tissue.

cytoma and I anaplastic ganglioglioma), and 6 cases of grade II (5 fibrillary astrocytoma and 1 gemisto- cytic astrocytoma). The tumor tissue for histological diagnosis was obtained within 1 month from the PET study in 17 cases, 2 months in 1, 3 months in 3 and 4 months in 1. Informed consent for the PET study was obtained from the patients and/or rela- tives. The protocol was also approved by the Com- mittee for Clinical PET Study of Tohoku Universi- ty.

Scanner and procedure

The ECAT II (EG&G, Ortec) [30] and PT-931 (CTI, Knoxville, Tennessee) [31] were employed. The spatial resolutions of the images were 17 and 8 mm, and the slice thickness were 18 and 7 mm in FWHM for the ECAT II and PT-931 respectively. 18F-FUdR was synthesized using an automated synthesis system [32], which provides a radiochemical purity of over 98%. Following intravenous administration of 4 to 11 mCi of 18F-FUdR, sequential scanning (each scan being of 5 min duration) was per- formed for 45 rain, then additional images in other

Table 2. Patients scanned (PET) during or after treatment

Case Age Sex Histological CT DAR Ratio

grade enhancement

Tumor Contralateral

13 27 F IV + 0.42 0.12 3.5

14 45 M IV + 0.83 0.24 3.5

15 44 M IV + 0.37 0.15 2.5

16 35 M III + 0.51 0.12 4.3

17 44 F III + 0.73 0.12 6.1

18 36 M III - 0.54 0.20 2.7

19 50 M III + 0.44 0.09 4.9

20 45 M II - 0.29 0.24 1.2

21 38 M II - 0.17 0.19 0.9

22 49 M II - 0.18 0.18 1.0

DAR: differential absorption rate, contralateral: contralateral brain tissue, ratio: DAR ratio of tumor/contralateral brain tissue.

55

Fig. 1. A C T scan of case 3 revealed an enhanced tumor with a surrounding low density area in the right fronto-temporal region (A). A PET scan with 18F-FUdR clearly showed a lesion with high accumulation (B).

56

Fig. 2. A C T scan of case 12 revealed a low density lesion in the right frontal region (A). A PET scan with 18F-FUdR showed no positive image (B).

positions were obtained. Usually three images were obtained with the ECAT II at 1 cm center to center spacing and 7 images were obtained simultaneously with the PT-931 at 7 mm spacing. The PET images were reconstructed using a measured attenuation correction. The injected dose of ~SF-FUdR as 5-fluoro-2'-deoxyuridine was 2.0 to 5.8 rag, which was much lower than doses of fluorinated pyrimidines used clinically as chemotherapeutic agents [33].

Tissue uptake of lSF-FUdR was also calculated and expressed as the differential absorption rate (DAR) [34, 35], which is related to % injected dose and is expressed as:

DAR = Cpet x W/D

where Cpet is the tissue concentration of lSF expressed in mCi/g, W and D are body weight in g and injected dose in mCi. Regions of interest were lo- cated on the brain tumor and the contralateral brain tissue in the sequential images using CT images as an anatomical guide, and the DAR was calculated. Statistical analysis was done by Welch's t test.

Also the graphical analysis of 18F-FUdR in the tumor was investigated. An operational equation of graphical analysis is expressed as:

Ci(t)/Cp(t) -- Ki Cp(t)dt/CP(t) + Vp

where Ci and Cp are the tissue concentration of the tracer in tissue and plasma, Ki is rate constant for the tracer transfer from blood to tissue and Vp is distribution volume of the tracer [36].

Results

In all 16 cases of high grade glioma (III and IV) showed a positive image of the brain tumor clearly with high contrast (Fig. 1). On the other hand, a positive image could not be obtained in 6 cases of low grade glioma (II) (Fig. 2).

In the high grade glioma cases, the sequential value of the DAR in the tumor was much higher than that in the contralateral brain tissue throughout the scanning. The DAR of the low grade glioma cases,

OAR

1.0-

0,9-

0,8-

0,7-

0.6-

0.5-

0,4-

0,3-

0.2-

0.1-

57

o

~--__~____~ . . . . ~__22".~::::.'~:21_'2z$222-~:2~-~

1'o ~o ~o 4'o ~o ~i~

Fig. 3. Sequential changes in DAR in case 3 (closed circles: tumor, open circles: contralateral brain tissue), and case 12 (closed triangle: tumor, open triangle: contralateral brain tissue).

in contrast, was indistinguishable from that of the contralateral brain tissue (Fig. 3).

The results of DAR at 45-50 rain after the administration of lSF-FUdR are summarized in Tables 1 and 2. The mean DAR and standard deviation was 0.64 _+ 0.20 in the 5 grade IV tumors and 0.64 _+ 0.38 in the 11 grade III tumors. When these two groups were combined it was 0.64 _% 0.34. The value for the 6 grade II tumors, on the other hand, was 0.21+ 0.042. A significant difference was observed between high grade glioma (III and IV) and low grade glioma (p < 0.01), between grade IV and II (p < 0.005) and between grade III and II (p < 0.05).

The mean DAR and standard deviation for contralateral brain tissue for the 22 patients was 0.18 + 0.053. There were no statistical difference in the val- ues of the DAR with regard to histological grades, treatment or the different type of scanner.

The results of DAR ratio of tumor/contralateral brain tissue were more striking. A significant difference was observed between high grade glioma and low grade glioma (p < 0.001), between grades IV and II (p < 0.005), and between grades III and II (p < 0.001). The mean DAR value of grade I I tumors, however, did not differ from that of homolat- eral brain tissue (Fig. 4). A clear difference between low grade and high grade glioma was observed at a DAR ratio of approximately 2.0.

The graphical analysis [36] of lSF-FUdR in high grade gliomas showed positive Ki value (Fig. 5) which suggests active uptake of 18F-FUdR in the tumor. On the other hand, in low grade glioma cases, these pattern was not observed.

58

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e~

O E

4- 4 o

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K.

n,

2

�9 O

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0 I I I lI 11I 1V

Fig. 4. DAR ratio of tumor/contralateral brain tissue. (open circle: before treatment, closed circle: during or after treatment).

Discussion

PET provides a unique opportunity to obtain three- dimensional information on physiological process- es in a noninvasive manner. Accordingly, there have been various metabolic studies of brain tumors [2-19]. Di Chiro et al. reported that 18F-fluorodeoxyglucose (FDG) was useful in differentiating high and low grade glioma [7, 8], and they also suggested that glucose metabolism significantly corre- lates with the prognosis of patients [8, 16]. Accord- ing to the recent report by Tyler et al. [19], however, the rate of glucose utilization did not correlate with tumor grade. Believing that information on nucleic acid metabolism would provide us with the opportunity to investigate the proliferation potential of brain tumors, we undertook a PET study with 18F- FUdR.

In the present study, 18F-FUdR was used as a tracer of nucleic acid metabolism for the following reasons; 1) fluorinated pyrimidines are known to show close correlation with the metabolism of nucleic

acid [37], 2) in experiments using an implanted sub- dermal tumor, the intratumoral accumulation of 18F-FUdR was high in comparison with other fluorinated pyrimidines such as 5-fluorouridine and 5- fluorouracil [22], 3) double-labeled autoradiogra- phy with laFUdR and 14C-thymidine revealed similar brain tumor images in an experimental rat brain tumor model [29].

Generally, two metabolic pathways are proposed for 18F-FUdR [23, 24, 37]. One entails the conversion of FUdR into 5-fluoro-2'-deoxyuridine-5'- monophosphate (FdUMP), which forms a complex with thymidylate synthetase. The physiological role of this is the conversion of 2"-deoxyuridine-5'- monophosphate into 2'-deoxythymidine-5'-monophosphate, which is thereafter incorporated into the deoxyribonucleic acid (DNA) synthesis pathway. The enzymatic reaction with FdUMP is stop- ped at the stage of formation of the FdUMP-thymidylate synthetase complex. The other pathway entails FUdR being converted to nucleotides, such as 5-fluorouridine-5'-monophosphate or 5-fluorou- dine-5"-diphosphate (via 5-fluorouracil or 5-fluorouridine), and its incorporation of ribonucleic acid (RNA). Washiten et al. [41], reported that most of the FUdR metabolites taken up by the tumor cell belonged to the FdUMP-thymidylate synthetase complex rather than RNA when FUdR was incu- bated with hempatoma tissue culture cells. In light of what is known about the metabolic pathways of 18F-FUdR and the above findings, it is suggested that lSF-FUdR is taken up by brain tumor tissue and

I00

50

1

0 1500 I i

500 I000

equivalent time

Fig. 5. Graphical analysis of 18F-FUdR in case 3.

phosphorylated into 18F-FdUMP and mainly forms a complex with thymidylate synthetase [29].

The results of our PET-~SF-FUdR study showed a clear differentiation between high and low grade glioma. A region with a high accumulation of 18F- FUdR was observed in all high grade glioma, whereas a positive image could not be obtained in low grade glioma cases. Not only was there a visual distinction in PET images, but also the DAR of the tumor disclosed a significant difference between the high and low grade glioma. In the present study, however, there was a large variation in the DAR in high grade glioma. There are several possible reasons for this; 1) A relatively small number of patients was examined in this study. 2) The heteroge- neity of high grade gliomas, with a mixture of ne- crotic tissue and actively growing cells, and different tumor cell density, all of which can cause a wide variation in the DAR. In fact, the DAR of 0.26 in case 7 was relatively low in comparison with other grade III cases. Histological examination disclosed, however, a mixture of oligodendroglioma (grade II) and anaplastic astrocytoma (grade III), which probably resulted in the low DAR value. 3) The lim- itations of the reliability of biopsies should not be overlooked [38]. Since only a small part of the tumor tissue can be obtained by this procedure, the existence of a grade IV component in the grade III group cannot be denied. 4) The effect of treatment may play another role. Since the metabolic state of brain tumor is known to change according to the treatment procedure [2, 14, 27], care must be taken in analyzing clinical data. 5) Finally, as reported by Hoshino etal . [39], the cell proliferative potential of high grade gliomas determined by S-phase fraction showed wide variation even in the same graded glioma. And other reports have stated that PET- FDG studies correlated better with the prognosis of brain tumor patients than did histological subclassi- fication [8, 9, 16]. These results may support the large deviation of DAR in high grade gliomas in the present study.

Di Chiro et al. emphasized the possible errors caused by a partial volume effect in PET-FDG study [40]. Although in the present series, false neg- ative results were not observed in the high grade glioma patients, care should be taken to note pos-

59

sible errors caused by this partial volume effect when studying very small tumors or tumors with a cavitation component surrounded by a thin rim of solid tumor [7]. In PET-FDG studies, however, even the glucose utilization rate of high grade glioma is sometimes lower than the contralateral gray matter [19]. Our PET-18F-FUdR study, on the con- trary, clearly demonstrated a high grade glioma image, since the uptake of 18F-FUdR in the brain is low. This may lead to fewer errors in diagnosing high grade glioma and also provides supplementary information suggesting the most appropriate target for biopsy [15, 20].

The present results may be debated since the sta- tus of the blood-brain barrier was not thoroughly investigated. However, we consider that the 18F- FUdR PET image mainly reflects the metabolism of nucleic acid by forming 18F-FdUMP-thymidylate synthetase complex for the above mentioned and the following reasons: 1) In our experiments using rat brain tumors [29], double labeled autora- diography with 18F-FUdR and 14C-thymidine revealed similar brain tumor images. In contrast, an autoradiographic comparison of lSF-FUdR and 14C- aminoisobutyric acid, which demonstrates impair- ment of the blood-brain barrier, showed clearly different images. 2) Also, in an experimental study, the ~SF radioactivity in tumor tissue remained at a constant level from 30 to 120 min, whereas a notable increase in ~SF activity with time was observed in nucleotides and acid-insoluble fractions [29]. 3) In a study investigating the metabolic response following chemotherapy using tumor bearing rat, the changes of 18F-FUdR uptake in the tumor parallel- ed with that of 14C-thymidne and bromodeoxyuri- dine (BUdR) labeling index [27]. 4) The sequential value of DAR stayed relatively constant following the administration of 18F-FUdR. Since the clear- ance of 18F-FUdR in blood is fast [23, 42], if the ~SF- FUdR accumulation in the tumor is dependent on breakdown of the blood-brain barrier, it should have been decreased with time due to the concentration gradient between the plasma and brain tumor tissue. 5) The results of graphical analysis [36] showed the active uptake pattern of ~SF-FUdR in high grade tumors.

PET studies using ~SF-FUdR will give us the op-

60

portunity to investigate the in vivo cell proliferation potential of brain tumor and open a new field for management of these patients from the viewpoint of nucleic acid metabolism.

Acknowledgment

The authors thank to Mr. S. Watanuki and Mr. S. Seo for their excellent PET operation and help for data analysis. The collaboration of the staff mem- bers of Cyclotron RI Center, Tohoku University are also acknowledged.

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Address for offprints: M. Kameyama, Department of Emergency & Critical Care Medicine, Tohoku University School of Med- icine, 1-1 Seiryo-machi, Sendai, 980-77, Japan

Clinical application of18F-FUdR in glioma patients ? PET study of nucleic acid metabolism

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