Optimization of semi-quantification in metabolic PET studies with 18F-fluorodeoxyglucose and 11C-methionine in the determination of malignancy of gliomas

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Abstract

The treatment of the glioma patient depends on the nature of the lesion and on the aggressiveness of the tumor. The management of gliomas continues to be a challenging task, because morphological neuroimaging techniques do not always differentiate them from nontumoral lesions or high grade tumors from low grade lesions. Positron Emission Tomography (PET) offers the possibility of the in vivo quantitative characterization of brain tumors. Despite decades of useful application of PET in the clinical monitoring of gliomas, no consensus has been reached on the most effective image analysis approach for providing the best diagnostic performance under heavy-duty clinical diagnostic circumstances. The main objective of the present study was to find and validate optimal semi-quantitative search strategies for metabolic PET studies on gliomas, with special regard to the optimization of those metabolic tracer uptake ratios most sensitive in predicting histologic grade and prognosis. 11C-Methionine (11C-Met, n = 50) and/or 18F-Fluorodeoxyglucose (18F-FDG, n = 33) PET measurements were performed in 59 patients with primary and recurrent brain gliomas (22 high grade and 37 low grade tumors) in order to correlate the biological behavior and 11C-Met/18F-FDG uptake of tumors. Data were analyzed by region-of-interests (ROI) methods using standard uptake value calculation. Different ROI defining strategies were then compared with each other for two of the most commonly used metabolic radiotracers, 18F-FDG and 11C-Met, in order to determine their usefulness in grading gliomas. The results were compared to histological data in all patients. Both ANOVA and receiver operating characteristic (ROC) analysis indicated that the performance of 18F-FDG was superior to that of 11C-Met for most of the ratios. 18F-FDG is therefore suggested as the tracer of choice for noninvasive semi-quantitative indicator of histologic grade of gliomas. 11C-Methionine has been suggested as a complimentary tracer, useful in delineating the extent of the tumor. The best diagnostic performance was obtained by calculating the ratio of the peak 18F-FDG uptake of the tumor to that of white matter (p < 0.001; ANOVA). This metabolic tracer uptake ratio is therefore suggested as an easily obtained semi-quantitative PET indicator of malignancy and histological grade in gliomas.

Introduction

Despite optimal surgical, radiation and medical therapy, survival of patients with gliomas remains disappointing and has not changed substantially during the last decades [1], [2], [3], [4], [5], [6]. In the early imaging-based evaluation of gliomas, most investigators considered Computerized Tomography (CT) and Magnetic Resonance Imaging (MRI) enhancement as a rather non-specific indication of malignancy as they do not always differentiate tumors from nontumoral tissues or low grade tumors from high grade lesions [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. MRI with routine pulse sequences is also of limited use in grading of gliomas [17], [18], [19], [20]. Magnetic Resonance Spectroscopy (MRS) is capable of providing useful biochemical information by detecting the concentration of certain metabolites but it still has only limited clinical utility [21], [22], [23], [24]. In contrast to these techniques, Positron Emission Tomography (PET) can routinely provide us with valuable biochemical information in various neurological diseases, especially in brain tumors [25], [26], [27], [28]. Different radiotracers have been used thus far to evaluate the biochemistry of intracranial tumors, the most frequently used of them being 18F-fluorodeoxyglucose (18F-FDG). In the assessment of protein synthesis, the most experience was obtained with l-methyl-11C-methionine (11C-Met), although its uptake predominantly reflects amino acid transport and blood–brain barrier disruption [29].

In previous reports, a relationship was found between the histologic grade of gliomas and the uptake of 18F-FDG [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], and between histological grade and 11C-Met uptake [43], [44], [45], [46], [47], [48], [49], [50], [51]. Although 18F-FDG offers the possibility of absolute parametric quantification, the detailed procedure's invasivity (the need for arterial blood sampling) and time consuming nature (dynamic image sampling, kinetic modelling) limits the routine clinical applicability of quantitative FDG measurements. It has been claimed that semi-quantitative methods are also useful and reliable, including the region-of-interests (ROIs) based on standard uptake value (SUV) calculation and on the use of ratios comparing the tumor radiotracer uptake to the tracer uptake values in certain reference regions [48], [52], [53]. Despite the extensive literature on this subject, there is no consensus on delineating and localising the optimal reference region and tumor ROI in gliomas, the most common brain tumors.

In the present clinical exploratory study we compare, using semi-quantitative methods, different ROI- and reference region-defining strategies for two of the most commonly used radiotracers, 18F-FDG and 11C-Met, in order to determine their usefulness in the noninvasive grading of gliomas and to choose and validate a reliable semi-quantitative PET indicator of histological grade.

Section snippets

Patients

Fifty-nine patients (male: 35; female: 24; age range: 16–69 years, mean: 40.4 years, S.D.: 13.9 years) with primary (n = 34) and recurrent (n = 25) gliomas were studied by PET using 11C-Met (n = 50) and/or 18F-FDG (n = 33) as tracer. PET examination was performed on 24 patients with both tracers. All patients underwent at least one CT and/or MRI scan before the PET scanning. Tumors were classified as high grade or low grade, according to their histological diagnosis, using the World Health Organization

Results

According to the biopsy results 22 patients had high grade tumors (9 primary and 13 recurrent gliomas), whereas 37 patients had low grade (25 primary and 12 recurrent) tumors. The tumor location was frontal in 16 patients, temporal in 13 patients, frontal temporal in 11 patients, frontal precentral in 7 patients, central parietal in 6 patients, parietal in 4 patients, brain stem in 1 patient, and parietal occipital in 1 patient.

18F-FDG and/or 11C-Met data of 59 patients were assessed (9 with

Discussion

Several studies used 18F-FDG and/or 11C-Met PET to evaluate the malignancy of gliomas [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53]. However, no consensus has until today been achieved on delineating and localising the optimal reference region and tumor ROI or on choosing the metabolic ratio most optimal in

Conclusion

We performed 18F-FDG and 11C-Met PET examinations in a relatively large and homogenous population of patients suffering from intracranial gliomas. Different strategies of semi-quantitative analysis were compared regarding their diagnostic performance. The results demonstrated that for the non-invasive semi-quantitative determination of the malignancy of gliomas, the optimal tracer is 18F-FDG and the parameter with the best diagnostic performance is the tumor_max/wm ratio. 11C-Met was highly

Acknowledgments

The authors express their gratitude to Prof. Peter Collins (formerly: Department of Pathology, Karolinska Hospital, Stockholm; at present: Department of Pathology, University of Cambridge) and Dr. Zoltán Hanzély (Department of Pathology, National Institute of Neurosurgery, Budapest) for the histopathological diagnosis, to Dr. Dean Leslie (at the time of this study, research student at the Department of Neuroradiology, Karolinska Hospital, Stockholm) and Dr. Szabolcs Szakáll (PET Center,

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