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COMMENTARY
Year : 2017  |  Volume : 65  |  Issue : 2  |  Page : 302-304

Hybrid PET/MR imaging for evaluation of recurrence in gliomas: Standard of care or luxury?


Department of Nuclear Medicine and Positron Emission Tomography, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication10-Mar-2017

Correspondence Address:
B R Mittal
Department of Nuclear Medicine and Positron Emission Tomography, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.201846

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How to cite this article:
Mittal B R, Singh S. Hybrid PET/MR imaging for evaluation of recurrence in gliomas: Standard of care or luxury?. Neurol India 2017;65:302-4

How to cite this URL:
Mittal B R, Singh S. Hybrid PET/MR imaging for evaluation of recurrence in gliomas: Standard of care or luxury?. Neurol India [serial online] 2017 [cited 2017 May 29];65:302-4. Available from: http://www.neurologyindia.com/text.asp?2017/65/2/302/201846


The current standard of treatment for patients with a glioblastoma following surgery is radiotherapy and concomitant or adjuvant temozolomide. These patients have shown a significant survival benefit with minimal added toxicity.[1] Even after the multimodality treatment with surgery, chemotherapy and radiotherapy, tumor recurrence at the primary site is frequently noted in gliomas, especially in glioblastomas (GBMs). Reliable imaging techniques for better differentiation between recurrence and necrosis are challenging to perform and have to give results that are as close as possible to the results of biopsy from that site. Differentiation of tumor recurrence, or progression of residual tumor tissue, from cerebral necrosis after radiotherapy or chemotherapy is not easy with structural imaging techniques (computed tomography [CT] and magnetic resonance imaging [MRI]). This is largely due to the difficulty in distinguishing between tumor, gliosis and edema, all of which appear as mass lesions with nonspecific contrast enhancement due to blood brain barrier breakdown. The conventional or contrast enhanced MRI had been replaced by advanced MRI techniques such as diffusion weighted imaging, diffusion tensor imaging and magnetic resonance spectroscopy for differentiation between recurrence and necrosis. At the same time, several positron emission tomography (PET) tracers like F-18 fludeoxyglucose (FDG), C-11 methionine, F-18 dihydroxyphenylalanine (DOPA), F-18 fluorothymidine (FLT), F-18 fluorocholine and F-18 fluoroethyltyrosine (FET) have shown potential for the differentiation; however, the available imaging modalities or techniques have fallen short of the desired results. The usefulness of a few tracers is depicted in [Figure 1],[Figure 2],[Figure 3].
Figure 1: Tc99m-MIBI SPECT/CT, axial (a and d), sagittal (b and e), coronal (c and f) images of a 42-year male patient, a known case of astrocytoma grade II, in whom surgery followed by external irradiation was performed, showing tracer avid lesion in the left temporo-occipital region suggestive of tumor recurrence

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Figure 2: F-18 FET PET/CT images, axial (a and d), sagittal (b and e) and coronal (c and f) images of a 45-year male patient who had right posterior frontal space occupying lesion diagnosed to be an anaplastic oligodendroglioma; showing tracer avid (SUVmax 5.4) enhancing peripheral rim of a hypodense lesion in the right fronto-parietal cortex suggesting a post-treatment residual tumor

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Figure 3: A 49-year old female patient, who was operated for an oligodendroglioma, grade II, followed by concurrent chemotherapy (temazolamide), which was stopped after 9 months, presented with weakness of extremities, left > right. She was on clobazam and phenytoin at the time of imaging. F-18 FDG PET/CT images (a-transverse, b-sagittal, c-coronal) done for restaging of the disease showed non-FDG avid ill-defined hypodensity in the right frontal cortex, which may be due to post radiation/treatment sequel or residual disease. Subsequent F-18 fluorocholine PET/CT (d-axial, e-sagittal, f-coronal) showed tracer avidity (SUVmax 5.2) in the periphery of the irregular, iso-hypodense lesion in the right frontal cortex, suggesting a recurrent disease

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In this issue, Sogani et al., present their single center prospective study “Potential for differentiation of glioma recurrence from radionecrosis using integrated 18 F-fluoroethyl-L-tyrosine (FET) positron emission tomography/magnetic resonance imaging,” in which they evaluated post-surgery/chemoradiotherapy patients who had enhancing brain lesions that were suspicious of recurrent tumors, using integrated 18 F-FET PET/MRI, and subsequently followed up in their recruited patients with histopathology or clinical/MRI evaluation or PET/MRI imaging.[2] In this paper, the authors highlighted the diagnostic accuracy, sensitivity, and specificity for recurrence detection using three MRI parameters namely Cho: Cr ratio (choline: creatine), N rCBVmean (normalized relative cerebral blood volume) and ADCmean (apparent diffusion coefficient). Addition of FET PET TBR (tumor to background ratios) i.e., TBRmax and TBRmean values, improved the diagnostic accuracy, sensitivity, and specificity for the recurrence detection. The positive correlation between N rCBV mean and FET uptake was suggestive of coupling of tumor vascularity and amino acid uptake with mitotic activity and endothelial proliferation, while the negative correlations between ADCmean and TBR values were indicative of a high FET uptake with lower ADC values in areas of high mitotic potential and increased cellularity. FET images were useful in guiding the MRS voxel selection. The integrated PET/MRI evaluation for recurrent gliomas using multiple MR parameters along with FET PET uptake might be valuable in improving the diagnostic accuracy with a potential to differentiate true recurrence from radiation necrosis.

Levin criteria (using qualitative factors like edema and mass effect), World Health Organization (WHO) oncology response criteria, and MacDonald criteria using contrast enhanced computed tomography (CECT) were used for response assessment to therapy in patients with glioblastoma.[3],[4],[5] These criteria were limited by the subjective variability in interpretation of qualitative parameters, poorly defined response designations and non-specificity of contrast enhancement.[4] As MRI became more common in the1990s, some of these limitations were addressed by the Response Assessment in Neuro-Oncology (RANO) group, by inclusion of T2-weighted or fluid-attenuated inversion recovery (FLAIR) signal hyperintensity as a potential indicator of a non-enhancing tumor. Still, the T2/FLAIR signal was unable to distinguish a non-enhancing tumor from gliosis and/or edema and an inaccurate measurement of regions of T2/FLAIR signal abnormality secondary to ill-defined margins was only possible.[6]

Pseudo-progression and pseudo-response are two recognized challenges faced by clinicians. Pseudo-progression is seen as an area of increased contrast enhancement that eventually subsides without any change in therapy in 20-30% of patients undergoing their first post-radiation MRI. This is likely to result from transiently increased permeability of the tumor vasculature due to irradiation and chemotherapy.[7],[8] Pseudo-response is seen after treatment with anti-angiogenesis agents such as bevacizumab and cediranib, which produce a rapid decrease in enhancement, resulting in high response rates.[9] Thus, additional methods are needed to overcome these pitfalls, and functional imaging using various radiotracers could be valuable along with various MR parameters.

Functional imaging using single photon emission computed tomography (SPECT) tracers like thallium-201, Tc99m sestamibi, Tc99m tetrofosmin, Tc99m glucoheptonate (GHA) have been extensively evaluated for differentiating tumor recurrence from treatment necrosis in the recent past. These tracer agents are preferentially taken up by viable tumor cells but not by necrotic tissues.[10],[11] F-18 fluorodeoxyglucose (FDG) PET has also been tried in differentiating tumor recurrence from tumor necrosis with a variable sensitivity and specificity.[12] The recurrent tumor exhibits a higher tracer uptake due to increased glucose metabolism compared to necrotic lesions post- treatment, though its utility is limited due to the physiological uptake of FDG in glucose-dependent brain tissue. The amino acid radiotracers offer an advantage over FDG PET owing to significantly lower uptake in normal brain parenchyma and inflammatory cells.[13],[14],[15] SPECT tracer agent, iodine-123 IMT (iodo-α-methyltyrosine) exhibits a high tumoral uptake without incorporating into cellular proteins. The issue of availability and lower sensitivity in detecting the small sized lesions has restricted the widespread use of iodine-123 IMT though studies have reported a high degree of accuracy. Similarly, the efficacy of C-11MET (methionine) is limited due to its accumulation in necrotic tissues and the very short half-life of C-11. F-18 FDOPA, with a low normal gray matter tracer uptake, performs superiorly to F-18FDG in evaluating the brain tumor recurrence, and in distinguishing them from treatment necrosis.

F-18 FET PET has been used for tumor delineation and grading, for selection of the best site for biopsy in heterogeneous tumors without contrast enhancement on MRI, therapy planning, early detection of residual tumor after resection, early assessment of tumor response to radiation therapy or chemotherapy, detection of tumor grade transformation, differentiation of progression versus pseudo-progression and prognosis.[16],[17] Dynamic F-18 FET PET can potentially assist in differentiating between different grades of gliomas by generating a time activity curve over the region of interest.[18]

In the era of hybrid imaging, there is a great excitement for combining PET and MRI, which enables us to circumvent the shortcomings of the individual modality and provides a higher diagnostic accuracy than is achieved by a stand-alone modality. Sogani et al., noted that additional MR parameters helped in increasing the diagnostic accuracy over perfusion MR, which was further improved with the addition of FET PET parameters.[2] In a study involving 50 patients with intracerebral lesions that were supposed to be diffuse gliomas on MR imaging, FET-PET and MR spectroscopy analyses markedly improved the diagnostic efficacy of targeted biopsies.[19]

FET images in the current study were useful in guiding MRS voxel selection. The centers without hybrid PET/MRI modality can still use the F-18 FET PET data in selecting area for MRS voxel selection. The improved accuracy and sensitivity with the addition of FET PET findings to advanced MRI parameters are always desirable to achieve the highest diagnostic accuracy. The authors in their study rightfully point to the possibility of combining integrated PET/MR using FET and this needs to be evaluated by further studies. Thus, in conclusion, new therapeutic agents are showing promise in the management of gliomas as well as in presenting us with new diagnostic challenges. The time has come to use the integrated modalities for providing what is best for the patients.

 
  References Top

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Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al.; European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups.; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009; 10: 459–66.  Back to cited text no. 1
    
2.
Sogani SK, Jena A, Taneja S, Gambhir A, Mishra AK, D'Souza MM, et al. Potential for differentiation of glioma recurrence from radionecrosis using integrated 18 F-fluoroethyl-L-tyrosine (FET) positron emission tomography/magnetic resonance imaging: A prospective evaluation. Neurol India 2017;65:293-301.  Back to cited text no. 2
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