Towards standardization of ¹⁸F-FET PET imaging: do we need a consistent method of background activity assessment?

PET with O-(2-¹⁸F-fluoroethyl)-L-tyrosine (¹⁸F-FET) has reached increasing clinical significance for the workup of patients suffering from brain neoplasms as an additional and highly valuable imaging tool. As recently emphasized by the RANO working group [1], clinical applications of ¹⁸F-FET PET are represented by, e.g., treatment planning [2], patient monitoring [3], prognostication at initial diagnosis [4, 5], and evaluation of pseudoprogression [6]. Particularly, PET parameters such as the maximal tumor-to-background-ratio (TBR_max) are used in clinical routine, e.g., for response assessment of alkylating and antiangiogenic agents [7‐9] or differentiation of viable tumor from treatment-related changes [10‐13].

For evaluation of ¹⁸F-FET PET parameters, a background-activity reference in unaffected brain tissue is used to enable intra- and inter-individual comparability of PET results. The European Association of Nuclear Medicine (EANM) guideline for brain tumor imaging stated “Interpretation of quantitative results is based on the comparison of tumor-to-background uptake ratio,” and although the guideline pointed to a potential source of error by “small regional differences in uptake in normal brain, emphasizing the need for careful choice of an appropriate reference region” [14], there is no procedural recommendation regarding the method of background assessment. Therefore, several different and inconsistent approaches for background assessment are used in the current literature and in the clinical routine: one approach uses a region of interest (ROI) in the contralateral hemisphere including white and gray matter [15, 16], which is in line with the German guideline for amino acid imaging, which stated that a ROI should be placed in unaffected contralateral brain tissue, “e.g., with a diameter of 50 mm” [17]. Other approaches apply volumes-of-interest (VOI) including gray and white matter, i.e., a spherical VOI with a diameter of 30 mm [18, 19] or a VOI consisting of crescent-shaped ROIs [13, 20]. Although first suggestions were made regarding a software-based assessment using [¹¹C]-methionine PET previously [21], there is still no standardized and consistent procedure used in the clinical routine.

Hence, we intended to elucidate the effects of different approaches for background activity assessment and to evaluate simple and clinically applicable methods of background activity assessment for ¹⁸F-FET PET imaging regarding their inter- and intra-reader variability in the light of an emphasized comprehensive standardization of amino acid PET.

Complementary to MRI, ¹⁸F-FET PET has gained clinical importance for the diagnostic workup of brain tumor patients in all disease stages, as recently recommended by the RANO and EANO working group [1]. However, the methods of PET evaluation are not yet standardized. In particular, the approaches for background activity assessment are variable, although background assessment is essential for the evaluation of TBR values as well as quantification of biological tumor volume. For the implementation of ¹⁸F-FET PET into clinical trials, a methodological PET standardization is urgently needed to enable more precise and reproducible ¹⁸F-FET PET quantification.

Looking at the present data it can be stated that the different approaches under investigation show a certain variability on an intra-individual as well as on an inter-individual basis with expectable background SUV changes up to ±8% (which means a notable dispersion of up to 16%) and might therefore be considered as potential source of methodological error besides known influencing factors such as different reconstruction algorithms and diverging PET scanners.

When evaluating the different background assessment approaches, the use of a single ROI showed a relatively high intra- and inter-reader variability; this might be due to the assessment of a relatively small regional part of unaffected brain only (ROI vs. VOI in the other approaches) as well as unprecise description regarding shape and spatial localization, as ambiguously stated in the German guideline for amino-acid PET (“[…] a larger background ROI in the contralateral and unaffected hemisphere including gray and white matter (diameter, e.g., 50 mm)”) [17].

Although the application of a spherical VOI with a fixed diameter of 3 cm represents a uniform approach without individual changes regarding the shape of the VOI, this approach likewise showed a relatively high variability; the rigid shape did not necessarily lead to high stability of SUV measurement since areas inappropriate for background assessment might be included inevitably due to individual morphologic properties, e.g., the ventricular system.

In comparison to these two approaches, the use of crescent-shaped VOIs provided both the lowest intra-reader and inter-reader variability. An advantage of this approach might be the possible adaption of the individual morphologic properties. Nonetheless, some single outlining scans with an inter-reader CoV up to 7% occurred in our analysis, most likely due to a differing localization of the six sequential crescent-shaped ROIs in different brain areas with slightly different background activities throughout the six readers. This can be stated since the variabilities were very small within single readers, leading to the assumption that every single reader had a constant method of manual VOI definition. Therefore, we consequently intended to guide the manual defining of the crescent-shaped VOI to further reduce the inter-reader variability using the instructions described in the “Methods” section. These instructions intended to provide a high standardization in terms of shape and localization of the applied VOIs. Indeed, this approach showed the lowest variability between the readers with a median inter-reader CoV of 1.19% (range 0.84–1.89%) and therefore a maximum expectable dispersion <4% regarding the background SUV. Interestingly, this approach could additionally reduce the individual intra-reader variabilities when compared to the “unguided” crescent-VOI approach (1.10% (range 0.52–2.36%) vs. 1.52% (range 0.48–3.78%)). Besides, the possibility of an adaption of the VOI shape according to individual morphologic properties, an explanation for the low variability of the crescent-shaped VOI approach might be that the summation of six crescent-shaped ROIs led to relatively large volumes, which could also contribute to the higher stability. Furthermore, the crescent-shaped VOI is characterized by a balanced inclusion of gray and white matter, while the proportion and composition of included structures might be more variable depending on the exact positioning of a ROI/VOI with a fix shape.

Although the overall variability might seem moderate at first sight, it is important to note that there are outliners up to a CoV of 8% when using the spherical approach. In clinical routine, this leads to an expectable difference of up to +8% as well as −8% of the background SUV. This would not only lead to substantially different TBR values but also to substantially different thresholds for the delineation of the BTV, which is commonly defined by 1.6 × background activity. For visualization, the maximal intra-reader as well as inter-reader differences and their consequences on the clinically important ¹⁸F-FET PET parameters are presented in clinical examples (see Fig. 4).

In the clinical routine, high differences regarding the TBR could substantially influence the conclusion of a PET scan and thereby hamper the diagnostic value, e.g., when used for differentiation of treatment-related changes and viable tumor [11‐13]. In particular, distinct cutoff values for the evaluation of gliomas are used in clinical routine [3, 10], e.g., the cutoff TBR_mean ≥ 2.0 differentiates progressive disease from treatment-related changes with a high accuracy. This is also true for the BTV evaluation, e.g., when used for response-assessment during chemotherapy [7‐9], where distinct changes of, e.g., 20% are considered as treatment response and vice versa. Additionally, besides the mere quantitative information of the volumetric measure, the spatial localization and extent of the tumor tissue, influenced by the background assessment, might also have an impact on the clinical workup, e.g., regarding radiotherapy planning [2, 24]. Nonetheless, the interfering factor can considerably be reduced as highlighted using the crescent-shaped VOI approach for background activity assessment.

This is especially the case since the application of the crescent-shaped VOI showed the lowest variabilities in the subgroups of the experienced and unexperienced readers in terms of both intra- and inter-reader variability. Additionally, the use of the detailed instructions for a guided VOI could additionally reduce the variability. It should be pointed out that possibly influencing factors, such as “non-neoplastic” lesions (e.g., major infarctions in MRI, cysts), should not be included in the background VOI.

Our results are of high interest with regard to multicenter comparisons and anticipated multicenter studies, which require a high degree of standardization in order to provide reproducible and reliable PET data in all sites performing amino acid imaging of brain tumors. Besides the standardization of ordinary influencing factors such as reconstruction algorithms and PET scanner type, it will, according to our results, be important to standardize the particular method of background activity assessment.

Although a software-based method had already been suggested for [¹¹C]-methionine PET 10 years ago [21], it is essential to find a quick and unpretentious, but reliable approach without any need of further hardware or software solutions, which might be suitable for basic research applications, but surely hamper the clinical implementation. Within the commonly applied methods, the crescent-shaped VOI assessment showed the lowest variabilities even in unexperienced readers and the best results were reached with simple instructions for a guided VOI assessment. We therefore propose this method as possible and clinically applicable approach for methodological standardization, which is strongly needed, since the current RANO/EANO recommendations for the clinical use of PET imaging in gliomas, which were recognized very positively in the literature [25, 26], emphasized the implementations of amino acid PET in future prospective multicenter trials but pointed out that “[…] numerous studies differed in terms of methodology, which limits comparability of data and might eventually jeopardize acceptance in the clinical setting.” [1]. In the context of the anticipated standardized technical guidelines for glioma PET imaging procedures and recommendations by the EANM, EANO, and RANO [1], the use of a standardized approach for background activity assessment might be an important methodological landmark.

Among the commonly used methods for the assessment of background activity in ¹⁸F-FET PET, the (guided) crescent-shaped VOI in the contralateral hemisphere reveals the most stable results and can substantially minimize both intra- and inter-reader variability. It represents a quick and easily applicable approach for the clinical routine, which might facilitate comprehensive methodological standardization of amino acid PET evaluation and strengthen its value in the clinical setting.