¹⁸F-fluorodopa positron-emission tomography: an emerging imaging modality for patients with brain metastases

Abstract

MRI is the preferred method for the diagnosis and monitoring of brain metastases. However, MRI does not provide enough information in some important instances. We explore the potential applications of ¹⁸F-fluorodopa (¹⁸F-FDOPA) PET for patients with brain metastases. Accurate differentiation between tumor recurrence and radiation injury might be possible with the use of ¹⁸F-FDOPA PET. Semi-quantitative and qualitative parameters achieved similar results. Kinetic analysis and time-activity curve patterns could further improve accuracy. ¹⁸F-FDOPA PET also had prognostic value in this setting. Combining the high resolution of MRI with the metabolic information provided by ¹⁸F-FDOPA PET could improve recurrent tumor contouring precision for biopsy, resection or radiation. The promising applications of ¹⁸F-FDOPA PET imaging in the treatment monitoring and planning of brain metastatic tumors require further corroboration but could soon become important instruments to improve diagnostic accuracy, prognosis prediction and treatment planning of the growing population of patients with brain metastatic disease.

Keywords::

• ¹⁸F-FDOPA
• brain metastases
• diagnosis
• PET
• treatment

Brain metastases are the most common type of brain tumor occurring in 20–40% of all cancer patients. They are typically associated with poor outcomes, with median overall survivals reported in the range of 2–9 months. The incidence of brain metastases is estimated to be rising due to an aging population, advances in systemic disease control and improvement in MRI technique and resolution [1]. Several imaging modalities are available for the diagnosis and surveillance of patients with brain metastases. Particularly, the use of brain MRI with contrast is clinical gold standard.

The distinction between radiation injury & tumor progression or recurrence

High-resolution anatomical information can be obtained with MRI. However, there are several instances in which MRI does not provide enough information to guide clinical decision making. One of the most relevant difficulties for patients with brain metastatic lesions is the differentiation between radiation injury and tumor recurrence or progression, particularly in patients treated with radiosurgery [2].

Treatment of brain metastatic lesions encompasses surgical resection, radiotherapy and/or chemotherapy. Radiotherapy has become part of the standard of care for patients with brain metastatic lesions. Hence, radiation injury is not uncommon. In fact, it has been reported in up to 24% of the patients treated with radiosurgery [3].

Serial MRI studies are used for surveillance after radiation therapy. The distinction between tumor recurrence or progression and radiation injury is challenging, given the fact that both types of lesions can have similar clinical (i.e., seizures, focal neurological deficits, intracranial hypertension) and MRI manifestations (i.e., central T1-weighted hypointensity with ring enhancement and surrounding edema) [2]. Opportune distinction can significantly affect patient care and outcomes.

New imaging modalities have been under investigation in an attempt to solve this important clinical question. PET provides metabolic information by measuring the cellular uptake of nuclear tracers. The first one to be used was ¹⁸F-fluoro-desoxyglucose (¹⁸F-FDG) [4,5]. Unfortunately, several studies have shown the diagnostic limitations of ¹⁸F-FDG in brain tumor imaging as normal gray matter has high physiological glucose metabolism. Furthermore, ¹⁸F-FDG uptake can also be affected by inflammation, radiation injury, repair mechanisms and steroid treatment [6,7]. Thus, the accuracy of ¹⁸F-FDG PET to aid in the distinction between radiation injury and tumor progression is limited.

Amino acid analogs are another class of PET tracers for brain tumor imaging [8,9]. Tumor tissue has a high uptake of amino acids. On the contrary, their uptake in normal brain tissue is intrinsically low, thus providing favorable target-to-background ratios and increasing imaging contrast. It is worth to consider that the specificity of amino acid PET imaging for neoplastic lesions could be reduced by the presence of amino acid transporters in glial cells, particularly astrocytes.

¹¹C-methionine (C-MET) has been studied for brain metastatic tumors, with reported sensitivities of 77.8 and 79%, and specificities of 100 and 75% [10,11]. Nonetheless, its short half-life (20 min) makes it difficult for routine clinical application. ¹⁸F-labeled aromatic amino acids such as ¹⁸F-fluoroethyl-tyrosine and ¹⁸F-fluorodopa (¹⁸F-FDOPA) have longer half-lives and other practical advantages for mass production, storage and carriage [12].

Tumor uptake of ¹⁸F-FDOPA is similar to that of C-MET [13]. The distinction of tumor recurrence or progression from radiation injury is possible with the use of ¹⁸F-FDOPA PET [14,15]. A sensitivity of 81.3% and specificity of 84.3% have been recently reported [15]. The sensitivity of ¹⁸F-FDOPA PET could be affected by lesion size, variability in amino acid transport and proliferation rate. Similarly, its specificity could be altered by blood–brain barrier breakdown, inflammation and other variables.

¹⁸F-FDOPA is actively transported into tumor tissue by a neutral amino acid transporter. Interestingly, tumoral time-activity curves are different than those from the striatum. Thus, dopaminergic metabolism or pharmacological agents probably do not influence tumoral ¹⁸F-FDOPA uptake [16].

A qualitative analysis of ¹⁸F-FDOPA PET images visually comparing the uptake of the lesion with that of the contralateral striatum has been proposed. A four-point visual scale was used to qualify lesions as follows: 0, lesion not visible on PET; 1, lesion visible but uptake less than that of the contralateral striatum; 2, lesion uptake isointense to that of the contralateral striatum; and 3, lesion uptake greater than that of the contralateral striatum [15].

Remarkably, this qualitative visual scale achieved diagnostic and prognostic results similar to those of semi-quantitative indices [15]. Striatal ¹⁸F-FDOPA uptake could be influenced by several physiological, pharmacological and pathophysiological processes because of its intrinsic dopaminergic metabolism. Nevertheless, the use of a visual scale could be practical when ¹⁸F-FDOPA uptake quantitative measurements are not available such as in a busy clinical setting.

Patients with a negative ¹⁸F-FDOPA PET (visual scale = 0 or 1) had a significantly longer mean time to progression than those with positive results (visual scale = 2 or 3) (76.5 vs 16.7 months). Additionally, a tendency to better survival for patients with negative ¹⁸F-FDOPA PET lesions was observed (p = 0.06, log rank test). These results suggest a potential use of ¹⁸F-FDOPA PET as a prognostic tool for patients with brain metastatic disease.

It has been observed that increases in ¹⁸F-FDOPA PET uptake after bevacizumab therapy can predict poor response to treatment in recurrent malignant gliomas [17]. Consequently, the intensity of ¹⁸F-FDOPA uptake by the targeted brain metastatic lesion might be used to predict and/or follow its response to treatment with systemic chemotherapy and/or radiotherapy. The use of the above-mentioned visual scale might be practical in this scenario.

Biopsy, surgery & radiation planning

Exact delineation of tumor volume has important implications for biopsy, resection and radiation treatment planning. Unfortunately, PET provides images with low anatomical resolution. Consequently, tumor contouring based solely on PET imaging might not be precise enough.

Comparison of C-MET PET with MRI and computed tomography suggested that PET imaging offers better tumor definition for supratentorial gliomas [18]. In another study, ¹⁸F-FDOPA PET-based target volume definition did not result in better outcomes in patients with high-grade gliomas compared with MRI-based planning [19]. In addition to PET low resolution, these results might be related to the very diffuse nature of these tumors.

Volume definition after the initial diagnosis of brain metastatic tumors is currently best achieved with MRI technology. However, tumors that have already been treated surgically or with radiation become a mixture of neoplastic and non-neoplastic cells (inflammation, necrosis). Anatomic information provided by MRI discloses mostly the breakdown of the blood–brain barrier. Blood–brain barrier breakdown occurs to a variety of causes, tumors, infection, radiation damage and even the mechanic effects of surgery itself. This information is obviously spurious to guide therapy of metastatic lesions. Metabolic information provided by ¹⁸F-FDOPA PET might be valuable for a more precise targeting of the neoplastic component when a clarifying biopsy or further therapy is indicated, either resection or radiation.

Combining the higher spatial resolution of MRI with the metabolic information provided by ¹⁸F-FDOPA PET imaging could be useful to enhance recurrent tumor contouring precision. Studies in patients with brain metastases are needed to define these potential applications.

Conclusion

The promising applications of ¹⁸F-FDOPA PET imaging in the treatment monitoring and planning of brain metastatic tumors require further corroboration. Small sample sizes, retrospective design and lack of pathological confirmation for most of the lesions might have introduced bias in prior reports. Ideally, future studies should be prospective and should compare ¹⁸F-FDOPA PET imaging with histological confirmation, particularly in the setting of recurrent brain metastases. The addition of tracer kinetic analysis and time-activity curve patterns of ¹⁸F-FDOPA PET could also significantly improve sensitivity and specificity, such as has been demonstrated with ¹⁸F-fluoroethyl-tyrosine PET [20].

¹⁸F-FDOPA PET imaging has the potential to soon become an important instrument to improve the diagnostic accuracy, prognosis prediction, surgical treatment planning and ultimately the outcomes of the growing population of patients with brain metastatic disease.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.