Preamble
The Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and professional organization founded in 1954 to promote the science, technology, and practical application of nuclear medicine. Its 18,000 members are physicians, technologists and scientists specializing in the research and practice of nuclear medicine. In addition to publishing journals, newsletters and books, the SNMMI also sponsors international meetings and workshops designed to increase the competencies of nuclear medicine practitioners and to promote new advances in the science of nuclear medicine. The European Association of Nuclear Medicine (EANM) is a professional nonprofit medical association that facilitates communication worldwide among individuals pursuing clinical and research excellence in nuclear medicine, and had 2,800 members in 2017. The EANM was founded in 1985.
The SNMMI/EANM will periodically define new standards/guidelines for nuclear medicine practice to help advance the science of nuclear medicine and to improve the quality of service to patients. Existing standards/guidelines will be reviewed for revision or renewal, as appropriate, on their fifth anniversary or sooner, if indicated. As of February 2014, the SNMMI guidelines will now be referred to as procedure standards. Any previous practice guidelines or procedure guidelines that describe how to perform a procedure are now considered SNMMI procedure standards. Each of the standards/guidelines, that represents a policy statement by the SNMMI/EANM, has undergone a thorough consensus process in which it has been subjected to extensive review. The SNMMI/EANM recognizes that the safe and effective use of diagnostic nuclear medicine imaging requires specific training, skills and techniques, as described in each document.
The EANM and SNMMI have written and approved these standards/guidelines to promote the use of nuclear medicine procedures of high quality. These standards/guidelines are intended to assist practitioners in providing appropriate nuclear medicine care for patients. They are not inflexible rules or requirements of practice and are not intended, nor should they be used, to establish a legal standard of care. For these reasons and those set forth below, the SNMMI/EANM cautions against the use of these standards/guidelines in litigation in which the clinical decisions of a practitioner are called into question.
The ultimate judgment regarding the propriety of any specific procedure or course of action must be made by medical professionals taking into account the unique circumstances of each case. Thus, there is no implication that an approach differing from the standards/guidelines, standing alone, is below the standard of care. To the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set forth in the standards/guidelines when, in the reasonable judgment of the practitioner, such course of action is indicated by the condition of the patient, limitations of available resources, or advances in knowledge or technology subsequent to publication of the standards/guidelines.
The practice of medicine involves not only the science but also the art of dealing with the prevention, diagnosis, alleviation and treatment of disease. The variety and complexity of human conditions make it impossible to always reach the most appropriate diagnosis or to predict with certainty a particular response to treatment. Therefore, it should be recognized that adherence to these standards/guidelines will not ensure an accurate diagnosis or a successful outcome. All that should be expected is that the practitioner will follow a reasonable course of action based on current knowledge, available resources and the needs of the patient to deliver effective and safe medical care. The sole purpose of these standards/guidelines is to assist practitioners in achieving this objective.
The present guidelines/standards were developed collaboratively by the EANM and SNMMI with the European Association of Neurooncology (EANO) and the working group for Response Assessment in Neurooncology with PET (PET-RANO). They summarize the views of the Neuroimaging, Oncology and Physics Committees of the EANM, the Brain Imaging Council of the SNMMI, the EANO, and PET-RANO, and reflect recommendations for which the EANM cannot be held responsible. The recommendations should be taken into the context of good practice of nuclear medicine and do not substitute for national and international legal or regulatory provisions.
Introduction
Gliomas are the second most common primary brain tumour with an annual incidence rate of around six cases per 100,000 individuals worldwide [
1]. Gliomas represent approximately 27% of all central nervous system (CNS) tumours and 80% of malignant CNS tumours, and are a leading cause of cancer mortality in adults. The most common of all malignant brain and CNS tumours is glioblastoma (46%) which is associated with a median overall survival of 15 months in patients treated with maximal safe tumour resection, concomitant radiotherapy/chemotherapy and adjuvant chemotherapy [
2].
Magnetic resonance imaging (MRI) is the primary clinical imaging modality in patients with glioma at all disease stages including the primary evaluation, presurgical planning, early postsurgical evaluation of residual tumour, radiotherapy planning, surveillance during chemotherapy, and definition of recurrence.
There are defined objective and standardized MRI-based criteria for response assessment in neurooncology (RANO) applied to clinical trials in patients with brain tumours. However, MRI contrast enhancement can be unreliable as a surrogate for tumour size or growth. It nonspecifically reflects vascular surface area and the permeability of the contrast agent across a disrupted blood–tumour barrier and may represent tumour biology or a number of other factors including therapy-induced inflammation. Contrast enhancement can be influenced by therapeutics that affect tumour vascular permeability, such as corticosteroid, antiangiogenic [
3] or immunotherapy agents [
4]. Because of the growing awareness of significant limitations of MRI in the management of glioma, the RANO criteria were recently updated [
5]. Hence, to identify infiltrative glioma tissue, the RANO definition of tumour progression was supplemented by inclusion of “significant” enlarging areas of nonenhancing tumour on MRI T2-weighted and fluid-attenuated inversion recovery (FLAIR) image sequences. However, precise quantification of increases in the T2/FLAIR signal could not be defined and other causes of increased T2 or FLAIR signal, such as radiation effects, demyelination, ischaemic injury and oedema have to be considered in the evaluation of progression.
Molecular imaging using positron emission tomography (PET) is a well-established method in systemic oncology [
6], and is being increasingly used to supplement MRI in the clinical management of glioma [
7‐
9]. PET imaging could have an important role in clinical trials of new strategies for the treatment of glioma, e.g. immunotherapy, where pseudoprogression is particularly challenging for MRI [
4]. Recently an evidence-based recommendation by the PET-RANO working group and EANO on the clinical use of PET imaging in gliomas has been published focusing on radiotracers used in clinical practice imaging, i.e. glucose metabolism, 2-deoxy-2-[
18F]fluoro-
D-glucose (FDG), and system L amino acid transport comprising [
11C-methyl]-methionine (MET),
O-(2-[
18F]fluoroethyl)-
L-tyrosine (FET) and 3,4-dihydroxy-6-[
18F]fluoro-
L-phenylalanine (FDOPA) [
7].
The present guidelines/standards focus on the technical aspects of PET image acquisition with the above-mentioned radiotracers, and thus replace all previously published guidelines on glioma imaging [
10].
Aim
The aim of these standards/guidelines is to assist nuclear medicine practitioners in recommending, performing, interpreting, and reporting the results of brain PET imaging in patients with glioma.
Definitions
1.
PET systems provide static, dynamic or gated images of the distribution of positron-emitting radionuclides within the body by detecting pairs of photons produced in coincidence by the annihilation of a positron and an electron. PET images are produced by a reconstruction process using the coincidence pair data.
2.
PET is generally combined with computed tomography (CT) in a single system (PET/CT). Combined PET/MRI systems are also available for clinical use but are currently less widely available.
3.
Nuclear medicine computer systems and software applications collect, quantitate, analyse and display the imaging information.
Common clinical indications
Common indications for PET imaging in glioma include, but are not limited to, the following [
7]:
1.
At primary diagnosis
(a)
Differentiation of grade III and IV tumours from nonneoplastic lesions or grade I and II gliomas
(b)
Prognostication of gliomas
(c)
Definition of the optimal biopsy site (e.g. site of maximum tracer uptake)
(d)
Delineation of tumour extent for surgery and radiotherapy planning
2.
Diagnosis of tumour recurrence
(a)
Differentiation of glioma recurrence from treatment-induced changes, e.g. pseudoprogression, radionecrosis
3.
Disease and therapy monitoring
(a)
Detection of malignant transformation in grade I and II gliomas
(b)
Response assessment during and after radiotherapy and/or chemotherapy
(c)
Differentiation of tumour response from pseudoresponse during antiangiogenic therapy
The performances of the PET tracers presented in this guideline are different as discussed in a recent evidence-based recommendation [
7].
FDG PET plays a more limited role than amino acid PET in the imaging of gliomas due to the high physiological uptake of FDG in normal brain grey matter and variable uptake by inflammatory lesions. FDG PET is most often used to distinguish tumour recurrence from radiation necrosis in enhancing brain lesions or to distinguish glioma from CNS lymphoma or opportunistic infection.
Qualifications and responsibilities of personnel
Examination procedures/specifications
Recommendations for FDG-specific procedures are defined in previous guidelines, and only recommendations that are new or particular to glioma are discussed [
12,
13].
Request
A nuclear medicine imaging facility staff member should check with the nuclear pharmacy provider as to the availability of the radiotracer before scheduling the examination. Advanced notice may be required for tracer delivery.
The study requisition should include:
1.
Appropriate clinical information about the patient and a clearly specified clinical question to justify the study and to allow appropriate examination/study coding (
see section
Common clinical indications).
2.
Information about the ability of the patient to cooperate with the examination and the participation of a carer may be helpful.
3.
Information about current medications, including glucocorticoids, for correct study interpretation and to avoid unwanted pharmacological interaction effects if mild sedation is necessary.
4.
History of prior therapy, including prior chemotherapy, surgery and radiotherapy, which might affect radiopharmaceutical distribution.
5.
Results of pertinent imaging studies, resections and biopsies performed, and laboratory results.
6.
For PET/MRI, all patients should be screened at request for relevant contraindications to MRI using a standardized checklist (e.g. pregnancy, contrast agent reactions, implants, ports, catheters, metallic implants, vascular stents, coils, active implants, cardiac pacemakers, claustrophobia, etc.) [
14].
Patient preparation and precautions
1.
The height and body weight of the patient must be documented for measurement of standardized uptake values (SUV;
see section
Static FET, MET, FDOPA PET,
item 1).
2.
Recent morphological imaging with MRI (T1, T1 + contrast medium, T2/FLAIR) should be available for image fusion.
3.
The patient should be informed about the procedure to guarantee optimal compliance.
4.
The patient should be able to lie down quietly for at least 30 to 40 min.
5.
If sedation is required for MET, FET or FDOPA imaging, it should start about 20–60 min before the examination. If sedation is required for FDG imaging, sedation should start as late as possible after FDG administration, ideally at least 30 min after FDG injection but prior to imaging.
6.
The patient should be required to fast before the examination to ensure stable metabolic conditions. A minimum 4-h fast is recommended for MET, FET, FDOPA, and FDG imaging.
7.
Serum glucose should/may be measured before FDG administration so that the interpreting physician is aware of the potential for altered biodistribution.
8.
Before scanning, patients should empty their bladder for maximum comfort during the study and in order to reduce the absorbed dose to the bladder (
see section
Radiation safety).
9.
In pregnant patients, it is necessary to make a clinical decision that weighs the benefits to the patient against possible harm [
6].
10.
For FDOPA PET, premedication with carbidopa is not necessary. Most published studies to date with FDOPA PET in patients with brain tumour have not used carbidopa or other inhibitors of peripheral FDOPA metabolism.
11.
If the PET study is to be acquired as part of a PET/MRI study:
(a)
Check MRI contraindications from checklist (
see section
Request,
item 6).
(b)
Remove all metal from the patient (e.g. dental prostheses, clothing with zippers and buttons), and provide cotton clothing for the patient.
(c)
In patients with an implant, the specific type of implant, its location and its component materials need to be known before an MRI examination. The patient should be asked for an implant pass. The safety level of an implant/device should be checked with the manufacturer (e.g. online): “MRI unsafe” is an absolute contraindication; “MRI conditional” is a relative contraindication, conditions apply; “MRI safe” is no contraindication.
(d)
If the patient has a metal implant or active device labelled “MRI conditional”, information should be obtained about all the conditions that may apply for safe MRI examination (e.g. from the implant pass or online).
(e)
Beyond safety concerns, implants may cause artefacts, large-volume signal voids and geometric distortions on MRI images. These may hamper image reading.
12.
It is recommended that the patient stay well hydrated and empty the bladder often.
Radiopharmaceuticals
-
2-Deoxy-2-[18F]fluoro-D-glucose; fludeoxyglucose F18 (FDG)
-
O-(2-[18F]Fluoroethyl)-L-tyrosine (FET)
-
L-[methyl-11C]Methionine; methionine C11 (MET)
-
3,4-Dihydroxy-6-[18F]fluoro-L-phenylalanine; fluorodopa F18 (FDOPA)
The above radiopharmaceuticals should be injected as a bolus.
PET acquisition protocols
PET image reconstruction
1.
During image reconstruction, all corrections for quantitative interpretation are required including attenuation, scatter, random, dead time and decay corrections, as well as detector sensitivity normalization.
2.
Time of flight acquisitions and reconstructions are allowed, although the benefit for brain imaging has not yet been fully investigated.
3.
Iterative reconstruction is the field standard and should be applied. However, if iterative reconstruction would result in upward bias due to non-negativity constraints applied during reconstruction, filtered back-projection reconstruction may be used as an alternative method.
4.
The use of resolution modelling during reconstruction, so-called point-spread-function (PSF) reconstructions, may give rise to Gibbs artefacts and quantitative errors [
26], and this method is not recommended.
5.
To harmonize PET image quality, the following reconstruction settings/protocols are recommended:
(a)
One of the reconstructions should be performed using settings such that the reconstructed images meet EARL requirements for image quality recovery [
6], thereby allowing harmonization of PET data for multicentre settings or for use with reference datasets.
(b)
As the above harmonizing reconstruction settings will ensure comparable image quality among different generations of PET/CT systems, a higher resolution reconstruction may be desired or required for visual interpretation or tumour delineation. When a specific PET system allows the use of multiple reconstructions, a high-resolution dedicated brain reconstruction protocol may be applied. Such a protocol should preferably meet the following requirements:
-
Voxels size 1–2 mm, but <3 mm in any direction
-
Reconstructed spatial resolution <6 mm full-width at half-maximum
Interpretation/quantification
Standardized uptake value calculations and image analysis
Documentation and reporting
Description of findings in brain tumour imaging should generally comply with previously published guidelines for FDG imaging in oncology and with regard to general aspects of reporting such as due diligence [
6].
The content of the report affects patient management and clinical outcomes, and is a legal document. It is good practice to provide a structured report with concise concluding statements intended to answer the specific clinical question(s) posed, if possible.
Regardless of the radiotracer, reports should follow the general structure outlined below.
Equipment specifications
System specifications
The use of state-of-the-art 3D PET/CT or PET/MRI systems is recommended. The system should allow collection of low-dose CT images or MRI-based sequences that can be used for attenuation and scatter correction of the PET emission data. A dedicated brain PET-only system may be used provided it is equipped with transmission scan sources of sufficient strength – as recommended by the manufacturer – to ensure sufficient quality of the transmission scans and thereby of the PET emission data attenuation correction. PET(/CT) systems should have a minimal axial field of view of 15 cm to ensure sufficient coverage of the entire brain, including cerebellum and brainstem.
PET acquisition
The system should be able to acquire both static and dynamic or list-mode PET emission data in 3D mode. Data should be reconstructed online or offline (i.e. retrospectively) in single or multiple frames, as specified by the study protocols and these guidelines. In addition, PET images should be able to be reconstructed with and without attenuation correction. The PET images without attenuation correction should not be used for primary interpretation but can be useful for recognizing attenuation artefacts in the attenuation-corrected PET images. The system should have all functionalities and methods available as required for quantitative brain PET imaging and reconstruction, including, but not limited to, online randoms correction, scatter correction, attenuation correction, dead time correction, decay and abundance correction and normalization (correction for detector sensitivities).
Quality control and improvement
Quality control and interinstitutional PET system performance harmonization
Various factors affecting PET image quality and quantification have previously been reviewed [
91]. Although this review focused on the use of radiolabelled amino acids and FDG for glioma imaging, the technical and imaging physics uncertainties indicated in that review are valid for any PET examination regardless of radiotracer or specific application. The use of brain PET examinations in multicentre studies and/or when data are compared with a reference database or disease pattern, it is of the utmost importance that PET data are collected in such a manner that they can be pooled and compared. In order to guarantee sufficient image quality, quantitative performance and image harmonization, the performance of the PET systems must be regularly checked by several QC experiments. All regular and vendor-provided maintenance and QC procedures should be followed. QC experiments should at least address the following:
-
Daily check of detector performance, i.e. with point, rod or cylindrical sources to automatically test and visualize the proper functioning of detector modules including inspection of 2D sinograms.
-
Daily check of PET activity concentration measurement calibration using an activity filled cylindrical phantom source following the procedure recommended by the manufacturer.
-
Cross-calibration of the PET(/CT) system against the locally used dose calibrator to prepare and measure patient-specific radiotracer activities. Cross-calibrations should be performed following EARL recommendations and criteria.
-
Correct alignment between PET and CT should be verified according to the procedure and frequency recommended by the manufacturer.
-
Additional QC procedures performed less frequently following the instructions provided by the manufacturer and the EANM recommendations for routine QC of nuclear medicine equipment [
92].
MR quality control in PET/MRI
While there are no regulatory requirements for special/standard QC/QA procedures for MRI systems, numerous points should be considered for conducting safe and high-quality MRI examinations as outlined in section
Examination procedures/specifications. It is advisable to adhere to the recommendations of the manufacturer (i.e. follow the planned maintenance intervals). For PET/MRI systems an approach to basic MRI QC to be performed by the user is described in a review by Sattler et al. [
93].
Radiation safety
The systemic use of radiotracers leads to systemic exposure of the patients to radiation. The amounts of radioactivity usually delivered with the administration of
11C-labelled and
18F-labelled PET radioligands (
see section
Administered activity in adults) result in effective doses (ED) of the same order of magnitude as delivered by other
11C-labelled and
18F-labelled radiotracers [
94]. The radiation dose from low-dose CT scans of the head region depends on the CT scanning parameters and is generally well below 0.5 mSv. The overall ED from PET/CT investigations of the head region, when accounting for the whole-body exposure, should remain near or below 5 mSv. In adults, the organ with the highest radiation dose for all the above tracers is the urinary bladder wall (Table
3).
Table 3
Radiation dosimetry
18F-FDG | Urinary bladder wall: 0.13 | 0.019 | 1 year: 0.095 5 years: 0.056 10 years: 0.037 15 years: 0.024 | |
18F-FET | Urinary bladder wall: 0.085 | 0.016 | 1 year: 0.082 5 years: 0.047 10 years: 0.031 15 years: 0.021 | |
11C-MET | Urinary bladder wall: 0.092 | 0.0082 | 1 year: 0.047 5 years: 0.025 10 years: 0.016 15 years: 0.011 | |
18F-FDOPA | Urinary bladder wall: 0.30 | 0.025 | 1 year: 0.10 5 years: 0.07 10 years: 0.049 15 years: 0.032 | |
Conclusion
Since the previous EANM guidelines in 2006 [
10], the clinical use of molecular imaging with PET and PET/CT in the diagnosis of glioma has continuously increased in Europe and the US. For successful and appropriate use of this technology, a clear understanding of the capabilities and limitations of the technology and appropriate patient selection, preparation, scan acquisition and image reconstruction are required. This document attempts to provide some guidance on the performance and interpretation of molecular imaging to supplement recent clinical guidelines [
7], and to bring PET brain imaging into daily clinical practice and into larger scale interinstitutional clinical neurooncological trials across imaging platforms.
Acknowledgments
These guidelines were brought to the attention of all other EANM committees and the national societies of nuclear medicine, and received confirmatory statements from Italy, Latvia and Germany. The comments and suggestions from the EANM Radiation Protection and the Technologist Committee are highly appreciated and were considered in the preparation of these guidelines. We acknowledge the contribution of previous guidelines on which the present are based [
10,
12,
13,
96].
Compliance with ethical standards
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.