Francesco Cicone

Amino acid PET and MR perfusion imaging in brain tumours

PurposeDespite the excellent capacity of the conventional MRI to image brain tumours, problems remain in answering a number of critical diagnostic questions. To overcome these diagnostic shortcomings, PET using radiolabeled amino acids and perfusion-weighted imaging (PWI) are currently under clinical evaluation. The role of amino acid PET and PWI in different diagnostic challenges in brain tumours is controversial.MethodsBased on the literature and experience of our centres in correlative imaging with PWI and PET using O-(2-[18F]fluoroethyl)-l-tyrosine or 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine, the current role and shortcomings of amino acid PET and PWI in different diagnostic challenges in brain tumours are reviewed. Literature searches were performed on PubMed, and additional literature was retrieved from the reference lists of identified articles. In particular, all studies in which amino acid PET was directly compared with PWI were included.ResultsPWI is more readily available, but requires substantial expertise and is more sensitive to artifacts than amino acid PET. At initial diagnosis, PWI and amino acid PET can help to define a site for biopsy but amino acid PET appears to be more powerful to define the tumor extent. Both methods are helpful to differentiate progression or recurrence from unspecific posttherapeutic changes. Assessment of therapeutic efficacy can be achieved especially with amino acid PET, while the data with PWI are sparse.ConclusionBoth PWI and amino acid PET add valuable diagnostic information to the conventional MRI in the assessment of patients with brain tumours, but further studies are necessary to explore the complementary nature of these two methods.

Prognostic value of FDG uptake by the bone marrow in squamous cell carcinoma of the head and neck.

BackgroundThe appearance of natural suppressor cells and circulating endothelial progenitor cells in tumour tissue has been associated with myelopoetic stimulation by growth factors that may increase fluorodeoxyglucose (FDG) uptake by the bone marrow and high FDG uptake by bone marrow in patients suffering from human malignancies is a not uncommon finding. MethodsThis study looked at the relationship between bone marrow FDG uptake, biochemical (Hb level, RBC count, WBC count and platelet count), clinical and radiological findings and outcome in a series of 35 patients suffering from squamous cell carcinoma of the head and neck (SCCHN), consecutively referred for FDG PET as part of their routine staging procedure. Results and conclusionIn SCCHN, mean FDG standardized uptake values (SUVs) of the primary tumour correlate significantly with blood WBC count (r=0.44; P=0.011, Bonferroni corrected P=0.04) and mean FDG SUVs of bone marrow are significantly correlated to the maximum FDG SUVs of the primary tumour (r=0.523; P=0.002). Finally, FDG uptake by the bone marrow is related to disease-free and overall survival. These findings warrant confirmation in a larger patient series.

Variations in the practice of molecular radiotherapy and implementation of dosimetry: results from a European survey

BackgroundCurrently, the implementation of dosimetry in molecular radiotherapy (MRT) is not well investigated, and in view of the Council Directive (2013/59/Euratom), there is a need to understand the current availability of dosimetry-based MRT in clinical practice and research studies. The aim of this study was to assess the current practice of MRT and dosimetry across European countries.MethodsAn electronic questionnaire was distributed to European countries. This addressed 18 explicitly considered therapies, and for each therapy, a similar set of questions were included. Questions covered the number of patients and treatments during 2015, involvement of medical specialties and medical physicists, implementation of absorbed dose planning, post-therapy imaging and dosimetry, and the basis of therapy prescription.ResultsResponses were obtained from 26 countries and 208 hospitals, administering in total 42,853 treatments. The most common therapies were 131I-NaI for benign thyroid diseases and thyroid ablation of adults. The involvement of a medical physicist (mean over all 18 therapies) was reported to be either minority or never by 32% of the responders. The percentage of responders that reported that dosimetry was included on an always/majority basis differed between the therapies and showed a median value of 36%. The highest percentages were obtained for 177Lu-PSMA therapy (100%), 90Y microspheres of glass (84%) and resin (82%), 131I-mIBG for neuroblastoma (59%), and 131I-NaI for benign thyroid diseases (54%). The majority of therapies were prescribed based on fixed-activity protocols. The highest number of absorbed-dose based prescriptions were reported for 90Y microsphere treatments in the liver (64% and 96% of responses for resin and glass, respectively), 131I-NaI treatment of benign thyroid diseases (38% of responses), and for 131I-mIBG treatment of neuroblastoma (18% of responses).ConclusionsThere is a wide variation in MRT practice across Europe and for different therapies, including the extent of medical-physicist involvement and the implementation of dosimetry-guided treatments.

Follicular lymphoma at relapse after rituximab containing regimens: comparison of time to event intervals prior to and after 90Y‐ibritumomab‐tiuxetan

Radioimmunotherapies with Zevalin® (RIT‐Z) showed encouraging results in patients with relapsed/refractory follicular lymphoma (FL), leading frequently to failure‐free intervals longer than those achieved by the last previous therapy. We compared time‐to‐event variables obtained before and after RIT‐Z in patients with relapsed FL, previously exposed to rituximab. All patients with relapsed non‐transformed, non‐refractory, non‐rituximab‐naïve FL who have been treated with RIT‐Z in two different centres in Europe were included. Staging and response were assessed by contrast‐enhanced CT in all patients; PET/CT was performed according to local availability. Event‐free survival (EFS) and time to next treatment (TTNT) following the last previous therapy and after RIT‐Z were compared. Pre‐therapy characteristics were tested in univariate analyses for prediction of outcomes. A description of the patterns of relapse was also provided. Among 70 patients treated, only 16 fulfilled the inclusion criteria. They were treated with a median of 3 prior lines of chemo‐immunotherapies, including a median of 2 rituximab‐containing regimens; 6 patients had undergone myeloablative chemotherapy with autologous stem cell rescue (ASCT). Overall response rates were 10 (62%) CR/CRu, 3 (19%) PR and 3 (19%) PD; response rates were similar in patients with prior ASCT. After RIT‐Z only few patients obtained EFS and TTNT longer than after the last previous therapy. All four patients receiving rituximab maintenance were without progression 12 months after RIT‐Z. Relapses occurred in both previously and newly involved sites; a significant association was found between the number of pathologic sites involved prior to RIT‐Z and subsequent TTNT. Despite the excellent response rate, the duration of response was shorter than the previous one confirming the known trend of relapses to occur earlier after subsequent treatments. Rituximab maintenance after RIT‐Z showed encouraging results in terms of prolonging EFS, warranting further studies. Copyright

Multiparametric evaluation of low grade gliomas at follow-up: comparison between diffusion and perfusion MR with 18F-FDOPA PET

OBJECTIVE To compare MRI using perfusion and diffusion techniques with 6-[(18)F]-fluoro-L-3,4-dihydroxyphenylalanine ((18)F-FDOPA) positron emission tomography (PET) in the follow-up of low-grade gliomas (LGGs) and to identify the best imaging parameter to differentiate patients with different prognosis. METHODS Between 2010 and 2015, 12 patients with a pathology-proven diagnosis of LGG and MR (with perfusion and diffusion sequences) and a PET study during their follow-up were retrospectively included in our study. Cerebral blood volume (CBV) and apparent diffusion coefficient (ADC) maps on MR studies and PET images were evaluated using a region of interest-based method. All patients were categorized as stable or as having progressive disease at 1-year follow-up. Statistical analysis was performed using Pearsons correlation test and multivariate analysis of variance (p < 0.05). RESULTS No significant correlations were found between PET parameters [maximum tumour-to-controlateral normal brain ratio (T/Nmax) and tumour-to-striatum ratio] and ADC or relative CBV values measured in both PET hotspot regions and areas of maximum signal alterations. T/Nmax demonstrated a good sensitivity (83%) and specificity (100%) for differentiating two subgroups of patients with different outcomes at 1-year-follow-up (p < 0.05). CONCLUSION Perfusion and diffusion MR images provide different information compared with (18)F-FDOPA PET in LGGs during follow-up and therefore, they should be considered as complementary tools in the evaluation of these tumours. (18)F-FDOPA PET showed a significant prognostic role in the follow-up of LGGs and appeared to be a better tool than MR advanced techniques for outcome prediction. These results need to be confirmed with longitudinal studies on a larger population. ADVANCES IN KNOWLEDGE This is the first study that compared (18)F-FDOPA PET with perfusion and diffusion MR in LGGs during follow-up. These preliminary results highlight the importance of a multimodality approach in this field and evidence a potential role for (18)F-FDOPA PET to predict patients at risk for tumour progression.

Quantification of Dose Nonuniformities by Voxel-Based Dosimetry in Patients Receiving 90Y-Ibritumomab-Tiuxetan

UNLABELLED Abstract Objective: To assess the impact of nonuniform dose distribution within lesions and tumor-involved organs of patients receiving Zevalin(®), and to discuss possible implications of equivalent uniform biological effective doses (EU-BED) on treatment efficacy and toxicity. MATLAB™ -based software for voxel-based dosimetry was adopted for this purpose. METHODS Eleven lesions from seven patients with either indolent or aggressive non-Hodgkin lymphoma were analyzed, along with four organs with disease. Absorbed doses were estimated by a direct integration of single-voxel kinetic data from serial tomographic images. After proper corrections, differential BED distributions and surviving cell fractions were estimated, allowing for the calculation of EU-BED. To quantify dose uniformity in each target area, a heterogeneity index was defined. RESULTS Average doses were below those prescribed by conventional radiotherapy to eradicate lymphoma lesions. Dose heterogeneity and effect on tumor control varied among lesions, with no apparent relation to tumor mass. Although radiation doses to involved organs were safe, unexpected liver toxicity occurred in one patient who presented with a pattern of diffuse infiltration. CONCLUSION Voxel-based dosimetry and radiobiologic modeling can be successfully applied to lesions and tumor-involved organs, representing a methodological advance over estimation of mean absorbed doses. However, effects on tumor control and organ toxicity still cannot be easily predicted.

Dosimetry-based treatment planning for molecular radiotherapy : A summary of the 2017 report from the Internal Dosimetry Task Force

BackgroundThe European directive on basic safety standards (Council directive 2013/59 Euratom) mandates dosimetry-based treatment planning for radiopharmaceutical therapies. The directive comes into operation February 2018, and the aim of a report produced by the Internal Dosimetry Task Force of the European Association of Nuclear Medicine is to address this aspect of the directive. A summary of the report is presented.ResultsA brief review of five of the most common therapy procedures is included in the current text, focused on the potential to perform patient-specific dosimetry. In the full report, 11 different therapeutic procedures are included, allowing additional considerations of effectiveness, references to specific literature on quantitative imaging and dosimetry, and existing evidence for absorbed dose-effect correlations for each treatment. Individualized treatment planning with tracer diagnostics and verification of the absorbed doses delivered following therapy is found to be scientifically feasible for almost all procedures investigated, using quantitative imaging and/or external monitoring. Translation of this directive into clinical practice will have significant implications for resource requirements.ConclusionsMolecular radiotherapy is undergoing a significant expansion, and the groundwork for dosimetry-based treatment planning is already in place. The mandated individualization is likely to improve the effectiveness of the treatments, although must be adequately resourced.

Three-Dimensional Patient-Specific Dosimetry in Radioimmunotherapy with 90Y-Ibritumomab-Tiuxetan

Aim of the present article was to perform three-dimensional (3D) single photon emission tomography-based dosimetry in radioimmunotherapy (RIT) with (90)Y-ibritumomab-tiuxetan. A custom MATLAB-based code was used to elaborate 3D images and to compare average 3D doses to lesions and to organs at risk (OARs) with those obtained with planar (2D) dosimetry. Our 3D dosimetry procedure was validated through preliminary phantom studies using a body phantom consisting of a lung insert and six spheres with various sizes. In phantom study, the accuracy of dose determination of our imaging protocol decreased when the object volume decreased below 5 mL, approximately. The poorest results were obtained for the 2.58 mL and 1.30 mL spheres where the dose error evaluated on corrected images with regard to the theoretical dose value was -12.97% and -18.69%, respectively. Our 3D dosimetry protocol was subsequently applied on four patients before RIT with (90)Y-ibritumomab-tiuxetan for a total of 5 lesions and 4 OARs (2 livers, 2 spleens). In patient study, without the implementation of volume recovery technique, tumor absorbed doses calculated with the voxel-based approach were systematically lower than those calculated with the planar protocol, with average underestimation of -39% (range from -13.1% to -62.7%). After volume recovery, dose differences reduce significantly, with average deviation of -14.2% (range from -38.7.4% to +3.4%, 1 overestimation, 4 underestimations). Organ dosimetry in one case overestimated, in the other underestimated the dose delivered to liver and spleen. However, both for 2D and 3D approach, absorbed doses to organs per unit administered activity are comparable with most recent literature findings.

18F-DOPA Positron Emission Tomography in Medulloblastoma: 2 Case Reports

BACKGROUND Medulloblastoma (MDB) is an aggressive embryonal brain tumor, with underlying altered genetics and biological pathways that account for very heterogeneous natural histories and clinical behaviors. Positron emission tomography (PET) using radiolabeled amino acids provides important metabolic information for the diagnosis of cerebral glioma but only a few data are available on amino acid PET in MDB. In particular, no cases of MDB imaging with 6-[(18)F]-fluoro-L-3,4-dihydroxyphenylalanine (F-DOPA) have previously been described. CASE DESCRIPTION Two patients with different histologic subtypes of MDB were referred for F-DOPA PET to define the extent and metabolic degree of their diseases. The patients had a newly diagnosed large-cell/anaplastic MDB and a fourth relapse of classic MDB, respectively. F-DOPA PET was unremarkable in the first case; F-DOPA uptake was low in the second patient with the tumor/background ratio as high as 1.29. Comparison was made with magnetic resonance imaging, which showed fluid-attenuated inversion recovery positive diseases. Aggressive tumor growth was shown in the clinical course of both patients. CONCLUSIONS The 2 cases reported here suggest that sensitivity of F-DOPA PET in MDB can be low. However, more comprehensive data are needed to conclude on the overall accuracy of F-DOPA PET in MDB.

Comment on Hatzoglou et al: Dynamic contrast-enhanced MRI perfusion versus 18FDG PET/CT in differentiating brain tumor progression from radiation injury

We read with great interest the paper by Hatzoglou et al, recently published in Neuro-Oncology,1 concerning the discrimination between progressive disease and radiotherapyinduced changes in brain tumors, which is a clinical challenge of paramount importance. To address this diagnostic problem, the authors compared dynamic contrast enhanced (DCE) MRI and fluorine-18-fluorodeoxyglucose (FDG) PET/CT in a total of 53 patients with primary brain tumors (n = 29) or brain metastases (n = 26). They found that the DCE MRI–derived plasma volume ratio (Vpratio) and transfer coefficient ratio (K trans ratio), as well as the FDG PET–derived standardized uptake value ratio (SUVratio) were useful in distinguishing between progression and radiation injury, both in the overall cohort and in the 2 main subgroups (primary and secondary brain tumors). They concluded, however, that DCE MRI–derived Vpratio was the “most robust” predictor of progression after showing a trend toward higher performances for Vpratio with respect to SUVratio (sensitivity and specificity = 92% and 77% vs 68% and 82%; AUC = 0.87 vs 0.75, P = .061, for Vpratio and SUVratio, respectively). Perfusion-weighted MRI and FDG PET are widely available imaging modalities which have proven to be useful to complement standard MRI in this setting. However, we would like to emphasize that, in the last decade, PET using radiolabeled amino acids has developed as a powerful diagnostic tool in brain tumor diagnostics. Recently, the Response Assessment in Neuro-Oncology (RANO) working group and the European Association for Neuro-Oncology (EANO) have published their recommendations for the clinical use of PET imaging in gliomas in Neuro-Oncology.2 These recommendations clearly favor amino acid PET over FDG PET and claim the superiority of amino acid PET over standard MRI in several clinical scenarios, including the differentiation of glioma recurrence from treatment-induced changes. To the best of our knowledge, no such level of evidence and consensus has been reached with regard to perfusion-weighted MRI in this field. The fact that amino acid PET is widely used in centers that have full access to the spectrum of functional and molecular MRI techniques emphasizes the value of amino acid PET beyond these alternative MRI methods.3 These important aspects are not mentioned in the paper by Hatzoglou et al and should be disclosed to the readers. Fewer data are available on the implementation of amino acid PET in brain metastases and no specific recommendations have been published so far. Nonetheless, the results of a direct comparison between perfusion-weighted MRI and 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine (FDOPA) PET demonstrated a higher accuracy of amino acid PET in classifying indeterminate enlarging brain metastases after radiation treatment.4 Additionally, further studies have confirmed the high accuracy of different amino acid PET tracers in this setting, although no comparison with advanced MRI techniques was included.5,6 In single centers, combined MRI and amino acid PET criteria are already being clinically used for this problem solving.7 Finally, we would also like to remark that Hatzoglou et al have probably compared DCE MRI with an underpowered FDG PET technique, as a single time point PET has already shown to be less accurate than dual time point acquisitions in the same setting.8 In conclusion, we agree that the results of Hatzoglou et al are valuable, since it is the largest, albeit heterogeneous prospective series providing a comparison between DCE MRI and FDG PET/CT in differentiating brain tumor progression from radiation injury after cranial irradiation. However, the emerging role of amino acid PET imaging in this field is not adequately addressed and needs to be disclosed to the readers.