Current Radiopharmaceuticals - Volume 13, Issue 3, 2020

Neuroendocrine tumors (NETs) consist of a relatively rare spectrum of malignancies that can arise from neuroendocrine cells; lung NETs (L-NETs) represent about 25% of primary lung neoplasm and 10% of all carcinoid tumors. Diagnostic algorithm usually takes into consideration chest Xray, contrast-enhanced CT and MRI. Nuclear medicine plays a crucial role in the detection and correct assessment of neoplastic functional status as it provides in vivo metabolic data related to the overexpression of Somatostatin Receptors (SSTRs) and also predicting response to peptide receptor radionuclide therapy (PRRT). 111In-Pentreotide (Octreoscan®) is commercially available for imaging of neuroendocrine tumors, their metastases and the management of patients with NETs. More recently, 99mTc-EDDA/HYNIC-TOC(Tektrotyd®) was introduced into the market and its use has been approved for imaging of patients with L-NETs and other SSTR-positive tumors. 99mTc-EDDA/HYNIC-TOC could also represent a good alternative to 68Ga-DOTA-peptides (DOTA-TOC, DOTA-NOC, DOTATATE) in hospitals or centers where PET/CT or 68Ge/68Ga generators are not available. When compared to 111In-Pentetreotide, Tektrotyd® showed slightly higher sensitivity, in the presence of higher imaging quality and lower radiation exposure for patients. Interesting perspectives depending on the kinetic analysis allowed by Tektrotyd® may be obtained in differential diagnosis of non-small cells lung cancer (NSCLC) versus small cells lung cancer (SCLC) and NETs. An interesting perspective could be also associated with a surgery radio-guided by Tektrotyd® in operable lung tumors, including either NETs and NSCLC.

Objective: In recent years, the introduction of immune checkpoint inhibitors has significantly changed the outcome of patients affected by lung cancer and cutaneous melanoma. Although the clinical advantages, the selection of patients and the evaluation of response to immunotherapy remain unclear, the immune-related Response Evaluation Criteria in Solid Tumor (irRECIST) was proposed as an update of the RECIST criteria for the assessment of response to immunotherapy. However, morphological images cannot predict early response to therapy that represents a challenge in clinical practice. 18F-FDG PET/CT before and after immunotherapy has an indeterminate role, demonstrating ambiguous results due to inflammatory effects secondary to activation of the immune system. The aim of the present review was to analyze the role of PET/CT as a guide for immunotherapy, by analyzing the current status and future perspectives. Methods: A literature search was conducted in order to select all papers that discussed the role of PET/CT with FDG or other tracers in the evaluation or prediction of response to immunotherapy in lung cancer patients. Results: Many papers are now available. Many clinical trials have demonstrated the efficacy of immunotherapy in lung cancer patients. FDG PET/CT can be used for the prediction of response to immunotherapy, while its utility for the evaluation of response is not still clearly reported. Moreover, the standardization of FDG PET/CT interpretation is missing and different criteria, such as information, have been investigated until now. Conclusion: The utility of FDG PET/CT for patients with lung cancer undergoing immunotherapies is still preliminary and not well addressed. New agents for PET are promising, but large clinical trials are mandatory.

Background: FDG PET/CT imaging has an established role in lung cancer (LC) management. Whilst it is a sensitive technique, FDG PET/CT has a limited specificity in the differentiation between LC and benign conditions and is not capable of defining LC heterogeneity since FDG uptake varies between histotypes. Objective: To get an overview of new radiopharmaceuticals for the study of cancer biology features beyond glucose metabolism in LC. Methods: A comprehensive literature review of PubMed/Medline was performed using a combination of the following keywords: “positron emission tomography”, “lung neoplasms”, “non-FDG”, “radiopharmaceuticals”, “tracers”. Results: Evidences suggest that proliferation markers, such as 18F-Fluorothymidine and 11CMethionine, improve LC staging and are useful in evaluating treatment response and progression free survival. 68Ga-DOTA-peptides are already routinely used in pulmonary neuroendocrine neoplasms (NENs) management and should be firstly performed in suspected NENs. 18F-Fluoromisonidazole and other radiopharmaceuticals show a promising impact on staging, prognosis assessment and therapy response in LC patients, by visualizing hypoxia and perfusion. Radiolabeled RGD-peptides, targeting angiogenesis, may have a role in LC staging, treatment outcome and therapy. PET radiopharmaceuticals tracing a specific oncogene/signal pathway, such as EGFR or ALK, are gaining interest especially for therapeutic implications. Other PET tracers, like 68Ga-PSMA-peptides or radiolabeled FAPIs, need more development in LC, though, they are promising for therapy purposes. Conclusion: To date, the employment of most of the described tracers is limited to the experimental field, however, research development may offer innovative opportunities to improve LC staging, characterization, stratification and response assessment in an era of increased personalized therapy.

Background: Accurate staging is crucial for the proper management of patients with nonsmall cell lung cancer, especially for choosing the best treatment strategy. Different Imaging methods are used to stage patients with non-small cell lung cancer. In the last two decades, FDG PET/CT is carried out in almost all the main Hospitals around the world in this setting. Objective: The aim of this paper is to focus on the value of integrated FDG PET/CT in the TNM staging of the non-small cell lung cancer. Methods: A non-systematic revision of the literature was performed in order to identify all papers about the role of FDG PET/CT in the evaluation of non-small cell lung cancer and to highlight the value of FDG PET/CT in this setting. Results: Many data are now available about this topic, including also randomized controlled trials. FDG PET/CT is of limited added value in the characterization of T status but it increases the diagnostic accuracy for the assessment of the nodal status. The main advantage of FDG PET/CT over conventional imaging methods is its higher sensitivity in identifying extra-thoracic metastases, especially bone and adrenal lesions. Conclusion: PET/CT with FDG should be included in the diagnostic work-up of patients with lung cancer, because it provides useful information for appropriate therapy.

Introduction: In patients suitable for radical chemoradiotherapy for lung cancer, 18F-FDGPET/ CT is a proposed management to improve the accuracy of high dose radiotherapy. However, there is a high rate of locoregional failure in patients with locally advanced non-small cell lung cancer (NSCLC), probably due to the fact that standard dosing may not be effective in all patients. The aim of the present review was to address some criticisms associated with the radiotherapy image-guided in NSCLC. Materials and Methods: A systematic literature search was conducted. Only published articles that met the following criteria were included: articles, only original papers, radiopharmaceutical ([18F]FDG and any tracer other than [18F]FDG), target, only specific for lung cancer radiotherapy planning, and experimental design (eventually “in vitro” studies were excluded). Peer-reviewed indexed journals, regardless of publication status (published, ahead of print, in press, etc.) were included. Reviews, case reports, abstracts, editorials, poster presentations, and publications in languages other than English were excluded. The decision to include or exclude an article was made by consensus and any disagreement was resolved through discussion. Results: Hundred eligible full-text articles were assessed. Diverse information is now available in the literature about the role of FDG and new alternative radiopharmaceuticals for the planning of radiotherapy in NSCLC. In particular, the role of alternative technologies for the segmentation of FDG uptake is essential, although indeterminate for RT planning. The pros and cons of the available techniques have been extensively reported. Conclusion: PET/CT has a central place in the planning of radiotherapy for lung cancer and, in particular, for NSCLC assuming a substantial role in the delineation of tumor volume. The development of new radiopharmaceuticals can help overcome the problems related to the disadvantage of FDG to accumulate also in activated inflammatory cells, thus improving tumor characterization and providing new prognostic biomarkers.

Background: Motion artifacts related to the patient’s breathing can be the cause of underestimation of the lesion uptake and can lead to missing of small lung lesions. The respiratory gating (RG) technology has demonstrated a significant increase in image quality. Objective: The aim of this paper was to evaluate the advantages of RG technique on PET/CT performance in lung lesions. The impact of 4D-PET/CT on diagnosis (metabolic characterization), staging and re-staging lung cancer was also assessed, including its application for radiotherapy planning. Finally, new technologies for respiratory motion management were also discussed. Methods: A comprehensive electronic search of the literature was performed by using Medline database (PubMed) searching “PET/CT”, “gated” and “lung”. Original articles, review articles, and editorials published in the last 10 years were selected, included and critically reviewed in order to select relevant articles. Results: Many papers compared Standardized Uptake Value (SUV) in gated and ungated PET studies showing an increase in SUV of gated images, particularly for the small lesions located in medium and lower lung. In addition, other features as Metabolic Tumor Volume (MTV), Total Lesion Glycolysis (TLG) and textural-features presented differences when obtained from gated and ungated PET acquisitions. Besides the increase in quantification, gating techniques can determine an increase in the diagnostic accuracy of PET/CT. Gated PET/CT was evaluated for lung cancer staging, therapy response assessment and for radiation therapy planning. Conclusion: New technologies able to track the motion of organs lesion directly from raw PET data, can reduce or definitively solve problems (i.e.: extended acquisition time, radiation exposure) currently limiting the use of gated PET/CT in clinical routine.

Background: Metabolic information provided by 18F-FDG PET/CT are useful for initial staging, therapy planning, response evaluation, and to a lesser extent for the follow-up of non-small cell lung cancer (NSCLC). To date, there are no established clinical guidelines in treatment response and early detection of recurrence. Objective: To provide an overview of 18F-FDG PET/CT in NSCLC and in particular, to discuss its utility in treatment response evaluation and restaging of lung cancer. Methods: A comprehensive search was used based on PubMed results. From all studies published in English those that explored the role of 18F-FDG PET/CT in the treatment response scenario were selected. Results: Several studies have demonstrated that modifications in metabolic activity, expressed by changes in SUV both in the primary tumor as well as in regional lymph nodes, are associated with tumor response and survival. Beside SUV, other metabolic parameters (i.e. MTV, TLG, and percentage changes) are emerging to be helpful for predicting clinical outcomes. Conclusion: 18F-FDG parameters appear to be promising factors for evaluating treatment response and for detecting recurrences, although larger prospective trials are needed to confirm these evidences and to determine optimal cut-off values.

Background: Lung cancer is the neoplasm with the highest prevalence and mortality rates in the world. Most patients with lung cancer that are symptomatic have hemoptysis, coughing, shortness of breath, chest pain and persistent infections. Less than 10% of patients are asymptomatic when the tumor is detected as an incidental finding. Objective: The present expert review aims to describe the use of radiological imaging modalities for the diagnosis of lung cancer. Methods: Some papers were selected from the international literature, by using mainly Pubmed as a source. Results: Chest x-ray (CXR) is the first investigation performed during the workup of suspected lung cancer. In the absence of a rib erosion, CXR cannot distinguish between benign and malignant masses, therefore computed tomography (CT) with contrast enhancement should be performed in order to obtain a correct staging. Magnetic resonance imaging of the chest is considered a secondary approach as the respiratory movement affects the overall results. Conclusion: Radiological imaging is essential for the management of patients affected by lung cancer.

Purpose: The Italian Tailored Assessment of Lung Indeterminate Accidental Nodule (ITALIAN) trial is a trial drawn to determine the performance of 18F-FDG-PET/CT in patients with solitary pulmonary nodules (SPN), stratified for a different kind of risk. An additional end-point was to compare the diagnostic information and estimated dosimetry, provided by a segmental PET/CT (s-PET/CT) acquisition instead of a whole body PET/CT (wb-PET/CT), in order to evaluate if segmental thoracic PET/CT can be used in patients with SPN. Methods: 18F-FDG PET/CT of 502 patients, stratified for pre-test cancer risk, was retrospectively analyzed. FDG uptake in SPN was assessed by a 4-point scoring (4PS) system and a semiquantitative analysis using the ratio between SUVmax in SPN and SUVmean in mediastinal blood pool (BP), and between SUVmax in SPN and SUVmean in the liver (L). Histopathology and/or follow-up data were used as a standard of reference. Data obtained on the thoracic part of wb-PET/CT, defined as s - PET/CT, were compared with those deriving from wb-PET/CT. Results: SPNs were malignant in 180 patients (36%), benign in 175 (35%), and indeterminate in 147 (29%). The 355 patients diagnosed with a definitive SPN nature (malignant or benign) were considered for the analysis of PET performance. Sensitivity, specificity, positive (PPV) and negative (NPV) predictive values, and accuracy were 85.6%, 85.7%, 86%, 85.2%, and 85.6%, respectively. Sensitivity and PPV were higher in intermediate and high-risk patients. 18F-FDG uptake indicative of thoracic and extra-thoracic lesions was detectable in 13% and 3% of the patients. Compared to wb-PET/CT, s-PET/CT could save about 2/3 of 18F-FDG dose, radiation exposure or scan-time, without affecting the clinical impact of PET/CT. Conclusion: In patients with SPN, the pre-test likelihood of malignancy stratification allows to better define PET clinical setting and its diagnostic power. In subjects with low-intermediate pre-test likelihood of malignancy, s-PET/CT might be planned in advance. The adoption of this segmental strategy could reduce radiation exposure, scan-time, and might allow individually targeted protocols.