Current Radiopharmaceuticals

Lung cancer is considered the most common malignancy in males and females and it is associated with a poor prognosis. Five-year survival in patients affected by lung cancer varies from 4-17% based on stage and regional differences [1]. The introduction of alternative treatment strategies, such as high-dose stereotactic body radiation therapy [2], targeted therapies [3] and immunotherapy has had a profound impact on the management and survival of patients with lung cancer. Moreover, imaging modalities, both anatomical and functional, have changed the prediction and the assessment of response to therapy [4]. In the present monothematic issue, we have discussed the current role of radiological and nuclear medicine techniques. In the first manuscript by Panunzio et al. [5], the utility of radiological images for the staging of lung cancer has been discussed. Farsad et al. [6] completed the assessment of the staging of this neoplasm by using 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT). Moreover, Castello et al. [7] and Evangelista et al. [8] analysed the ability of FDG PET/CT in predicting the response to systemic and immunotherapies, respectively. Filice et al. [9] described the impact of FDG PET/CT in radiotherapy planning for the treatment of lung tumor and Crivellari et al. [10] discussed the implementation of respiratory gating for the improvement of the diagnostic performance. Similarly, Spadafora et al. [11] introduced the concept of a segmental PET acquisition for the evaluation of solitary lung nodules, particularly in patients with a low likelihood of distant metastases. Finally, Telo et al. [12] and Briganti et al. [13] reported some data about the future of molecular imaging in lung cancer by suggesting new alternative radiopharmaceuticals for PET and single photon emission tomography (SPET) imaging.

Melanoma is the most biologically aggressive tumor of the skin, responsible of the majority of deaths due to skin cancer [1]. In the last few decades, clinicians improved dramatically their ability to recognize melanoma in its early phase but, still, about 20% of the patients die due to disease progression [2-4]. In the context of advanced disease, the introduction of new target therapies and immunotherapy allowed a substantial improvement of the prognosis of patients with metastases. Ten years ago, the average overall survival of stage 4 melanoma patients was only 6 months. Today, the average overall survival reached 2 years, with several patients achieving the status of long-term survivors [5]. Due to these dramatic changes in life expectation of advanced melanoma patients, management protocols and follow-up procedures changed consequently. Before the era of target and immune-therapies, there was basically no need to perform aggressive imaging procedures to monitor disease-free patients. In other words, early diagnosis of disease recurrence was not sufficient to improve patient survival. In contrast, with the introduction of the new treatments of advanced disease, the early recognition of metastatic disease became definitely important in order to start, as soon as possible, the proper treatment and to efficiently prolong survival. This is why imaging of disease-free patients became strictly relevant. In this hot topic issue on the developing role of nuclear medicine in melanoma, the value of diagnostic imaging is presented to individuate fields of actual application and perspectives. Being the main indications connected with staging and restaging, we will also discuss here the possible role in better defining diagnosis and prognostic stratification of the primary lesion, and in the early evaluation of therapeutic response. As reported above, melanoma is an aggressive tumour, historically with poor prognosis and high mortality, although recent advances in chemotherapy and immunotherapy regimes granted improved survival. At the first diagnosis, to define therapeutic strategies, the most important prognostic factors are the vertical growth of the tumour (pathologic Breslow index) and the invasion of the dermis. To acquire information on these issues, a contribution by diagnostic imaging may be given by Ultrasounds. In particular, as described by Reginelli et al. [6], High Frequency Ultrasonography (HFUS) may allow a reliable in vivo evaluation of the superficial cutaneous layer, with a spatial resolution in the order of microns. The preliminary experience presented by the authors suggests the possibility that HFUS could be already included as support to traditional diagnostic methods in patients diagnosed with a nodular melanoma. In particular, HFUS may reliably determine the lateral margins and therefore the thickness of the lesion. Together with a prognostic stratification of the primary tumor, the preoperative evaluation of the presence of secondary lesions is essential for establishing an optimal therapeutic approach and for improving the survival rate. Over primary tumor delineation, an accurate lymph-nodal staging, mainly based on a sentinel-node evaluation using nuclear medicine procedures, is mandatory. In their contribution, N. Quartuccio et al. [7] described the current clinical impact, also discussing the possible improvement at staging associated either with SPECT/CT and using new emerging radiotracers, such as Tc99m-Tilmanocept. 18F-Fluorodeoxyglucose (FDG) PET/CT has been for many years suggested as a reliable and effective tool to complete the staging of patients affected by melanoma, with an advanced disease status. In their paper, R. Laudicella et al. [8] evaluated the increased contribution achievable using new PET/CT facilities and acquisition protocols. In particular, higher spatial resolution realizable with full digital PET/CT scanners, improving diagnostic accuracy either in the detection of lymph node and or distant metastases and a better definition of tumor relapse have been demonstrated. The Clinical Value of PET/CT at Staging and the potential role of new radiotracers are reported by S. Annunziata et al. [9]. In this setting, according to the preclinical data, new radiotracers, such as 18F-29-fluoro-29-deoxy-1-b-D-b-arabinofuranosyl-5- ethyluracil (18F-FEAU), 64Cu-CB-TE2A-c(RGDyK) and 64Cu-diamsar-c(RGDfD), integrine-analogues, 18F-FMISO, 18Fbenzamines, such as 18F-MEL05, 18F-5-fluoro-N-(2-(Diethylamino)ethyl)picolinamide (18F-5-FPN), 18F-CCZ01064, 68Ga- DOTA-Pip-Nle-CycMSHhex (CCZ01048), could permit a better detection of melanoma lymph-node and distant metastases, because of the possibility to reach a higher target to background ratio with respect to FDG. Furthermore, a wider molecular evaluation, allowing the definition of a more precise tailored therapy, could be defined. In humans, a better characterization of tumor proliferation with respect to FDG may be already allowed using 18F-Fluoro-thymidine (FLT). This radiopharmaceutical could be also useful for a more precise evaluation of therapeutic response. The consolidated clinical and prognostic value of PET/CT in the restaging process of Melanoma is presented by D. Albano et al. [10], describing how the use of this approach could be important to better define therapeutic strategies. Particularly relevant is the contribution of E. Lopci et al [11], concerning the evaluation of the role of PET/CT in evaluating the response to new immune therapy agents in Melanoma. In the treatment management, new agents, the so-called immune checkpoint inhibitors (ICI), have achieved astonishing results and improved overall survival (OS). New response criteria have been introduced on time and are being continuously updated. Along with morphologic criteria, expressed by Response Evaluation Criteria in Solid Tumors (RECIST), and including more recent classifications, such as immune-RECIST (iRECIST), other response criteria have been proposed, based on metabolic parameters. In this setting, the role of FDG PET/CT for response assessment and prediction is still in an early phase and not sufficiently robust. For now, the recommended approach is to evaluate morphologic and metabolic changes in the patient’s clinical context. The development of more specific imaging biomarkers could potentially allow an early response evaluation and also provide a better patients’ selection eligible to ICI treatment. The prognostic role of restaging PET has been demonstrated in different tumours after treatment [12-15]. Nevertheless, its role to restage patients with recurrent CM needs still to be defined. The last contribution is presented by Sinagra et al [16], who described a rare clinical case of ileal melanoma where FDG PET/CT completed correctly the staging by identifying a bone metastasis and changing therapy management. On the basis of the papers presented in this thematic issue, we hope to contribute to the literature either by presenting and/or reviewing consolidated procedures and supporting the possible application of new diagnostic methods, with main reference to those utilizing nuclear medicine imaging procedures.

The present thematic “hot topic” issue in Current Radiopharmaceuticals is dedicated to the applications of molecular imaging as major player in the diagnostic scenario of pancreatic neuroendocrine tumours (PanNETs). The therapeutic aspects using radiopharmaceuticals have also been considered. In the last years, we assisted to a progressive evolution of the available radionuclide imaging techniques dedicated to Pan- NETs investigation, starting from the conventional Octreoscan© and moving forward to more sophisticated techniques such as 68Ga-DOTA-Peptides PET/CT. The possibility to provide an accurate characterization both of primary and metastatic disease is of utmost importance in the clinical work-up of PanNETs and molecular imaging has revealed to be a cornerstone for Physicians to support the therapeutic decision process. The present issue starts with an accurate description of physiopathological premises underlying the mechanisms of uptake of several radiotracers that can be used, with main reference to those characterizing the presence of Somatostatin Receptors (SSTRs), expressed by different subtypes of PanNETs. In this paper, Cuccurullo et al. begins with the explanation of the ancillary role of 18F- Fluorodeoxyglucose (18F-FDG) [1]. In NETs, 18F-FDG may act mainly as a negative prognostic indicator, having capability to reveal dedifferentiated lesions in the restaging of individual patients with a critical clinical evolution. The reason for its infrequent indication is consequently connected with the favorable biological behavior of the majority of Pan- NETs, which are typically slow growing and express SSTRs according to their degree of differentiation. Therefore, using somatostatin analogs (SSA) labeled with gamma or positron emitters, SSTRs can be used not only as a target for both diagnosis and therapy, but also for a prognostic evaluation. Currently, the somatostatin theranostic model, based on diagnosis with radiotracers and a Peptide Receptor Radionuclide Therapy (PRRT) performed with a similar molecule radiolabeled with a β- (or α, hopefully in the future) emitter, represents one of the most successful options for the targeted therapy. Although radio-labeled agonists usually provide efficient results, somatostatin antagonists (SS-ANTs) have been recently also proposed, being usable for imaging and therapy. The Cuccurullo’s paper also highlights the reasons why the theranostic model based on SSTRs doesn’t work in insulinoma, which scarcely express SSTR2 and SSTR5, wich are. the most important targets for the routinely used radiolabeled somatostatin analogues. Therefore, in patients with a suspicious of insulinoma, different radiotracers, such as 18F FluoroDOPA (18F-DOPA) or tracers targeting glucagon-like peptide-1 receptor, have to be preferred. However, it has to be pointed out that, although F-DOPA showed interesting results in patients with PanNETs, its role is currently considered secondary compared to somatostatin analogues, especially because of the lack of a theranostic model. Starting from the classification and physiopathology of PanNETs, the paper by Briganti et al. deeply analyse the currently available gamma-emitters for SSTRs evaluation [2]. A detailed comparison of the diagnostic performance of the available tracers and of hybrid machines compared to the traditional stand-alone tools is also included. In this paper, it is reported that 111Inpentetreotide (Octreoscan©), successfully applied in well-differentiated (G1-G2) tumors, has lost its primary position because of the better diagnostic accuracy of 68Ga DOTA-Peptides PET/CT, maintaining an ancillary role in PanNETs. Briganti et al. also discuss preliminary data obtained with 99mTc-EDDA/HYNIC-TOC (Tektrotyd©), labeled with 99mTc, having more favorable energy characteristics compared to 111Indium, radiolabeling Octreoscan©. To better identify a possible clinical role for Tektrotyd ©, in terms of cost/effectiveness, its pharmacokinetics and pharmacodynamics have been compared with respect to those of Octreoscan© and PET DOTA-peptides. The paper by Carollo et al. is focused on radiochemical issues, providing deep insights of the molecular imaging techniques that can be applied in this setting, including a discussion on the comparison between the different radiotracers; the therapeutic implications that might rise from a precise definition of disease extension and metabolic characterization are also evaluated [3]. This paper shows an overview of the radiopharmaceuticals that have been used so far in the imaging of PanNETs with insights on the potential of new radiopharmaceuticals currently under clinical evaluation. The implications for therapy of SSTRs imaging are fundamental for PanNETs patients work-up [1]. The expression of SSTRs is a pre-requisite for the success of PRRT, which has been tackled by Alsadik et al. in the current issue [4]. The authors used a comprehensive literature search strategy of all studies published in English that can be found on SCOPUS and PubMed. The results of PRRT, using 177Lutetium or 90Yttrium- DOTA- conjugated peptides in p-NETs, individuated either as a standalone entity or as subgroup within the wider category of Gastro-entero-pancreatic neuroendocrine tumours (GEP NETs), have been evaluated. This meta-analysis confirms that PRRT is a well-tolerated and effective treatment option for non-operable and/or metastatic PanNETs. A strong support on a wider diffusion could be achieved from larger randomized controlled trials, comparing PRRT with other treatment modalities. The radiological aspects regarding the theranostic of PanNETs should not be underestimated neither be allocated on a second level in comparison to molecular imaging. For this reason, this issue also includes an outline on the available conventional radiological techniques that are currently used in PanNETs work-up [5]. In the presence of a primary role of nuclear medicine, either for a whole body analysis or for a molecular characterization, an extensive conventional radiological imaging is however requested, remaining the foundation for the initial diagnosis and staging of these tumors. In terms of technological advances, a significant improvement has been obtained with the advent of new hybrid machines that could potentially improve the management of these patients [6]. Hybrid PET/MRI systems are currently available in few Centres world-wide, providing excellent results derived from the combination of PET with MRI, which is better for soft tissue characterization and for reducing radiation exposure compared to CT [7]. Furthermore, Diffusion-Weighted Imaging (DWI) is an invaluable tool to depict small liver lesions undetectable by PET or CT; a further improvement allowed by MR in detecting small hepatic metastases may be achieved combining 3-Tesla and DWI together with the administration of liver specific contrast media. Hence, the best candidates to be imaged with SSTR PET/MRI are patients selected for hepatic de-bulking or having liver predominant disease. in the perspective by Mapelli and Picchio, the capability of PET/MRI to better evaluate tumor response to treatment difficult to be analyzed using traditional RECIST criteria is also discussed. The better evaluation of anatomic changes and enhancement characteristics allowed by MRI may significantly implement SSTR PET, defining a more reliable procedure to be used in place of CT and MRI alone or of PET/CT. In this context, SSTR-RADS Version 1.0 response criteria have been recently introduced as a promising alternative and valuable tool for response assessment in NETs [8]. To better define the clinical role of PET/MRI in patients with p-NETs, it has to be pointed out that at present, this tool doesn’t show, using a standard approach, the same diagnostic accuracy in detecting small lung lesions with respect to PET/CT. Therefore, in presence of a negative or dubious pattern at pulmonary level, a chest CT scan would be recommended additionally to PET/MRI [9, 10]. Moreover, MRI has a lower sensitivity in identifying hypersclerotic bone lesions compared to other imaging modalities and SUV quantification with attenuation correction is still suboptimal [11]. At present, these limitations, although scarcely significant for a clinical utilization in PanNETs, have to be taken in account, looking forward to technological improvements, allowing to obtain similar accuracies as for PET/CT Based on the contents reported in the present issue, it can be concluded that in patients with PanNETs, a protean disease often presenting with liver metastases, many topics have to be considered to understand the role of molecular imaging in the different clinical scenarios. At first diagnosis, it is mandatory to detect primary tumour, more frequently identified using radiological techniques, and to define whole body diffusion and molecular characterization. In the latter field, nuclear medicine techniques are determinant. Being the major role actually played by PET/CT with 68Ga-DOTA peptides, the use of Octreoscan© is considered to be a second choice, while the clinical position of Tektrotyd© is still to be fully defined. In patients with insulinoma, waiting for radiopharmaceuticals having a better diagnostic accuracy, 18F-DOPA has to be preferred compared to radiolabeled somatostatin analogues. Interesting perspectives seem to be related to a wider evaluation of innovative radiotracers, including GLP-1 Receptor Peptides, as exendin, GRP receptor ligands, as bombesin agonists and antagonists, and gastrin/cholecystokinin analogs, as minigastrin. Nevertheless, further studies, also better evaluating radiochemistry and pharmacokinetics, are needed before their possible clinical application. Similarly, new approaches capable to early predict the efficacy of anti-angiogenesis treatments could be defined through a research based on radiolabeled new drugs, such as bevacizumab. Conversely, it is currently too early to predict the clinical impact of a technological revolution associated with fully digital PET scanners or with the use of alternative radionuclides, with main reference to Cu-64. This means that in the near future, the primacy of somatotastatin analogues labelled with 68Ga will remain unquestionable in the general evaluation of PanNETs, also because of the theranostic model associated with PRRT. Regarding innovative radiopharmaceuticals, neither radiolabeled somatostatin antagonists nor 11C-5-hydroxy-tryptophan (HTP), negatively affected by the labelling with the short life radionuclide C-11, may actually cover a clinical role. Conversely, 18F-FDG may find a clinical utility in restaging patients in whom a dedifferentiation is suspected, in order to better define therapeutic strategies. Future developments will be based on a wider diffusion of more performing technologies, such as PET/MRI or digital PET, in the clinical application of new radiopharmaceuticals and a more comprehensive multilevel integration of biologic information pertaining to a specific tumor and single patient. This approach, possibly encompassing genomic considerations, is currently evolving as a new entity denoted ‘precision medicine’ [12]. In this context, together with nonspecific biomarkers, such as chromogranin-A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA), the evaluation of proliferative activity (Ki67) should be considered. In the future, the clinical application of specific NET transcripts in whole blood could potentially conduct to an earlier diagnosis, also providing information useful for prognostic stratification and a better definition of therapeutic strategies [11]. A further improvement is also required for an improved monitoring of tumor response. In PanNETs, radiological procedures based on RECIST are unsatisfactory while newer radiological criteria are not yet consolidated; therefore, validated techniques utilizing molecular imaging, supported by the morpho-structural information allowed by CT or MRI should be implemented. In this direction, more reliable results could be obtained through the development of new criteria, eventually including the adoption of functional MRI, of more precise hematic biomarkers, of quantitative methods not only based on SUV. In conclusion, a multidisciplinary approach is mandatory in clinical practice in roder to reach the best consensus on treatment approach for each patient. In this context, together with the major role of nuclear medicine physicians and radiologists, of oncologists, endocrinologists and surgeons, the contribution of experts in epidemiology, laboratory medicine and genomics is advocated. Therefore, in agreement with L. Bodei, we can conclude that “a fusion product of molecular and genomic information with tumor imaging is likely to be the quintessence of future NET diagnosis and define the progress from darkness to light” [13].

In this special CRP issue, the production, radiochemical aspects, chelation and latest pre-clinical and clinical results are presented for the application of 225Ac and 213Bi-based radiopharmaceuticals for Targeted Alpha Therapy (TAT). The first block of papers discusses the production, radiochemical and chelation aspects for the production of radiopharmaceuticals based on 225Ac and 213Bi. In the review by A. Robertson et al. [1], an overview of the current supply of 225Ac/213Bi is discussed as well as alternative production strategies to meet the current demand. Radiochemical aspects for isolating 225Ac from 229Th or from irradiated target materials are discussed in the second part of this review. Finally, chelation aspects and challenges associated with the delivery of alpha-emitting radionuclides to the targeting sites are described. All of these aspects are also discussed from the experiences, capabilities and perspectives of TRIUMF. The review by J. Engle [2] specifically aims to provide a broad overview of the current supply and possible additional strategies for the production of 225Ac and 213Bi. These include discussion of the current status of 229Th, as well as alternative production by irradiation of 226Ra with neutrons, protons and electrons and thorium with high energy protons. In the review by J. Harvey [3], specific efforts pursued by the NorthStar company are reported and include the recovery of 229Th from fuel pellets, irradiation of 226-Radium with electrons and 232-Throium with high energy protons and testing of radiochemical separation based on solid phase chromatography resins. The next block of reviews and research articles report the results of pre-clinical and clinical studies using 225Ac and 213Bi. In the research article by Z. Jiang et al. [4], in vivo animal studies using two different sources of 225Ac were evaluated. One source was derived from the standard decay of 229Th and the second source was 225Ac extracted from proton irradiated thorium target (containing 227Ac). Biodistribution studies of 225Ac in free form and chelated with DOTA were examined. A research article by N. Pfankuchen et al. [5] provides results from the work on radiolabeling and pre-clinical evaluation of 225Ac attached to the zoledronic acid bone-seeking agent. In the review by J. Jurcic [6], clinical results of using the 213Bi- and 225Ac-radiolabelled monoclonal antibody (Lintuzumab) for therapy of acute myeloid leukemia (AML) are discussed. In the review article by A. Morgenstern et al. [7] the current status of the field of TAT is given, including an overview of the availability of the 225Ac and 225Ac/213Bi generator, as well as a broad overview of clinical trials using 225Ac and 213Bi. The last review article discuss the importance of dosimetric and radiobiological considerations for the application of alpha emitters by G. Sgouros et al. [8]. This special issue of Current Radiopharmaceuticals provides an up-to-date and useful comprehensive overview describing the production, radiochemistry and use of both 213Bi and 225Ac and their important emerging clinical roles for therapeutic treatment of a variety of specific cancers and chronic diseases.