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Molecular imaging in oncology: Common PET/CT radiopharmaceuticals and applications

  • Elisa Franquet
    Correspondence
    Correspondence to: Department of Radiology, Nuclear Medicine and Oncologic Imaging, University of Massachusetts Memorial Medical Center, 119 Belmont St, Worcester, MA 01605, United States.
    Affiliations
    Department of Radiology, Nuclear Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02215, United States
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  • Author Footnotes
    1 Present address: Department of Radiology, Lahey Hospital & Medical Center, 41 Burlington Mall Road, Burlington MA 01805, United States.
    Hyesun Park
    Footnotes
    1 Present address: Department of Radiology, Lahey Hospital & Medical Center, 41 Burlington Mall Road, Burlington MA 01805, United States.
    Affiliations
    Department of Radiology, Nuclear Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02215, United States
    Search for articles by this author
  • Author Footnotes
    1 Present address: Department of Radiology, Lahey Hospital & Medical Center, 41 Burlington Mall Road, Burlington MA 01805, United States.
Open AccessPublished:November 23, 2022DOI:https://doi.org/10.1016/j.ejro.2022.100455

      Abstract

      PET/CT is a commonly used modality in cancer imaging, as it can help in diagnosis, staging and assessment of treatment response in many cancer types. A better understanding of the tumor microenvironment and identification of multiple selective targets are promoting further investigation into different radiotracers for diagnosis and therapy. In the past few decades many radiopharmaceuticals have emerged for specific oncologic indications providing superior detection rate than some morphologic modalities. The purpose of this review is to provide an update on the most current radiopharmaceuticals used in cancer imaging including the mechanism of action, indications and pitfalls.

      Keywords

      1. Introduction

      Molecular imaging is a powerful tool that allows assessment of cancer and other non-cancer conditions non-invasively. By labeling different radiotracers, different biological functions or targets in the tumor are able to be visualized. Positron emission tomography (PET) is a functional imaging modality that is now well established in oncological imaging. Together with computed tomography (CT), PET/CT provides functional and anatomical information needed in diagnosis, staging and follow-up of many different tumors.
      There are many PET tracers available for clinical use and many more under current investigation. The main workhorse continues to be 18F-2-fluoro-2- deoxyglucose (FDG), however various other tracers have emerged in the past few decades for specific indications (Table 1). Rapid changes in our understanding of the tumor microenvironment and identification of multiple selective targets are promoting further investigation into different radiotracers for diagnosis and therapy. This review provides mechanism and clinical indication, as well as limitations and pitfalls of various PET tracers commonly used in cancer imaging.
      Table 1PET tracers commonly used in oncologic imaging.
      RadiopharmaceuticalLabeled moleculeMechanism/targetIndication
      18F-FDG2-fluoro-2-deoxyglucoseAssessment of increased glucose metabolism by overexpression of GLUT-1Oncology

      Infection/inflammation
      68Ga-DOTA-somatostatin receptor analog (e.g. DOTATATE)DOTA-octreotateDetection of increased expression of somatostatin receptorsNeuroendocrine tumors

      Meningioma
      68Ga-PSMA-11Prostate specific membrane antigenAnti-PSMA antibody targets PSMA glycoproteinProstate cancer
      18F-DCFPyL (PSMA)
      68Ga-FAPIFibroblast activation protein inhibitorTargets overexpression of fibroblast activating protein/fibroblast activated proteinTumors with significant stroma component
      18F-FESFluoroestradiolTargets estrogen receptor expressionEstrogen receptor + breast cancer
      Standardized uptake value (SUV) is a semiquantitative measure of normalized radioactivity concentration in PET images and is used in many tracers. Other quantitative measurement parameters include mean SUV, peak of SUV, metabolic tumor volume, and total lesion glycolysis.

      2. 18F-2-fluoro-2- deoxyglucose (FDG)

      2.1 Mechanism of action

      Glucose analog 18F-FDG is the most commonly used radiopharmaceutical in oncologic PET imaging. 18F-FDG is incorporated into cells via glucose transporters, and then phosphorylated to FDG-6-phosphate by hexokinases as a part of glycolysis pathway [
      • Farwell M.D.
      • Pryma D.A.
      • Mankoff D.A.
      PET/CT imaging in cancer: current applications and future directions.
      ]. Phosphorylated 18F-FDG cannot be rapidly metabolized further in the cells, and therefore 18F-FDG is essentially trapped within the cells, which proves as an ideal property for an imaging agent. Most tumor cells show increased 18F-FDG uptake because they preferably use glucose as an energy source and upregulate glucose transporters (GLUT 1) compared to normal cells [
      • Farwell M.D.
      • Pryma D.A.
      • Mankoff D.A.
      PET/CT imaging in cancer: current applications and future directions.
      ]. 18F-FDG reaches a plateau of accumulation in tumor cells at approximately 45 min post injection, and the best tumor-to-background ratio is reached at 2–3 h post injection. In 18F-FDG, maximum standardized uptake value (SUVmax) is the most commonly used to quantitatively measure radioactivity (FDG accumulation) in the cells.

      2.2 Normal tracer biodistribution

      Highest physiologic 18F-FDG activity is noted in the brain and urinary system and, to a lesser extent, other soft tissue organs including liver and spleen. Myocardium can demonstrate high physiologic activity, which can be related to prolonged fasting [

      R. Boellaard, R. Delgado-Bolton, W.J. Oyen, F. Giammarile, K. Tatsch, W. Eschner, F.J. Verzijlbergen, S.F. Barrington, L.C. Pike, W.A. Weber, S. Stroobants, D. Delbeke, K.J. Donohoe, S. Holbrook, M.M. Graham, G. Testanera, O.S. Hoekstra, J. Zijlstra, E. Visser, C.J. Hoekstra, J. Pruim, A. Willemsen, B. Arends, J. Kotzerke, A. Bockisch, T. Beyer, A. Chiti, B.J. Krause, M. European Association of Nuclear, FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0, Eur. J. Nucl. Med. Mol. Imaging, vol. 42(no. 2), 2015, pp. 328–54.

      ]. The laryngeal, pharyngeal and/or masticator muscles can show increased 18F-FDG uptake if the patient talks or chews gum during the exam. Typically, 4–6 h fasting prior to 18F-FDG injection is recommended [

      R. Boellaard, R. Delgado-Bolton, W.J. Oyen, F. Giammarile, K. Tatsch, W. Eschner, F.J. Verzijlbergen, S.F. Barrington, L.C. Pike, W.A. Weber, S. Stroobants, D. Delbeke, K.J. Donohoe, S. Holbrook, M.M. Graham, G. Testanera, O.S. Hoekstra, J. Zijlstra, E. Visser, C.J. Hoekstra, J. Pruim, A. Willemsen, B. Arends, J. Kotzerke, A. Bockisch, T. Beyer, A. Chiti, B.J. Krause, M. European Association of Nuclear, FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0, Eur. J. Nucl. Med. Mol. Imaging, vol. 42(no. 2), 2015, pp. 328–54.

      ]. The biodistribution of 18F-FDG is affected by blood glucose levels. High serum glucose can increase secretion of insulin, which will increase muscle uptake of 18F-FDG. In addition, high serum glucose will compete with 18F-FDG in cellular uptake. Therefore, serum glucose level < 150–200 mg/dL is recommended for optimal 18F-FDG PET/CT imaging. Short or regular acting insulin should not be used 2–4 h before the examination [

      R. Boellaard, R. Delgado-Bolton, W.J. Oyen, F. Giammarile, K. Tatsch, W. Eschner, F.J. Verzijlbergen, S.F. Barrington, L.C. Pike, W.A. Weber, S. Stroobants, D. Delbeke, K.J. Donohoe, S. Holbrook, M.M. Graham, G. Testanera, O.S. Hoekstra, J. Zijlstra, E. Visser, C.J. Hoekstra, J. Pruim, A. Willemsen, B. Arends, J. Kotzerke, A. Bockisch, T. Beyer, A. Chiti, B.J. Krause, M. European Association of Nuclear, FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0, Eur. J. Nucl. Med. Mol. Imaging, vol. 42(no. 2), 2015, pp. 328–54.

      ].

      2.3 Applications

      18F-FDG PET/CT is commonly used in many malignancies, including lung, skin, head and neck, GI, hepatobiliary, hematologic malignancies, and sarcomas. In this review, we included lung cancer and lymphoma as examples, as they are the most common indications for 18F-FDG PET/CT.
      Regarding lung cancer, CT is an important imaging modality for tumor staging due to its excellent anatomical resolution. For the primary tumor staging, CT is an important imaging modality for the evaluation of the primary tumor due to its excellent anatomical resolution. However, it can be difficult to evaluate the margin of active primary tumor especially when there is adjacent atelectasis due to bronchial obstruction or the mass is abutting the chest wall or mediastinal organs. Previous studies have shown that PET/CT correctly stages the primary mass in 86 % of patients compared to 79 % on chest CT, with no statistically significant differences [
      • Shim S.S.
      • Lee K.S.
      • Kim B.T.
      • Chung M.J.
      • Lee E.J.
      • Han J.
      • Choi J.Y.
      • Kwon O.J.
      • Shim Y.M.
      • Kim S.
      Non-small cell lung cancer: prospective comparison of integrated FDG PET/CT and CT alone for preoperative staging.
      ]. 18F-FDG PET/CT can be useful in defining the active tumor volume if surgery or radiation therapy is planned [
      • van Baardwijk A.
      • Baumert B.G.
      • Bosmans G.
      • van Kroonenburgh M.
      • Stroobants S.
      • Gregoire V.
      • Lambin P.
      • De Ruysscher D.
      The current status of FDG-PET in tumour volume definition in radiotherapy treatment planning.
      ]. The percentage of change in tumor volume after PET/CT for radiation therapy planning is widely variable, ranging from 27 % to 100 %, due to the exclusion of adjacent atelectasis or inclusion of PET-positive nodes. In addition, there was significant reduction of interobserver variability of target volume when PET/CT was used for planning. Furthermore, 18F-FDG PET/CT is more accurate in detecting nodal metastases compared to chest CT. The sensitivity, specificity, and accuracy of CT are 70 %, 69 %, and 69 %, whereas PET/CT are 85 %, 84 %, and 84 %, respectively [
      • Shim S.S.
      • Lee K.S.
      • Kim B.T.
      • Chung M.J.
      • Lee E.J.
      • Han J.
      • Choi J.Y.
      • Kwon O.J.
      • Shim Y.M.
      • Kim S.
      Non-small cell lung cancer: prospective comparison of integrated FDG PET/CT and CT alone for preoperative staging.
      ]. According to the study by Darling et al. which included a total of 149 patients with NSCLC, 8 out of 22 patients with 18F-FDG-avid mediastinal nodes were false positive [
      • Darling G.E.
      • Maziak D.E.
      • Inculet R.I.
      • Gulenchyn K.Y.
      • Driedger A.A.
      • Ung Y.C.
      • Gu C.S.
      • Kuruvilla M.S.
      • Cline K.J.
      • Julian J.A.
      • Evans W.K.
      • Levine M.N.
      Positron emission tomography-computed tomography compared with invasive mediastinal staging in non-small cell lung cancer: results of mediastinal staging in the early lung positron emission tomography trial.
      ]. Therefore, pathologic confirmation is usually recommended for suspicious metastatic lymph nodes seen on imaging. For extrathoracic metastases, PET/CT plays an important role for the evaluation of occult metastases, and can upstage or downstage disease, impacting the ultimate management plan. Previous study showed that among 537 patients with NSCLC, 91 (17%) patients were upstaged and 68 patients (13 %) were downstaged after PET/CT result [
      • Heo E.Y.
      • Yang S.C.
      • Yoo C.G.
      • Han S.K.
      • Shim Y.S.
      • Kim Y.W.
      Impact of whole-body (1)(8)F-fluorodeoxyglucose positron emission tomography on therapeutic management of non-small cell lung cancer.
      ]. In addition, there were a total of 118 patients (22 %) whose therapeutic management was modified because of stage migration realized by the use of PET/CT [
      • Heo E.Y.
      • Yang S.C.
      • Yoo C.G.
      • Han S.K.
      • Shim Y.S.
      • Kim Y.W.
      Impact of whole-body (1)(8)F-fluorodeoxyglucose positron emission tomography on therapeutic management of non-small cell lung cancer.
      ] (Fig. 1) 18F-FDG PET/CT is more sensitive to detect early bone metastases before sclerotic or lytic changes are seen on CT. Previous studies demonstrate that up to 25 % of skeletal metastasis showed 18F-FDG uptake without morphologic changes on CT [
      • Ahmed F.
      • Muzaffar R.
      • Fernandes H.
      • Tu Y.
      • Albalooshi B.
      • Osman M.M.
      Skeletal metastasis as detected by 18F-FDG PET with negative CT of the PET/CT: frequency and impact on cancer staging and/or management.
      ].
      Fig. 1
      Fig. 1Detection of metastasis on 18F-FDG PET/CT not otherwise seen on CT. 63-year-old woman presenting with left upper lobe mass. (A) Maximum-intensity-projection image (MIP) shows intense 18F-FDG uptake in the left upper lobe (solid arrow) and mediastinal nodes (dashed arrow) as well as focal liver uptake and uptake in the left shoulder. Axial fused PET/CT and CT images of the upper abdomen (B) and upper chest (C) show 18F-FDG-avid hepatic lesion (white arrow) and multiple osseous lesions in the left scapula (blue arrows) and thoracic vertebral body, which were not visualized on CT.
      Regarding lymphoma, PET/CT is recommended for staging according to the Lugano classification [

      S.F. Barrington, N.G. Mikhaeel, L. Kostakoglu, M. Meignan, M. Hutchings, S.P. Müeller, L.H. Schwartz, E. Zucca, R.I. Fisher, J. Trotman, O.S. Hoekstra, R.J. Hicks, M.J. O'Doherty, R. Hustinx, A. Biggi, B.D. Cheson, Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group, J. Clin. Oncol., vol. 32(no. 27), 2014, pp. 3048–58.

      ]. Lugano classification is the most commonly used system for lymphoma staging and response assessment [

      B.D. Cheson, R.I. Fisher, S.F. Barrington, F. Cavalli, L.H. Schwartz, E. Zucca, T.A. Lister, A.L. Alliance, G. Lymphoma, G. Eastern Cooperative Oncology, C. European Mantle Cell Lymphoma, F. Italian Lymphoma, R. European Organisation for, G. Treatment of Cancer/Dutch Hemato-Oncology, O. Grupo Espanol de Medula, G. German High-Grade Lymphoma Study, G. German Hodgkin's Study, G. Japanese Lymphorra Study, A. Lymphoma Study, N.C.T. Group, G. Nordic Lymphoma Study, G. Southwest Oncology, I. United Kingdom National Cancer Research, Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification, J. Clin. Oncol., vol. 32(no. 27), 2014, pp. 3059–68.

      ]. This system emphasized the role of PET/CT in staging of FDG-avid lymphoma and introduced metabolic response criteria (Deauville 5-point scale) which is based on the visual interpretation of tumor metabolism by comparing with FDG uptake in the mediastinal blood pool and liver [

      S.F. Barrington, N.G. Mikhaeel, L. Kostakoglu, M. Meignan, M. Hutchings, S.P. Müeller, L.H. Schwartz, E. Zucca, R.I. Fisher, J. Trotman, O.S. Hoekstra, R.J. Hicks, M.J. O'Doherty, R. Hustinx, A. Biggi, B.D. Cheson, Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group, J. Clin. Oncol., vol. 32(no. 27), 2014, pp. 3048–58.

      ]. Compared to the CT only, 18F-FDG-PET/CT is more sensitive and specific for detecting both nodal and extranodal disease (Fig. 2). According to the study by Barrington et al., among Hodgkin lymphoma patients, 14 % of the patients were upstaged due to 18F-FDG uptake in the marrow non-enlarged lymph nodes, and 6 % were downstaged because of splenomegaly without abnormal 18F-FDG uptake or enlarged lymph nodes without 18F-FDG-uptake on PET/CT [
      • Barrington S.F.
      • Kirkwood A.A.
      • Franceschetto A.
      • Fulham M.J.
      • Roberts T.H.
      • Almquist H.
      • Brun E.
      • Hjorthaug K.
      • Viney Z.N.
      • Pike L.C.
      • Federico M.
      • Luminari S.
      • Radford J.
      • Trotman J.
      • Fossa A.
      • Berkahn L.
      • Molin D.
      • D'Amore F.
      • Sinclair D.A.
      • Smith P.
      • O'Doherty M.J.
      • Stevens L.
      • Johnson P.W.
      PET-CT for staging and early response: results from the Response-Adapted Therapy in Advanced Hodgkin Lymphoma study.
      ]. Bone marrow involvement is reliably evaluated on baseline exams and can obviate the need for bone marrow biopsies in most known 18F-FDG-avid lymphomas. Evaluation on follow up 18F-FDG-PET/CT can be challenging in the setting of reactive marrow changes after G-CSF stimulating agent or hyperplastic marrow secondary to cytopenia, and bone marrow biopsy can be performed if it is equivocal. Management of lymphoma depends on the histologic subtype and grade. 18F-FDG uptake varies between histologic subtypes which is important for management plan [

      S.F. Barrington, N.G. Mikhaeel, L. Kostakoglu, M. Meignan, M. Hutchings, S.P. Müeller, L.H. Schwartz, E. Zucca, R.I. Fisher, J. Trotman, O.S. Hoekstra, R.J. Hicks, M.J. O'Doherty, R. Hustinx, A. Biggi, B.D. Cheson, Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group, J. Clin. Oncol., vol. 32(no. 27), 2014, pp. 3048–58.

      ]. Low grade lymphomas, such as follicular lymphoma or marginal zone lymphoma, generally show lower 18F-FDG uptake compared to the aggressive subtypes such as diffuse large B cell lymphoma, with SUVmax usually less than 10 [
      • Seam P.
      • Juweid M.E.
      • Cheson B.D.
      The role of FDG-PET scans in patients with lymphoma.
      ,
      • Noy A.
      • Schoder H.
      • Gonen M.
      • Weissler M.
      • Ertelt K.
      • Cohler C.
      • Portlock C.
      • Hamlin P.
      • Yeung H.W.
      The majority of transformed lymphomas have high standardized uptake values (SUVs) on positron emission tomography (PET) scanning similar to diffuse large B-cell lymphoma (DLBCL).
      ]. If an area of intense 18F-FDG uptake (SUVmax greater than 10) is identified in a patient with low grade lymphoma, it may suggest histologic transformation [
      • Alessandrino F.
      • DiPiro P.J.
      • Jagannathan J.P.
      • Babina G.
      • Krajewski K.M.
      • Ramaiya N.H.
      • Giardino A.A.
      Multimodality imaging of indolent B cell lymphoma from diagnosis to transformation: what every radiologist should know.
      ] (Fig. 3). Retrospective analysis of transformed lymphoma by Noy et al. showed that SUVmax can predict the aggressive lymphoma with > 80 % certainty using SUVmax cut-off of 10, and with > 90 % certainty using SUVmas cut-off of 15 [
      • Noy A.
      • Schoder H.
      • Gonen M.
      • Weissler M.
      • Ertelt K.
      • Cohler C.
      • Portlock C.
      • Hamlin P.
      • Yeung H.W.
      The majority of transformed lymphomas have high standardized uptake values (SUVs) on positron emission tomography (PET) scanning similar to diffuse large B-cell lymphoma (DLBCL).
      ]. Therefore, 18F-FDG PET/CT can aid in selecting biopsy site when there are findings suspicious high-grade transformation. After treatment, 18F-FDG avidity of lesions can be significantly decreased when there may be lesser degree of change in the anatomical extent of disease. Therefore, Lugano criteria (Deauville score) using 18F-FDG uptake is commonly used for treatment response evaluation in lymphoma. 18F-FDG PET/CT after treatment has a predictive value for clinical outcome [

      S.F. Barrington, N.G. Mikhaeel, L. Kostakoglu, M. Meignan, M. Hutchings, S.P. Müeller, L.H. Schwartz, E. Zucca, R.I. Fisher, J. Trotman, O.S. Hoekstra, R.J. Hicks, M.J. O'Doherty, R. Hustinx, A. Biggi, B.D. Cheson, Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group, J. Clin. Oncol., vol. 32(no. 27), 2014, pp. 3048–58.

      ].
      Fig. 2
      Fig. 2Evaluation of Lymphoma with 18F-FDG PET/CT. 43-year-old woman with recent diagnosis of Hodgkin’s Lymphoma, nodular sclerosis subtype. Baseline 18F-FDG PET/CT is shown. (A) Maximum-intensity-projection image (MIP), axial PET, fused PET/CT and CT (B) through the upper chest and (C) upper abdomen. Multistation intensely 18F-FDG-avid lymph nodes in the left axilla (dashed arrow), mediastinum (solid arrow) and retroperitoneum (blue arrow), as well as multiple 18F-FDG-avid foci of uptake in the spleen without CT correlate in non-enhanced CT (asterisk). Diffuse bone marrow uptake in the axial and appendicular skeleton is better appreciated in the MIP images, may indicate bone marrow involvement in the absence of ongoing treatment or be reactive to systemic process (bone marrow biopsy is needed). Physiologic uptake in the liver, brain, bowel, kidneys and breast tissue.
      Fig. 3
      Fig. 3Metabolic pattern of 18F-FDG suggesting transformation to high-grade lymphoma. 49-year-old woman with recently diagnosed stage I-II follicular lymphoma on an excisional biopsy of a left axillary lymph node. Patient presented with new acute onset abdominal pain and underwent evaluation with 18F-FDG PET/CT. (A and B) MIP and coronal fused PET/CT shows extensive 18F-FDG-avid disease including lymphadenopathy above and below the diaphragm and involvement of the liver, stomach, left kidney, bladder, uterus, multiple muscles and left clavicle involvement. High intensity of 18F-FDG uptake (SUVmax 22) is discordant with finding on pathology. 18F-FDG pattern of uptake is consistent with transformed follicular lymphoma to a high-grade lymphoma.

      2.4 Limitations and pitfalls

      18F-FDG uptake is not specific to the tumor cells and is commonly seen in the infection and inflammation due to accumulation of inflammatory cells. Benign inflammatory conditions such as sarcoidosis can mimic malignancy, and while pattern recognition can be helpful, tissue sampling may still be required in indeterminate cases or scenarios where coexistent inflammation and malignancy are possible. Several malignancies are known to demonstrate low 18F-FDG avidity, including indolent lung adenocarcinomas, lobular subtype breast cancer, well differentiated hepatocellular carcinoma, prostate cancer, or signet-ring cell type gastrointestinal malignancy, thus the sensitivity for disease detection is decreased.

      3. 68Ga-DOTA-conjugated peptides

      3.1 Mechanism of action

      Somatostatin receptor (SSTR) is highly expressed in the well-differentiated neuroendocrine tumor (NET) as well as normal organs including brain, peripheral neurons, endocrine pancreas, and gastrointestinal tracts. 68Ga-DOTA-conjugated peptides including [68Ga-DOTA0-Tyr3]octreotide (68Ga-DOTA-TOC), [68Ga-DOTA0-1NaI3]octreotide (68GaDOTA-NOC), and [68Ga-DOTA0-Tyr3]octreotate (68GaDOTA-TATE), as well as 64Cu analogs are radiolabeled somatostatin analogs that specifically bind to SSTR and can be used for PET imaging. All three agents bind to SSTR type 2, which is the most commonly found SSTR in NET, with a slightly different affinity profile for other SSTR subtypes. For example, 68Ga-DOTA-NOC has a high affinity for SSTR type 3 and 5 and 68Ga-DOTA-TOC for SSTR type 5 [
      • Hofmann M.
      • Maecke H.
      • Borner R.
      • Weckesser E.
      • Schoffski P.
      • Oei L.
      • Schumacher J.
      • Henze M.
      • Heppeler A.
      • Meyer J.
      • Knapp H.
      Biokinetics and imaging with the somatostatin receptor PET radioligand (68)Ga-DOTATOC: preliminary data.
      ,
      • Wild D.
      • Schmitt J.S.
      • Ginj M.
      • Macke H.R.
      • Bernard B.F.
      • Krenning E.
      • De Jong M.
      • Wenger S.
      • Reubi J.C.
      DOTA-NOC, a high-affinity ligand of somatostatin receptor subtypes 2, 3 and 5 for labelling with various radiometals.
      ]. Ga68-DOTATATE is widely used for PET/CT imaging of SSTRs in United States and has shown a selective and highest affinity for SSTR type 2 [
      • Antunes P.
      • Ginj M.
      • Zhang H.
      • Waser B.
      • Baum R.P.
      • Reubi J.C.
      • Maecke H.
      Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals?.
      ]. Compared to 111In-pentetreotide (a gamma emitter SSTR tracer imaged on SPECT), 68Ga-DOTATATE shows 100 times greater affinity to SSTR type 2, and therefore shows significantly improved diagnostic performance with lower radiation dose, superior imaging quality and shorter imaging acquisition time [
      • Deppen S.A.
      • Liu E.
      • Blume J.D.
      • Clanton J.
      • Shi C.
      • Jones-Jackson L.B.
      • Lakhani V.
      • Baum R.P.
      • Berlin J.
      • Smith G.T.
      • Graham M.
      • Sandler M.P.
      • Delbeke D.
      • Walker R.C.
      Safety and efficacy of 68Ga-DOTATATE PET/CT for diagnosis, staging, and treatment management of neuroendocrine tumors.
      ]. Currently, 68Ga-DOTATATE is a key component in the imaging workup for neuroendocrine tumor work up according to the national comprehensive cancer network (NCCN) guideline.

      3.2 Normal tracer biodistribution

      The normal biodistribution pattern for DOTATATE includes pituitary gland, liver, spleen, kidneys, and adrenal glands[
      • Sanli Y.
      • Garg I.
      • Kandathil A.
      • Kendi T.
      • Zanetti M.J.B.
      • Kuyumcu S.
      • Subramaniam R.M.
      Neuroendocrine tumor diagnosis and management: (68)Ga-DOTATATE PET/CT.
      ]. SSTRs are highly expressed throughout the nephron and collecting tubule, resulting in intense physiologic uptake, combined with renally excreted tracer in the collecting systems and bladder.

      3.3 Applications

      Neuroendocrine tumors (NETs) comprise a heterogeneous group of neoplasms that arise from neuroendocrine cells of the upper airways, small intestine, duodenum, and pancreas. NETs are classified based on morphologic appearance (well to poorly differentiated), as well as according to mitotic count and proliferative index (Ki=67). 68Ga-DOTATATE PET/CT is the imaging modality of choice for the initial staging of well-differentiated NET when there is a clinical suspicion of metastases (e.g., elevated chromogranin and synaptophysin) or surgical treatment is being considered. CT and MRI are commonly used in conjunction for the evaluation of the primary mass due to excellent imaging resolution and anatomic details, and the addition of 68Ga-DOTATATE PET/CT is useful in detecting unexpected metastases. Previous studies show that 68Ga-DOTATATE PET/CT is superior to identify both hepatic and extrahepatic metastases compared to CT or MRI alone, therefore it is a preferred imaging modality for the initial evaluation of tumor extent [
      • Jackson T.
      • Darwish M.
      • Cho E.
      • Nagatomo K.
      • Osman H.
      • Jeyarajah D.R.
      68Ga-DOTATATE PET/CT compared to standard imaging in metastatic neuroendocrine tumors: a more sensitive test to detect liver metastasis?.
      ,
      • Albanus D.R.
      • Apitzsch J.
      • Erdem Z.
      • Erdem O.
      • Verburg F.A.
      • Behrendt F.F.
      • Mottaghy F.M.
      • Heinzel A.
      Clinical value of (6)(8)Ga-DOTATATE-PET/CT compared to stand-alone contrast enhanced CT for the detection of extra-hepatic metastases in patients with neuroendocrine tumours (NET).
      ]. In addition, 68Ga- DOTATATE PET/CT provides an estimation of SSTR density and functionality, detection of tumor heterogeneity, and information to select the patient cohort who would benefit from SSA or peptide receptor radionuclide therapy (PRRT). Well-differentiated less aggressive NET (Ki-67 < 3 %) typically shows high uptake on 68Ga-DOTATATE PET/CT, and higher-grade NET shows less uptake due to loss of SSTR expression [
      • Kayani I.
      • Bomanji J.B.
      • Groves A.
      • Conway G.
      • Gacinovic S.
      • Win T.
      • Dickson J.
      • Caplin M.
      • Ell P.J.
      Functional imaging of neuroendocrine tumors with combined PET/CT using 68Ga-DOTATATE (DOTA-DPhe1,Tyr3-octreotate) and 18F-FDG.
      ].
      Pheochromocytomas and paragangliomas are tumors derived from sympathetic or parasympathetic tissue in adrenal or extra-adrenal locations. SSTR type 2 is highly expressed in pheochromocytoma/paraganglioma, which can be used as a target of SSTR imaging. Previous studies proved superior diagnostic performance of 68Ga-DOTA-conjugated SSTR PET imaging compared to other imaging modalities including 18F-FDG PET/CT, 18F-DOPA or 123/131 I-MIBG imaging [
      • Han S.
      • Suh C.H.
      • Woo S.
      • Kim Y.J.
      • Lee J.J.
      Performance of (68)Ga-DOTA-conjugated somatostatin receptor-targeting peptide PET in detection of pheochromocytoma and paraganglioma: a systematic review and metaanalysis.
      ,
      • Tan T.H.
      • Hussein Z.
      • Saad F.F.
      • Shuaib I.L.
      Diagnostic performance of (68)Ga-DOTATATE PET/CT, (18)F-FDG PET/CT and (131)I-MIBG scintigraphy in mapping metastatic pheochromocytoma and paraganglioma.
      ]. For example, Tan et al. reported that 68Ga-DOTATATE showed excellent diagnostic performance in detecting metastatic pheochromocytoma/paraganglioma with sensitivity and accuracy of 93.3 % and 94.1 %, respectively, compared to 131I-MIBG imaging with sensitivity and accuracy of 46.7 % and 52.9 %, respectively or 18F-FDG PET/CT with sensitivity and accuracy of 90.9 % and 91.7 % [
      • Tan T.H.
      • Hussein Z.
      • Saad F.F.
      • Shuaib I.L.
      Diagnostic performance of (68)Ga-DOTATATE PET/CT, (18)F-FDG PET/CT and (131)I-MIBG scintigraphy in mapping metastatic pheochromocytoma and paraganglioma.
      ] (Fig. 4).
      Fig. 4
      Fig. 4Systemic evaluation of neuroendocrine tumors expressing somatostatin receptors. 71-year-old woman with SDHD mutation and multiple paragangliomas. (A) MIP image demonstrates increased 68Ga-DOTATATE uptake at multiple soft tissue lesions. Axial PET, CT and fused PET/CT in the (B) skull base (right glomus vagale), (C) pericardial recess and (D) tail of the pancreas in the left upper quadrant consistent with paragangliomas expressing somatostatin receptors.

      3.4 Limitations and pitfalls

      The pancreatic head and uncinate process may demonstrate relatively increased physiologic uptake due to higher physiologic SSTR expression, which must be considered for image interpretation. 68Ga-DOTA-conjugated peptides are limited for evaluation of poorly differentiated NET due to low SSTR expression in the cell membrane. Combination of 18F-FDG and 68Ga-DOTA-peptides not only helps overcoming the limitation, with increased detection of high-grade component [
      • Naswa N.
      • Sharma P.
      • Gupta S.K.
      • Karunanithi S.
      • Reddy R.M.
      • Patnecha M.
      • Lata S.
      • Kumar R.
      • Malhotra A.
      • Bal C.
      Dual tracer functional imaging of gastroenteropancreatic neuroendocrine tumors using 68Ga-DOTA-NOC PET-CT and 18F-FDG PET-CT: competitive or complimentary?.
      ], but also provides prognostic information of NET [
      • Garin E.
      • Le Jeune F.
      • Devillers A.
      • Cuggia M.
      • de Lajarte-Thirouard A.S.
      • Bouriel C.
      • Boucher E.
      • Raoul J.L.
      Predictive value of 18F-FDG PET and somatostatin receptor scintigraphy in patients with metastatic endocrine tumors.
      ]. Radiotracer uptake can potentially be seen in other non-NETs, including meningioma, pituitary adenoma, intraosseous hemangioma, or prostatitis [
      • Ivanidze J.
      • Roytman M.
      • Lin E.
      • Magge R.S.
      • Pisapia D.J.
      • Liechty B.
      • Karakatsanis N.
      • Ramakrishna R.
      • Knisely J.
      • Schwartz T.H.
      • Osborne J.R.
      • Pannullo S.C.
      Gallium-68 DOTATATE PET in the evaluation of intracranial meningiomas.
      ,
      • Bashir A.
      • Broholm H.
      • Clasen-Linde E.
      • Vestergaard M.B.
      • Law I.
      Pearls and pitfalls in interpretation of 68Ga-DOTATOC PET imaging.
      ,
      • Hofman M.S.
      • Lau W.F.
      • Hicks R.J.
      Somatostatin receptor imaging with 68Ga DOTATATE PET/CT: clinical utility, normal patterns, pearls, and pitfalls in interpretation.
      ] (Fig. 5).
      Fig. 5
      Fig. 5Neuroendocrine tumor imaging and pitfalls. 68Ga-DOTATATE PET/CT in a patient with metastatic neuroendocrine tumor. (A) MIP shows multiple foci of increased radiotracer uptake in lymph nodes of the mediastinum, left supraclavicular region, upper and lower abdomen as well as many hepatic metastases. Faint 68Ga-DOTATATE uptake projecting in the left lower skull (solid arrow) corresponds to a partially calcified extra-axial lesion in the left posterior skull seen on fused PET/CT and CT (B and C). Subsequent MRI shows signal characteristics compatible with meningioma on T2 fat-sat and post-contrast T1 (D and E).

      4. Fibroblast Activation Protein Inhibitors (FAPI-tracers)

      4.1 Mechanism of action

      Fibroblast activation protein (FAP) is a novel target for molecular imaging. Tumors are comprised of two types of cells: cancer cells (malignant) and stroma (non-malignant). Stroma constitutes the predominant component of tumors, in some cases up to 90 % of the tumor mass (colon cancer, breast, and pancreas) [
      • Shiga K.
      • Hara M.
      • Nagasaki T.
      • Sato T.
      • Takahashi H.
      • Takeyama H.
      Cancer-associated fibroblasts: their characteristics and their roles in tumor growth.
      ,
      • Dendl K.
      • Koerber S.A.
      • Kratochwil C.
      • Cardinale J.
      • Finck R.
      • Dabir M.
      • Novruzov E.
      • Watabe T.
      • Kramer V.
      • Choyke P.L.
      • Haberkorn U.
      • Giesel F.L.
      FAP and FAPI-PET/CT in malignant and non-malignant diseases: a perfect symbiosis?.
      ,
      • Dvorak H.F.
      Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing.
      ,
      • Altmann A.
      • Haberkorn U.
      • Siveke J.
      The latest developments in imaging of fibroblast activation protein.
      ,
      • Loktev A.
      • Lindner T.
      • Mier W.
      • Debus J.
      • Altmann A.
      • Jäger D.
      • Giesel F.
      • Kratochwil C.
      • Barthe P.
      • Roumestand C.
      • Haberkorn U.
      • Tumor-Imaging A.
      Method targeting cancer-associated fibroblasts.
      ]. Stromal cells include immune cells, endothelial cells, fibroblasts, and others. All of these cells have the potential to transform into cancer-associated fibroblasts (CAFs). CAFs account for the majority of the tumor stroma and contribute to tumor proliferation, invasiveness, angiogenesis, and metastasis via expression of the surface antigen FAP [
      • Shiga K.
      • Hara M.
      • Nagasaki T.
      • Sato T.
      • Takahashi H.
      • Takeyama H.
      Cancer-associated fibroblasts: their characteristics and their roles in tumor growth.
      ,
      • Dendl K.
      • Schlittenhardt J.
      • Staudinger F.
      • Kratochwil C.
      • Altmann A.
      • Haberkorn U.
      • Giesel F.L.
      The Role of fibroblast activation protein ligands in oncologic PET imaging.
      ,
      • Toullec A.
      • Gerald D.
      • Despouy G.
      • Bourachot B.
      • Cardon M.
      • Lefort S.
      • Richardson M.
      • Rigaill G.
      • Parrini M.C.
      • Lucchesi C.
      • Bellanger D.
      • Stern M.H.
      • Dubois T.
      • Sastre-Garau X.
      • Delattre O.
      • Vincent-Salomon A.
      • Mechta-Grigoriou F.
      Oxidative stress promotes myofibroblast differentiation and tumour spreading.
      ,
      • De Wever O.
      • Demetter P.
      • Mareel M.
      • Bracke M.
      Stromal myofibroblasts are drivers of invasive cancer growth.
      ]. A variety of tumors that have shown FAP overexpression [
      • Dendl K.
      • Koerber S.A.
      • Kratochwil C.
      • Cardinale J.
      • Finck R.
      • Dabir M.
      • Novruzov E.
      • Watabe T.
      • Kramer V.
      • Choyke P.L.
      • Haberkorn U.
      • Giesel F.L.
      FAP and FAPI-PET/CT in malignant and non-malignant diseases: a perfect symbiosis?.
      ], which is associated with more aggressiveness and poor prognosis [
      • Liu F.
      • Qi L.
      • Liu B.
      • Liu J.
      • Zhang H.
      • Che D.
      • Cao J.
      • Shen J.
      • Geng J.
      • Bi Y.
      • Ye L.
      • Pan B.
      • Yu Y.
      Fibroblast activation protein overexpression and clinical implications in solid tumors: a meta-analysis.
      ,
      • Sharma P.
      • Singh S.S.
      • Gayana S.
      Fibroblast activation protein inhibitor PET/CT: a promising molecular imaging tool.
      ]. Many FAP-ligands variants have been progressively developed to accomplish higher tumor specificity and retention, and some have potential theranostic role, including FAPI-04, FAPI-46 and FAPI-74 [
      • Kuyumcu S.
      • Sanli Y.
      • Subramaniam R.M.
      Fibroblast-activated protein inhibitor PET/CT: cancer diagnosis and management.
      ]. While the majority of FAPI-derivates are labeled with 68Ga, some have been labeled with 99 mTc(FAPI-34), or either 18F or 68Ga (FAPI-74)[
      • Kuyumcu S.
      • Sanli Y.
      • Subramaniam R.M.
      Fibroblast-activated protein inhibitor PET/CT: cancer diagnosis and management.
      ].

      4.2 Normal tracer biodistribution

      While FAP expression in healthy tissues is lower than in malignancy, it is expressed in some normal tissues including uterine stroma (particularly in proliferative phase), pancreas alpha cells, human placenta, and some dermal fibroblasts [
      • Kuyumcu S.
      • Sanli Y.
      • Subramaniam R.M.
      Fibroblast-activated protein inhibitor PET/CT: cancer diagnosis and management.
      ,
      • Gundogan C.
      • Guzel Y.
      • Can C.
      • Kaplan I.
      • Komek H.
      FAPI-04 uptake in healthy tissues of cancer patients in (68)Ga-FAPI-04 PET/CT imaging.
      ]. Each variant of FAP-ligand (FAPI-01, FAPI-02, FAPI-04 among others) shows a slightly different biodistribution profile with varying degrees up uptake in certain organs, however, they commonly demonstrate low uptake in the brain parenchyma, liver, and oral mucosa [
      • Gundogan C.
      • Guzel Y.
      • Can C.
      • Kaplan I.
      • Komek H.
      FAPI-04 uptake in healthy tissues of cancer patients in (68)Ga-FAPI-04 PET/CT imaging.
      ]. Compared to 18F-FDG, there is less uptake in the brain, myocardium, blood pool, renal cortex, bowel, and pancreas [
      • Giesel F.L.
      • Kratochwil C.
      • Schlittenhardt J.
      • Dendl K.
      • Eiber M.
      • Staudinger F.
      • Kessler L.
      • Fendler W.P.
      • Lindner T.
      • Koerber S.A.
      • Cardinale J.
      • Sennung D.
      • Roehrich M.
      • Debus J.
      • Sathekge M.
      • Haberkorn U.
      • Calais J.
      • Serfling S.
      • Buck A.L.
      Head-to-head intra-individual comparison of biodistribution and tumor uptake of (68)Ga-FAPI and (18)F-FDG PET/CT in cancer patients.
      ]. An advantage of radiobound FAP compared to other tracers is high accumulation in tumors and low uptake in the majority of healthy tissues, providing a high tumor to background ratio. The tracer is rapidly cleared from the blood stream and is excreted renally, with expected activity in the renal pelvis and bladder at the time of imaging [
      • Altmann A.
      • Haberkorn U.
      • Siveke J.
      The latest developments in imaging of fibroblast activation protein.
      ].

      4.3 Applications

      According to the previous study by Kratochwil et al., highest tumor uptake (SUVmax > 12) was found in lung, breast and esophageal cancers, cholangiocarcinoma, and sarcoma [
      • Kratochwil C.
      • Flechsig P.
      • Lindner T.
      • Abderrahim L.
      • Altmann A.
      • Mier W.
      • Adeberg S.
      • Rathke H.
      • Rohrich M.
      • Winter H.
      • Plinkert P.K.
      • Marme F.
      • Lang M.
      • Kauczor H.U.
      • Jager D.
      • Debus J.
      • Haberkorn U.
      • Giesel F.L.
      (68)Ga-FAPI PET/CT: tracer uptake in 28 different kinds of cancer.
      ]. Colon and pancreatic cancers showed intermediate uptake (SUVmax 6–12), even though these have the highest desmoplastic reaction on histology. Relatively low uptake was seen in renal cell carcinoma, pheochromocytoma, and neuroendocrine tumors (including medullary thyroid cancer and insulinomas)[
      • Kratochwil C.
      • Flechsig P.
      • Lindner T.
      • Abderrahim L.
      • Altmann A.
      • Mier W.
      • Adeberg S.
      • Rathke H.
      • Rohrich M.
      • Winter H.
      • Plinkert P.K.
      • Marme F.
      • Lang M.
      • Kauczor H.U.
      • Jager D.
      • Debus J.
      • Haberkorn U.
      • Giesel F.L.
      (68)Ga-FAPI PET/CT: tracer uptake in 28 different kinds of cancer.
      ].
      FAPI-PET/CT has a very promising role in the imaging of multiple tumors, particularly in those that have low 18F-FDG consumption, or even on those patients with challenging glucose control. Chen et al. compared 18F-FDG and 68Ga-FAPI-04 in a total of 75 patients, 56 biopsy-confirmed primary lesions in 14 types of cancer [
      • Chen H.
      • Pang Y.
      • Wu J.
      • Zhao L.
      • Hao B.
      • Wu J.
      • Wei J.
      • Wu S.
      • Zhao L.
      • Luo Z.
      • Lin X.
      • Xie C.
      • Sun L.
      • Lin Q.
      • Wu H.
      Comparison of [(68)Ga]Ga-DOTA-FAPI-04 and [(18)F] FDG PET/CT for the diagnosis of primary and metastatic lesions in patients with various types of cancer.
      ]. 68Ga-FAPI-04 showed higher sensitivity (98.2 %) compared to 18F-FDG (82.1 %) in detecting primary lesions. Ten malignant lesions not seen on 18F-FDG were visualized on 68Ga-FAPI-04 (gastric cancer, lung adenocarcinoma, cholangiocarcinoma, pancreatic cancer, hepatocellular cancer, cervical cancer, and diffuse astrocytoma). The only cancer not visualized on 68Ga-FAPI-04 PET/CT was a pancreatic cancer in the uncinate process, obscured by diffuse background pancreatic uptake due to tumor-induced pancreatitis, which interestingly showed focally increased FDG uptake [
      • Chen H.
      • Pang Y.
      • Wu J.
      • Zhao L.
      • Hao B.
      • Wu J.
      • Wei J.
      • Wu S.
      • Zhao L.
      • Luo Z.
      • Lin X.
      • Xie C.
      • Sun L.
      • Lin Q.
      • Wu H.
      Comparison of [(68)Ga]Ga-DOTA-FAPI-04 and [(18)F] FDG PET/CT for the diagnosis of primary and metastatic lesions in patients with various types of cancer.
      ]. 68Ga-FAPI-04 showed higher sensitivity in the detection of biopsy-proven nodal disease but there were no statistically significant differences in the specificity between the tracers. Meanwhile, 68Ga-DOTA-FAPI-04 PET/CT showed superior sensitivity in the detection of metastatic lesions than 18F-FDG PET/CT in patients with either newly diagnosed or previously treated cancers, particularly those in the brain, liver, and peritoneum (Fig. 6, Fig. 7) [
      • Hicks R.J.
      • Roselt P.J.
      • Kallur K.G.
      • Tothill R.W.
      • Mileshkin L.
      FAPI PET/CT: will it end the hegemony of (18)F-FDG in oncology?.
      ]).
      Fig. 6
      Fig. 6Peritoneal carcinomatosis with 18F-FDG and 18F-FAPI-04 PET/CT. (Reprinted, with permission from Ref.
      [
      • Kratochwil C.
      • Flechsig P.
      • Lindner T.
      • Abderrahim L.
      • Altmann A.
      • Mier W.
      • Adeberg S.
      • Rathke H.
      • Rohrich M.
      • Winter H.
      • Plinkert P.K.
      • Marme F.
      • Lang M.
      • Kauczor H.U.
      • Jager D.
      • Debus J.
      • Haberkorn U.
      • Giesel F.L.
      (68)Ga-FAPI PET/CT: tracer uptake in 28 different kinds of cancer.
      ]
      ). (A) 18F-FDG PET maximum-intensity-projection image demonstrates focal uptake in the region of cecum and transverse colon and possible diffuse peritoneal disease. (B) Corresponding 18F-FAPI-04 PET maximum-intensity projection clearly demonstrates diffuse peritoneal disease including involvement of subphrenic spaces. These images were originally published in JNM. Rodney J. Hicks et al. J Nucl Med 2021;62:296–302 © SNMMI
      [
      • Hicks R.J.
      • Roselt P.J.
      • Kallur K.G.
      • Tothill R.W.
      • Mileshkin L.
      FAPI PET/CT: will it end the hegemony of (18)F-FDG in oncology?.
      ]
      .
      Fig. 7
      Fig. 7Evaluation of gastric cancer with 18F-FAPI PET/CT. Gastric cancer with node, liver, and brain metastases. (A) 18F-FAPI PET maximum-intensity projection. (B) Necrotic left occipital metastasis on transaxial 18F-FAPI PET. (C) Correlative CT. Adapted. These images were originally published in JNM. Rodney J. Hicks et al. J Nucl Med 2021;62:296–302 © SNMMI
      [
      • Hicks R.J.
      • Roselt P.J.
      • Kallur K.G.
      • Tothill R.W.
      • Mileshkin L.
      FAPI PET/CT: will it end the hegemony of (18)F-FDG in oncology?.
      ]
      For lung cancer, A prospective study by Wang et al. comparing 18F-FDG and 68Ga-FAPI PET/CT showed that solid lung lesions were better delineated with FAPI, even though the metabolic tumor volume was not statistically significant [
      • Wang L.
      • Tang G.
      • Hu K.
      • Liu X.
      • Zhou W.
      • Li H.
      • Huang S.
      • Han Y.
      • Chen L.
      • Zhong J.
      • Wu H.
      Comparison of (68)Ga-FAPI and (18)F-FDG PET/CT in the evaluation of advanced lung cancer.
      ]. An advantage of FAPI over 18F-FDG is that there should not be avidity within postobstructive atelectasis or pneumonia, whereas delineation of the tumor would likely be limited on 18F-FDG PET/CT. 68Ga-FAPI PET/CT performed better or equally in depicting positive lymph nodes compared to 18F-FDG PET/CT in 84 %. 68Ga-FAPI PET/CT performed better than 18F-FDG PET/CT in the visualization of positive lymph nodes in 73 %. Overall 68Ga-FAPI performed better on depicting distant lesions, with significant differences found in bones and pleural metastases. While 68Ga-FAPI outperformed 18F-FDG in the detection of brain metastasis, detection of brain metastasis is still poorer than that of MRI.
      Breast cancer is also accompanied by high desmoplastic reaction, for which FAPI could be a suitable diagnostic agent. A prospective study by Komek et al. compared 68Ga-FAPI-04 and 18F-FDG in 20 female patients with breast cancer, predominantly intraductal carcinoma. FAPI-04 was superior to 18F-FDG in detecting the primary tumor as well as metastatic disease. The sensitivity and specificity of FAPI and 18F-FDG for detecting primary lesion were 100 % and 95.6 % using FAPI PET/CT and 78.2 % and 100 % using 18F-FDG [
      • Komek H.
      • Can C.
      • Guzel Y.
      • Oruc Z.
      • Gundogan C.
      • Yildirim O.A.
      • Kaplan I.
      • Erdur E.
      • Yildirim M.S.
      • Cakabay B.
      68)Ga-FAPI-04 PET/CT, a new step in breast cancer imaging: a comparative pilot study with the (18)F-FDG PET/CT.
      ]. FAPI also detected brain metastasis, that were not seen on 18F-FDG and were subsequently confirmed on contrast-enhanced MRI [
      • Dendl K.
      • Koerber S.A.
      • Finck R.
      • Mokoala K.M.G.
      • Staudinger F.
      • Schillings L.
      • Heger U.
      • Rohrich M.
      • Kratochwil C.
      • Sathekge M.
      • Jager D.
      • Debus J.
      • Haberkorn U.
      • Giesel F.L.
      68)Ga-FAPI-PET/CT in patients with various gynecological malignancies.
      ].
      The study by Koerber et al. evaluated the role of FAPI in colon, sigmoid, rectal, and anal cancers and concluded that primary and metastatic lesions could be accurately detected by FAPI, changing TNM status and disease management [
      • Koerber S.A.
      • Staudinger F.
      • Kratochwil C.
      • Adeberg S.
      • Haefner M.F.
      • Ungerechts G.
      • Rathke H.
      • Winter E.
      • Lindner T.
      • Syed M.
      • Bhatti I.A.
      • Herfarth K.
      • Choyke P.L.
      • Jaeger D.
      • Haberkorn U.
      • Debus J.
      • Giesel F.L.
      The role of (68)Ga-FAPI PET/CT for patients with malignancies of the lower gastrointestinal tract: first clinical experience.
      ]. Evaluation of glioblastoma with FAPI led to increased gross tumor volumes (GTVs) compared to MRI, thus changing radiation treatment fields [
      • Windisch P.
      • Rohrich M.
      • Regnery S.
      • Tonndorf-Martini E.
      • Held T.
      • Lang K.
      • Bernhardt D.
      • Rieken S.
      • Giesel F.
      • Haberkorn U.
      • Debus J.
      • Adeberg S.
      Fibroblast activation protein (FAP) specific PET for advanced target volume delineation in glioblastoma.
      ]. FAPI can also aid in the delineation of target volume in esophageal cancer[
      • Kratochwil C.
      • Flechsig P.
      • Lindner T.
      • Abderrahim L.
      • Altmann A.
      • Mier W.
      • Adeberg S.
      • Rathke H.
      • Rohrich M.
      • Winter H.
      • Plinkert P.K.
      • Marme F.
      • Lang M.
      • Kauczor H.U.
      • Jager D.
      • Debus J.
      • Haberkorn U.
      • Giesel F.L.
      (68)Ga-FAPI PET/CT: tracer uptake in 28 different kinds of cancer.
      ], as well as in the evaluation of nodal staging [
      • Chen H.
      • Pang Y.
      • Wu J.
      • Zhao L.
      • Hao B.
      • Wu J.
      • Wei J.
      • Wu S.
      • Zhao L.
      • Luo Z.
      • Lin X.
      • Xie C.
      • Sun L.
      • Lin Q.
      • Wu H.
      Comparison of [(68)Ga]Ga-DOTA-FAPI-04 and [(18)F] FDG PET/CT for the diagnosis of primary and metastatic lesions in patients with various types of cancer.
      ,
      • Zhao L.
      • Chen S.
      • Lin L.
      • Sun L.
      • Wu H.
      • Lin Q.
      • Chen H.
      [(68)Ga]Ga-DOTA-FAPI-04 improves tumor staging and monitors early response to chemoradiotherapy in a patient with esophageal cancer.
      ].
      Many hepatobiliary tumors are characterized by a substantial fibrotic reaction. An example is pancreatic ductal adenocarcinoma (PDAC), in which fibrotic reaction leads to scarring and ductal dilation, which can be one of the early signs of disease. PDAC expresses high levels of FAP (> 90 %), leading to high uptake, and favorable target-to-background ratio. There is limited literature regarding the potential role of FAPI in pancreatic cancer, however it has shown higher sensitivity compared to 18F-FDG for the detection of local and metastatic disease. While in some cases tumor staging may be upgraded with FAPI, it is unclear how this tracer can change the overall management of patients [
      • Pang Y.
      • Zhao L.
      • Shang Q.
      • Meng T.
      • Feng L.
      • Wang S.
      • Guo P.
      • Wu X.
      • Lin Q.
      • Wu H.
      • Huang W.
      • Sun L.
      • Chen H.
      Positron emission tomography and computed tomography with [68Ga]Ga-fibroblast activation protein inhibitors improves tumor detection and staging in patients with pancreatic cancer.
      ].
      FAP is expressed in 97 % of all ovarian cancers and degree of expression correlates with poor clinical prognosis, chemotherapy resistance and shorter time until recurrence. 18F-FDG has limitations in detecting serosal implants due to physiological activity in the bowel, whereas FAPI has shown to be able to depict peritoneal disease not seen on 18F-FDG.

      4.4 Limitations and pitfalls

      FAP targets overexpression by CAFs, not tumor cells, and therefore can be found in healthy tissues and multiple benign processes. elevated uptake in the uterus of pre-menopausal and post-partum patients has been reported, and therefore the use of FAPI in endometrial and cervical malignancies may be limited. Also, normal uptake in sites of fibrosis, including post treatment fibrosis could lead to a false positive [
      • Dendl K.
      • Koerber S.A.
      • Finck R.
      • Mokoala K.M.G.
      • Staudinger F.
      • Schillings L.
      • Heger U.
      • Rohrich M.
      • Kratochwil C.
      • Sathekge M.
      • Jager D.
      • Debus J.
      • Haberkorn U.
      • Giesel F.L.
      68)Ga-FAPI-PET/CT in patients with various gynecological malignancies.
      ]. FAP are also expressed in non-oncologic processes, such as wound healing, chronic inflammation, arthritis, atherosclerotic plaques, and fibrosis including cirrhosis [
      • Loktev A.
      • Lindner T.
      • Mier W.
      • Debus J.
      • Altmann A.
      • Jäger D.
      • Giesel F.
      • Kratochwil C.
      • Barthe P.
      • Roumestand C.
      • Haberkorn U.
      • Tumor-Imaging A.
      Method targeting cancer-associated fibroblasts.
      ], which must be considered when interpreting studies. In addition, there is limited role for hematological malignancies.

      5. 18F-Fluoroestradiol 16α-[18F]fluoro-17β-estradiol (18F-FES)

      5.1 Mechanism of action

      18F-fluoroestradiol binds to estrogen receptors, serving as a good correlate for ER expression as measured by immunohistochemistry assay (IHC) and FES [
      • Peterson L.M.
      • Mankoff D.A.
      • Lawton T.
      • Yagle K.
      • Schubert E.K.
      • Stekhova S.
      • Gown A.
      • Link J.M.
      • Tewson T.
      • Krohn K.A.
      Quantitative imaging of estrogen receptor expression in breast cancer with PET and 18F-fluoroestradiol.
      ]. In conjunction with 18F-FDG or other techniques, 18F-FES has the potential to assess heterogeneity in ER expression and identify sites that have lost ER expression.

      5.2 Normal tracer biodistribution

      18F-FES is highly extracted and metabolized by the liver, resulting in rapid early blood clearance and stable blood activity over time after injection. Activity within the gastrointestinal tract is also high. 18F-FES metabolites are renally excreted and uptake in the bladder is high at the time of imaging. There is no uptake in the brain, resulting in good detection of brain metastases.

      5.3 Applications

      Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer worldwide, and the second leading cause of death worldwide [
      • Liao G.J.
      • Clark A.S.
      • Schubert E.K.
      • Mankoff D.A.
      18F-fluoroestradiol PET: current status and potential future clinical applications.
      ]. One of the histologic and treatment driving features of breast cancer is hormonal expression profile. Approximately 75 % of newly diagnosed breast cancers are estrogen-receptor positive (ER+). ER+ breast tumors are associated with a more favorable prognosis and potential response to hormonal therapy [
      • Liao G.J.
      • Clark A.S.
      • Schubert E.K.
      • Mankoff D.A.
      18F-fluoroestradiol PET: current status and potential future clinical applications.
      ]. The most common histology is invasive ductal carcinoma (IDC) which accounts for 80 % of cases, followed by invasive lobular carcinoma (ILC) representing 10–15 % of cases. Nearly 95 % of ILC are ER+. 18F-FES PET/CT is used for the detection of ER+ lesions, as an adjunct to biopsy, in patients with advanced, or metastatic breast cancer [
      • Chae S.Y.
      • Ahn S.H.
      • Kim S.B.
      • Han S.
      • Lee S.H.
      • Oh S.J.
      • Lee S.J.
      • Kim H.J.
      • Ko B.S.
      • Lee J.W.
      • Son B.H.
      • Kim J.
      • Ahn J.H.
      • Jung K.H.
      • Kim J.E.
      • Kim S.Y.
      • Choi W.J.
      • Shin H.J.
      • Gong G.
      • Lee H.S.
      • Lee J.B.
      • Moon D.H.
      Diagnostic accuracy and safety of 16alpha-[(18)F]fluoro-17beta-oestradiol PET-CT for the assessment of oestrogen receptor status in recurrent or metastatic lesions in patients with breast cancer: a prospective cohort study.
      ]. Currently, ER expression measured with IHC assay, requires biopsies and are subject to sampling errors [
      • Liao G.J.
      • Clark A.S.
      • Schubert E.K.
      • Mankoff D.A.
      18F-fluoroestradiol PET: current status and potential future clinical applications.
      ]. 18F-FES can provide an in vivo assessment of the ER expression across all tumor sites and limit the sampling error from biopsies. In addition, overall evaluation of the patient’s ER status can help predict endocrine responsiveness as higher levels of tumor ER expression are associated with greater clinical benefit from endocrine therapy [
      • Chae S.Y.
      • Ahn S.H.
      • Kim S.B.
      • Han S.
      • Lee S.H.
      • Oh S.J.
      • Lee S.J.
      • Kim H.J.
      • Ko B.S.
      • Lee J.W.
      • Son B.H.
      • Kim J.
      • Ahn J.H.
      • Jung K.H.
      • Kim J.E.
      • Kim S.Y.
      • Choi W.J.
      • Shin H.J.
      • Gong G.
      • Lee H.S.
      • Lee J.B.
      • Moon D.H.
      Diagnostic accuracy and safety of 16alpha-[(18)F]fluoro-17beta-oestradiol PET-CT for the assessment of oestrogen receptor status in recurrent or metastatic lesions in patients with breast cancer: a prospective cohort study.
      ]. There is limited evidence of utility for detection or staging in early breast cancer, but there is ongoing investigation on the role of FES PET/CT for detection or staging in early breast cancer. However, 18F-FES is most useful detecting metastases in vivo. Several studies have demonstrated that contrary to the primary tumor, metastatic lesions may no longer express ER or be non-functional, which is extremely important for patients with recurrent or metastatic disease.
      The lobular subtype of breast cancer is difficult to evaluate with 18F-FDG PET/CT due to low 18F-FDG avidity. However, it is nearly always estrogen-receptor positive (95 %), and 18F-FES PET/CT can better detect metastases including osseous lesions and serosal implants compared to 18F-FDG PET/CT. A meta-analysis of 9 studies (8 prospective) reported pooled sensitivity of 82 % and specificity of 95 % to detect ER+ tumors by quantitative assessment of lesions [
      • Evangelista L.
      • Guarneri V.
      • Conte P.F.
      18F-fluoroestradiol positron emission tomography in breast cancer patients: systematic review of the literature & meta-analysis.
      ] (Fig. 8).
      Fig. 8
      Fig. 818F-FES PET/CT in breast cancer. 18F-FES PET/CT and 18F-FDG PET/CT (performed one week prior) in an 85-year-old woman with newly diagnosed ER+ left breast invasive lobular carcinoma. (A) 18F-FES PET/CT MIP shows the primary lesion in the left breast (black arrowhead) with ipsilateral axillary lymphadenopathy (white arrowhead), right breast masses (white arrow) and multiple bone lesions (black arrows). Note the standard field of view for 18F-FES PET/CT includes the skull vertex for detection of additional bone metastases (black asterisk). Note physiologic biliary excretion of 18F-FES (white asterisk). (C-H) Representative axial fusion images show enhanced 18F-FES uptake in lesions compared to 18F-FDG using similar window level: (C) left axillary levels 1, 2, and 3 lymphadenopathy with SUVmax 32 on 18F-FES and (D) SUVmax 3.3 on 18F-FDG, (E) left third rib with SUVmax 4.3 with 18F-FES and (F) SUVmax 2.5 with 18F-FDG, and (H) right C5 pedicle with SUVmax 5 with 18F-FES without appreciable uptake above background with 18F-FDG (I). There is concordant uptake between 18F-FES and 18F-FDG PET/CT, more so with 18F-FES, suggesting a favorable response to hormone-directed therapies. Courtesy of Lacey McIntosh D.O., M.P.H. (University of Massachusetts Memorial Medical Center).

      5.4 Limitations and pitfalls

      One of the main limitations is that the sensitivity of FES decreases if there is concomitant treatment with ER down-regulator or modulator such as Fulvestrant or Tamoxifen and patients ideally would need to be off therapy for several weeks prior to the scan. Due to high hepatic uptake related to physiologic hepatobiliary excretion, detection of hepatic metastases may be poor. Therefore, other imaging modalities such as contrast-enhanced CT or MRI must be performed for the evaluation of hepatic metastasis. 18F-FES PET/CT ideally should be performed in conjunction with 18F-FDG PET/CT, which in practice can create challenges for insurance reimbursement.

      6. Commonly used radiotracers in prostate cancer

      Prostate cancer is the most diagnosed cancer among men worldwide and the second most common cause of oncologic death in men in the US (11 %), following lung cancer. However, the 5-year relative survival for all stages combined is the highest (98 %)[
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2022.
      ]. Biochemical recurrence occurs in approximately 20–30 % of patients with prostate cancer after curative prostatectomy, and recurrence is normally identified by elevation of PSA levels. Localizing the site of active metastatic disease can sometime be challenging. Conventional imaging techniques have traditionally failed to detect nodal disease in lymph nodes smaller than 8 mm. In addition, bone scan, commonly used for staging of bone metastatic disease, may not be specific enough. While there have been many different tracers used in the past decades including 11C-choline and 18F-fluciclovine, PSMA-based tracers have become the preferred tracer for diagnosis of prostate cancer in specific scenarios for biochemical recurrence.

      6.1 Prostate specific membrane antigen (PSMA) agents

      6.1.1 Mechanism of action

      PSMA, also known as glutamate carboxypeptidase II, is a type II transmembrane glycoprotein overexpressed by up to 1000-fold in prostate cancer epithelial cells [
      • Peterson L.M.
      • Mankoff D.A.
      • Lawton T.
      • Yagle K.
      • Schubert E.K.
      • Stekhova S.
      • Gown A.
      • Link J.M.
      • Tewson T.
      • Krohn K.A.
      Quantitative imaging of estrogen receptor expression in breast cancer with PET and 18F-fluoroestradiol.
      ]. Higher levels of PSMA expression are associated with poorer prognostic outcomes. PSMA expression levels increase with higher stage and tumor grade, and in castration resistant prostate cancers. However, aggressive tumors can undergo neuroendocrine differentiation and lose PSMA expression. This glycoprotein is located on the apical surface of cells. The intricacies of the molecular structure are beyond the scope of this review, but the newer radionuclide-based PSMA agents are internalized by the PSMA-expressing cells, which is the base of therapeutic applications. The imaging and therapeutic molecule is an anti-PSMA antibody targeting PSMA expressed in cells.
      Up to date, many prostate-specific membrane antigen (PSMA) based agents have been developed for management of prostate cancer. The most used in clinical practice are either 68Ga, such as 68Ga-PSMA-11 and 68Ga-PSMA-617, or 18 F labeled compounds, with 18F-DCFPyL and 18F-PSMA-1007 already established in clinical practice (Fig. 9). There is limited data on direct comparison of both agents, however there are probably no substantial differences in diagnostic accuracy.
      Fig. 9
      Fig. 969-year-old male with history of metastatic castration resistant prostate cancer with rising PSA on Cabazitaxel. Rising PSA levels, 4.98 ng/mL in September 2021 and 14.8 ng/mL in April 2022. (A) MIP 18F-DCFPyL PET/CT in October 2021 with multifocal PSMA-avid disease including uptake at the prostate bed (dashed arrows), pelvis nodes and bones of the axial and appendicular skeleton. (B) MIP PET/CT of 68Ga-PSMA-11 (May 2022) shows similar extent of disease. (C) 68Ga-PSMA-11 axial PET and fused PET/CT with focal uptake in the prostate gland at the right apex (dashed arrows). (D) 68Ga-PSMA-11 axial PET and CT showing right pelvic PSMA-avid lymph node.

      6.1.2 Normal tracer biodistribution

      PSMA expression has been found in the normal salivary and lacrimal glands, breast, proximal renal tubules, brain parenchyma, duodenal epithelium (brush border), Kupffer cells, cervical and stellate ganglion as well as nerve roots, commonly sacral nerve roots. There is no significant uptake in the bone marrow, which allows for good evaluation of osseous on marrow disease. Kidney, spleen, and salivary uptake are higher on 68Ga-PSMA-11 compared to 18F-DCFPyL, while the liver shows slightly lower uptake. Blood pool uptake is similar with both tracers. Both 68Ga-PSMA-11 and 18F-DCFPyL are renally excreted, so activity is seen in the ureters and the bladder. 18F-PSMA-1007 has hepatobiliary clearance and might improve local detection of prostate cancer. In all PSMA tracers, the highest uptake organ is the kidney.

      6.1.3 Applications

      The most recently published Appropriate Use Criteria for PSMA PET reported by Society of Nuclear Medicine and Molecular Imaging (SNMMI), in conjunction with other organizations, deems it appropriate to perform PSMA PET/CT in new prostate cancer diagnosis of unfavorable intermediate, high-risk/very high-risk patients for staging, particularly if conventional techniques (CT, MRI, or bone scan) have none to 5 distant metastasis or are equivocal, to help evaluate metastatic disease and help guide therapy options. On the contrary, if there is widespread metastatic disease on conventional techniques, PSMA PET/CT would not be indicated, as management would not change. PSMA PET/CT is usually not indicated for low-risk patients, or patients with Gleason score < 7. In rising PSA levels after radical prostatectomy or definitive radiotherapy, PSMA PET would also be appropriate (Fig. 10). PSMA can upgrade TNM staging in patients with early castrate-resistant prostate cancer (CRPC) or high-risk from M0 (on CT or bone scan) to M1 in up to 55 % of cases in retrospective studies [
      • Fendler W.P.
      • Weber M.
      • Iravani A.
      • Hofman M.S.
      • Calais J.
      • Czernin J.
      • Ilhan H.
      • Saad F.
      • Small E.J.
      • Smith M.R.
      • Perez P.M.
      • Hope T.A.
      • Rauscher I.
      • Londhe A.
      • Lopez-Gitlitz A.
      • Cheng S.
      • Maurer T.
      • Herrmann K.
      • Eiber M.
      • Hadaschik B.
      Prostate-specific membrane antigen ligand positron emission tomography in men with nonmetastatic castration-resistant prostate cancer.
      ]. PSMA PET/CT could also help confirm oligometastatic status for a more targeted therapy. Currently, PSMA PET/CT can also be performed to evaluate eligibility for PSMA-targeted radioligand therapy. Multiple studies have shown that PSMA has moderate sensitivity but very high specificity for nodal metastasis in intermediate and high- risk patients with reported sensitivity of 0.40 and specificity was 0.95 [
      • Hope T.A.
      • Eiber M.
      • Armstrong W.R.
      • Juarez R.
      • Murthy V.
      • Lawhn-Heath C.
      • Behr S.C.
      • Zhang L.
      • Barbato F.
      • Ceci F.
      • Farolfi A.
      • Schwarzenbock S.M.
      • Unterrainer M.
      • Zacho H.D.
      • Nguyen H.G.
      • Cooperberg M.R.
      • Carroll P.R.
      • Reiter R.E.
      • Holden S.
      • Herrmann K.
      • Zhu S.
      • Fendler W.P.
      • Czernin J.
      • Calais J.
      Diagnostic accuracy of 68Ga-PSMA-11 PET for pelvic nodal metastasis detection prior to radical prostatectomy and pelvic lymph node dissection: a multicenter prospective phase 3 imaging trial.
      ].
      Fig. 10
      Fig. 10Detection of subcentimeter active prostate disease with PSMA-based radiotracers. 79-year-old man with history of prostate cancer treated with prostatectomy, radiotherapy, and adjuvant androgen deprivation therapy (ADT) with biochemical recurrence and raising PSA levels, 2.02 ng/mL around the time of the scan. (A) MIP 18F-DCFPyL PET/CT and (B and C) axial PET, fused PET/CT and CT through the retroperitoneum show intense focal uptake in the right common iliac nodal station of the pelvis (dashed arrow). (B) 4 mm left para-aortic (blue arrow) and (C) 3 mm retro-aortic lymph nodes (white arrow) that would have not otherwise been detected on conventional imaging due to small size.

      6.1.4 Limitations and pitfalls

      As previously mentioned, a limitation of both 68Ga-PSMA-11 and 18F-DCFPyL, is renal excretion. For local prostate disease, PSMA PET has less spatial resolution than MRI, and therefore cannot be substitutive. Anecdotally, other prostatic entities have been described to show increased PSMA uptake, including granulomatous prostatitis [
      • Ruan D.
      • Sun L.
      68Ga-DOTATATE and 68Ga-PSMA uptake in granulomatous prostatitis.
      ]. PSMA uptake can be seen in other malignancies, including breast cancer, glioblastoma multiforme, pancreatic ductal adenocarcinoma, NSCLC, colorectal cancer, transitional cells carcinoma, gastric adenocarcinoma, and renal cell carcinoma (Fig. 11) In addition, some benign osseous lesions have demonstrated PSMA uptake, but the degree of uptake is generally much less than that seen in prostate cancer. Single rib lesions with low level of tracer uptake are likely benign [
      • Chen M.Y.
      • Franklin A.
      • Yaxley J.
      • Gianduzzo T.
      • McBean R.
      • Wong D.
      • Tatkovic A.
      • McEwan L.
      • Walters J.
      • Kua B.
      Solitary rib lesions showing prostate-specific membrane antigen (PSMA) uptake in pre-treatment staging (68) Ga-PSMA-11 positron emission tomography scans for men with prostate cancer: benign or malignant?.
      ].
      Fig. 11
      Fig. 11Non-prostatic lesions with increased PSMA uptake. 71-year-old man with history of metastatic renal cell carcinoma and prostate cancer. (A) Axial CT and fused PET/CT in the upper chest shows increased focal PSMA uptake associated with lytic bone lesions in a right anterior rib (white arrow) and (B) faint lytic lesion in the right scapula (blue arrow), consistent with metastases from renal cell carcinoma.

      6.2 18F-fluciclovine

      6.2.1 Mechanism of action

      18F-fluciclovine (anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid) is a radiolabeled synthetic amino acid analog of leucine that enters the cell via amino acid transporters, upregulated in prostate cancer. However, it is not a prostate cancer specific agent and can be taken up by multiple other malignancies, including lung cancer, lymphoma, renal cell carcinoma and multiple myeloma [
      • Niaz M.J.
      • Sun M.
      • Skafida M.
      • Niaz M.O.
      • Ivanidze J.
      • Osborne J.R.
      • O'Dwyer E.
      Review of commonly used prostate specific PET tracers used in prostate cancer imaging in current clinical practice.
      ].

      6.2.2 Normal tracer biodistribution

      Intense physiologic uptake is seen in the pancreas, followed by the liver. Moderate uptake is seen in the salivary glands and pituitary gland and variable mild to moderate uptake in the gastrointestinal tract. The red bone marrow uptake peaks at 10–15 min and muscle uptake is mild initially and increased over time. There is minimal uptake in the brain and minimal excretion through the kidneys, however the usual protocols scan from the pelvis to the skull to optimize visualization of pelvic structures at an earlier time. Organs with little to no uptake include the brain parenchyma and lungs. Increased fluciclovine uptake has been seen in infectious or inflammatory processes and adrenal adenomas [
      • Gusman M.
      • Aminsharifi J.A.
      • Peacock J.G.
      • Anderson S.B.
      • Clemenshaw M.N.
      • Banks K.P.
      Review of (18)F-fluciclovine PET for detection of recurrent prostate cancer.
      ]. Other malignancies may exhibit increased fluciclovine uptake, such as lung, breast, brain (including meningioma), gynecological malignancies and even osteoid osteoma.

      6.2.3 Applications

      Fluciclovine has been extensively studied in recurrent prostate cancer. The diagnostic performance of 18F-fluciclovine has been proven superior to CT in the setting of recurrent prostate cancer for detection of disease at the local prostatectomy bed or prostate, metastatic nodal or distant disease. fluciclovine in patients that have received prostate-sparing therapies may demonstrate non-specific pattern of uptake and can be confounded with prostatic hypertrophy and chronic inflammation. More recent studies have shown that PSMA-agents have better detection rates compared to fluciclovine in patients after prostatectomy following radical prostatectomy, particularly in detection of distant disease [
      • Niaz M.J.
      • Sun M.
      • Skafida M.
      • Niaz M.O.
      • Ivanidze J.
      • Osborne J.R.
      • O'Dwyer E.
      Review of commonly used prostate specific PET tracers used in prostate cancer imaging in current clinical practice.
      ,
      • Savir-Baruch B.
      • Zanoni L.
      • Schuster D.M.
      Imaging of prostate cancer using fluciclovine.
      ]. Calais et al. performed a single-centered prospective trial in 50 patients who underwent both fluciclovine and 68Ga-PSMA-11 PET/CT with biochemical recurrence after radical prostatectomy and reported a detection rate of 26 % for fluciclovine and 56 % for PSMA, 8 % compared to 30 % with p = 0.0034 for pelvic nodal disease and 0 % compared to 16 % with p = 0,0078 for extrapelvic disease. There were no statistically significant differences at the prostate bed, although this may have been due to small sample. After stratifying according to serum PSA levels there were no statistically significant differences, which may have been also due to small sample size [
      • Calais J.
      • Ceci F.
      • Eiber M.
      • Hope T.A.
      • Hofman M.S.
      • Rischpler C.
      • Bach-Gansmo T.
      • Nanni C.
      • Savir-Baruch B.
      • Elashoff D.
      • Grogan T.
      • Dahlbom M.
      • Slavik R.
      • Gartmann J.
      • Nguyen K.
      • Lok V.
      • Jadvar H.
      • Kishan A.U.
      • Rettig M.B.
      • Reiter R.E.
      • Fendler W.P.
      • Czernin J.
      (18)F-fluciclovine PET-CT and (68)Ga-PSMA-11 PET-CT in patients with early biochemical recurrence after prostatectomy: a prospective, single-centre, single-arm, comparative imaging trial.
      ].

      6.2.4 Limitations and pitfalls

      While primary prostatic cancerous lesions have higher uptake than background prostate, there is some overlap with non-malignant prostate uptake. As mentioned earlier, already treated prostate, benign prostatic hypertrophy or chronic inflammation can also show diffusely increased prostate uptake, which is one of the reasons why it’s role on primary staging is limited. Inguinal lymph nodes may show mild symmetric uptake and should not be interpreted as positive. There is significant bone marrow uptake with may mask underlying lesions. Uptake in lytic osseous lesions is typically intense, moderate in mixed lesions and absent on sclerotic lesions, which then additional imaging should be considered [
      • Calais J.
      • Ceci F.
      • Eiber M.
      • Hope T.A.
      • Hofman M.S.
      • Rischpler C.
      • Bach-Gansmo T.
      • Nanni C.
      • Savir-Baruch B.
      • Elashoff D.
      • Grogan T.
      • Dahlbom M.
      • Slavik R.
      • Gartmann J.
      • Nguyen K.
      • Lok V.
      • Jadvar H.
      • Kishan A.U.
      • Rettig M.B.
      • Reiter R.E.
      • Fendler W.P.
      • Czernin J.
      (18)F-fluciclovine PET-CT and (68)Ga-PSMA-11 PET-CT in patients with early biochemical recurrence after prostatectomy: a prospective, single-centre, single-arm, comparative imaging trial.
      ]. Ongoing therapy with androgen deprivation therapy may impact detection of disease. Early appearance of bladder or ureteral activity could be confused by local recurrence or abnormal pelvic lymph nodes.

      7. Conclusion

      This review explored some of the current tracers in use for cancer imaging with PET/CT. While 18F-FDG has been the major agent for many years, this is an exciting time in molecular medicine and imaging with the many recent developments in cancer- and receptor-specific tracers for diagnostic use in cancer imaging. These novel tracers have shown superior detection of disease when compared to traditional imaging modalities and are changing the landscape of staging and disease management for patients all over the world. These new diagnostic tracers serve as an important platform in the development of parallel theranostic agents, giving patients new treatment options for improved survival and quality of life.

      CRediT authorship contribution statement

      Elisa Franquet: Conceptualization, Writing – original draft. Hyesun Park: Writing – original draft, Writing – review & editing.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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