Positron emission tomography/computed tomography (PET/CT) is currently one of the main imaging modalities for cancer patients worldwide. Fluorodeoxyglucose (FDG) PET/CT has earned its global recognition in the modern management of cancer patients and is rapidly becoming an important imaging modality for patients with cardiac, neurological, and infectious/inflammatory conditions.
Despite its proven benefits, FDG has limitations in the assessment of several relevant tumours such as prostate cancer. Therefore, there has been a pressing need for the development and clinical application of different PET radiopharmaceuticals that could image these tumours more precisely. Accordingly, several non-FDG PET radiopharmaceuticals have been introduced into the clinical arena for management of cancer. This trend will undoubtedly continue to spread internationally. The use of PET/CT with different PET radiopharmaceuticals specific to tumour type and biological process being assessed is part of the personalised precision medicine approach.
The objective of this publication is to provide a case-based method of understanding normal biodistribution, variants, and pitfalls, including several examples of different imaging appearances for the main oncological indications for each of the new non-FDG PET radiopharmaceuticals. This should facilitate the interpretation and recognition of common variants and pitfalls to ensure that, in clinical practice, the official report is accurate and helpful.
Some of these radiopharmaceuticals are already commercially available in many countries (e.g. 68Ga-DOTATATE and DOTATOC), others are in the process of becoming available (e.g. 68Ga-PSMA), and some are still being researched. However, this list is subject to change as some radiopharmaceuticals are increasingly utilised, while others gradually decrease in use.
Carbon-11 is a PET radioisotope with a T1/2 of 20.4 min. Due to the abundance of carbon in the chemistry of biomolecules, all C-11 radiopharmaceuticals demonstrate identical behaviour to natural compounds, allowing real tracing of the biological processes.
Fluorine-18 is a PET radioisotope with a T1/2 of 109.7 min. Due to high chemical stability of the C-F bond in organic compounds, and the high water solubility of F-compounds, F-18 tracers usually exhibit suitable stability and biodistribution in humans. The vast clinical application of F-compounds has led to the development of efficient automated production methods of F-18 tracers for clinical use.
Gallium-68 has a T1/2 of 67.7 min, and is usually obtained from a germanium-68 generator. Due to the T1/2 of 271 days of the parent isotope, 68Ge, the generator can be used for in-hospital production of Ga-68.
After injection 11C-acetate is dispersed in many human tissues including the pancreas, bowels, liver, kidneys, and spleen. The tracer is not excreted in urine under normal circumstances. 11C-acetate is typically incorporated into the cellular membrane in proportion to the cellular proliferation rate or alternatively oxidised to carbon dioxide and water. 11C-acetate may also be converted into amino acids (Seltzer et al. 2004; Karanikas and Beheshti 2014).
The main clinical application of 11C-acetate is the detection of non 18F-FDG-avid neoplasm, such as differentiated hepatocellular carcinoma and renal cell carcinomas (Hain and Maisey 2003; Ho et al. 2003; Park et al. 2008). Some other applications of 11C-acetate PET are brain tumours (Liu et al. 2006) and lung carcinomas, while in the past the tracer has been used in prostate cancer (Sandblom et al. 2006).
After injection, the tracer is cleared from the blood and metabolised in 20 min. 18F-fluoroestradiol binds to the oestrogen receptors on the tumour cell surface as well as intratumoural receptors in oestrogen receptor-positive tumours (Liao et al. 2016).
Treatment with oestrogen receptor antagonists (e.g. tamoxifen, fulvestrant, faslodex, oestrogens) should be suspended for at least 5 weeks prior to performing the scan. Aromatase inhibitors and luteinizing hormone releasing hormone agonists may be continued
No fasting is required
200 MBq of 18F-fluoroestradiol iv
Level of binding of 18F-FES to the oestrogen receptors remains stable between 20 and 120 min postinjection. For logistical reasons, scanning procedure should start 60 min after injection
18F-fluoroestradiol is a valuable tracer for the studies of the oestrogen receptor status of primary and metastatic breast or ovarian cancers (Venema et al. 2016; van Kruchten et al. 2013a; van Kruchten et al. 2012; van Kruchten et al. 2013b; Peterson et al. 2011; Linden et al. 2011).
18F-FLT is an analogue of the nucleoside thymidine; however, substitution of the 3′-F atom prevents from further entering the regular biochemical pathway. FLT is transported from the blood into cells by active transport and phosphorylated by thymidine kinase I without incorporation into the DNA. The conjugated FLT is cleared via the kidneys and excreted in the urine. The accumulated activity in the cells is proportional to thymidine kinase 1 activity as well as cellular proliferation (Grierson and Shields 2000; Oh et al. 2004; Shankar 2012; Turcotte et al. 2007; Vesselle et al. 2003).
• No fasting is required
• 2–3 MBq\Kg of 18F-FLT iv
• Uptake time 50–60 min
Clinical indications in oncology (Figs. 12, 13, and 14)
18F-FLT is a marker for tumour cell proliferation that has been introduced to improve the accuracy of early FDG PET assessment (Kenny et al. 2007).
11C-Methionine, an essential amino acid, enters the cells by various aminoacid transporters and is involved in the synthesis of proteins and lipids, as well as in the regulation and synthesis of DNA and RNA (Davis et al. 1982; Deloar et al. 1998; Harris et al. 2013).
• Fasting for at least 2 h
• 3 MBq/kg of 11C-Methionine iv
• Injection immediately before the start of the emission
Clinical indications in oncology (Figs. 16, 17, and 18)
11C-Methionine is used in the detection of brain tumours, primarily gliomas. The gliomas present an increased protein metabolism and capture 11C-Methionine through specific carriers, in contrast to normal tissues that show low uptake.
After injection, the tracer rapidly clears from the circulation (< 3 min), with high clearance by liver and kidneys. Increased metabolism will lead to an increased uptake of choline in the cell membranes and tissues.
11C-choline distributes mainly to the pancreas, kidneys, liver, spleen, and colon. Based upon the relatively low urinary excretion of radioactivity, renal distribution is predominantly to the organ itself, rather than via formation of urine.
The urinary excretion of 18F-fluorocholine has been reported to be about 5% of the administered activity in female patients and 2% in male patients within 60 min after injection (Mitterhauser et al. 2005; DeGrado et al. 2001; DeGrado et al. 2002).
• Fasting of 4 h is suggested
• 4 or 5 MBq\Kg of 11C-choline iv/300 MBq 18F-fluorocholine iv
• Uptake time 2–5 min for 11C-choline/30 min for 18F-fluorocholine
• Acquisition starts from the pelvis for 11C-choline/head-thorax for 18F-fluorocholine
Clinical indications in oncology (Figs. 20, 21, 22, 23, and 24)
The main clinical application of choline is in prostate cancer patients for staging and restaging the disease in case of biochemical recurrence after primary treatment (Kryza et al. 2008; Evangelista et al. 2013).
Prostate specific membrane antigen (PSMA), a tumour-associated antigen and type II transmembrane protein, is expressed on the membrane of prostatic epithelial cells and overexpressed on prostate tumour cells. Upon internalisation of the radiotracer, PSMA-expressing tumour cells can be detected during PET imaging (Heidenreich et al. 2014; Afshar-Oromieh et al. 2016; Demirci et al. 2016).
The main clinical application of 68Ga-PSMA is in prostate cancer patients, namely initial diagnosis (Fendler et al. 2017), nodal staging (Schneider et al. 2016), restaging in case of biochemical recurrence (Calais et al. 2018; Maurer et al. 2016), and theranostic in case of 177Lu-PSMA treatment (Mottet et al. 2011; Zamboglou et al. 2016), or alfa emitters such as 225AcPSMA (Maurer et al. 2016).
18F-DOPA reflects all stages of DOPA transport, storage, and metabolism. The tracer is metabolised in the striatum, but also in peripheral tissues such as liver, kidneys, and lung (Rahbar et al. 2017).
• Fasting for more than 4 h
• 2–3 MBq/Kg of 18F-DOPA iv
• Uptake time 60 min for extra-cranial tumours. An additional acquisition of 10 min after injection is suggested in medullary thyroid cancer.
• Uptake time 10 min for primary brain tumours.
Clinical indications in oncology (Fig. 39, 40, 41, 42, and 43)
18F-DOPA is used in the detection of neuroendocrine tumours. It is the PET tracer of choice for recurrence detection in patients with medullary thyroid cancer and may play a role in the management of patients with pheochromocytoma and neuroblastoma. 18F-DOPA PET/CT is also used in recurrent glioma (Kratochwil et al. 2017; Chondrogiannis et al. 2013; Soussan et al. 2012; Amodru et al. 2018).
11C-HTP is taken up into neuroendocrine tumours cells by L-large amino acid transporter followed by decarboxylation to serotonin. The resulting end-product is then transported into storage vesicles through the vesicular monoamine transporter as well as went through the metabolic pathway of serotonin (Addeo et al. 2018; Piccardo et al. 2012).
11C-HTP is used in the detection of neuroendocrine tumours. Since the uptake is related to the serotonergic pathway, 11C-HTP is a possible alternative to 68Ga-DOTA-peptide or 18F-DOPA (Neels et al. 2006).
Synthetic somatostatin peptides show long biological half-life and stronger and more specific affinity for somatostatin receptors available on the cellular surface of neuroendocrine tumours. DOTATATE, DOTATOC, and DOTANOC have different affinities for receptor subtypes (Kroiss et al. 2013; Bergeret et al. 2019).
In the management of NETs 68Ga-DOTA-conjugated peptide, PET/CT is used to localise primary tumours and detect sites of metastatic disease (staging); follow-up patients with known disease to detect residual, recurrent or progressive disease (restaging); determine somatostatin status; monitor response to therapy; and select patients with metastatic disease for peptide receptor radionuclide therapy (Skoura et al. 2016; Sundin 2018; Singh et al. 2018; Waseem et al. 2019).
Nitro-group are postulated to undergo reduction in hypoxic condition (pO2 ≤ 2–3 mmHg), forming highly reactive oxygen radicals that subsequently bind covalently to macromolecules inside the cells (Visser et al. 2014; Orlefors et al. 2005).
18F-FMISO is relatively hydrophilic and diffuses across cell membranes, showing a passive distribution in normal tissues, resulting in slow clearance kinetics and a high lipophilicity, resulting in substantially high background.
PET-CT with 18F-FMISO is a non-invasive method for detecting and characterising hypoxia in several tumours. Ischemia in tumours is associated with a poor prognosis, increased invasion rate, metastasis, and resistance to chemo- and radiation therapy (Institute NC 2013; Nehmeh et al. 2008; Gagel et al. 2006; Hirata et al. 2012; Lin et al. 2008; Lopci et al. 2014; Reischl et al. 2007; Wack et al. 2015).
F-18 FAZA is a 2-nitroimidazole compound (reduced in hypoxic cellular media) with a sugar addition moiety showing more water solubility and better pharmacokinetics compared to 18F-FMISO (Zips et al. 2012; Bollineni et al. 2013; Bollineni et al. 2014).
Fluoride ions are deposited in the bone matrix and reflect: bone remodelling and blood flow. The target organ is bone, but approximately 20% is excreted through the kidney in the urine in the first 1-2 h (Bruine de Bruin et al. 2015; Beheshti et al. 2015).
• No special diet is required but good hydration is important
• 50–200 MBq of 18F-NaF iv
• Uptake time 20–60 min
Clinical indications in oncology (Figs. 70 and 71)
The indications are those of 99mTc-labelled diphosphonate bone scintigraphy. 18F-NaF PET/CT is more sensitive than bone scintigraphy, for most indications. The choice of PET or SPECT depends on the availability of the radiopharmaceuticals, PET/CT devices, and costs (Lofgren et al. n.d.).
The constant growth of PET/CT including the increasing use of novel non-FDG PET/CT radiopharmaceuticals in cancer patients creates a need for training in the proper interpretation of complex imaging studies with compounds that have very different biodistribution, normal variants, and pitfalls. In addition, the use of several of these non-FDG PET radiopharmaceuticals, such as 68Ga-PSMA and 68Ga-DOTA peptides, constitutes an integral part of the evaluation of patients with cancer for theranostics. As this further increases the radiopharmaceuticals’ clinical relevance, there is also the need for accurate interpretation of non-FDG PET/CT studies.
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