Non-FDG PET/CT in Diagnostic Oncology: a pictorial review

Francesco Giammarile; Paolo Castellucci; Rudi Dierckx; Enrique Estrada Lobato; Mohsen Farsad; Roland Hustinx; Amirreza Jalilian; Olivier Pellet; Susana Rossi; Diana Paez

doi:10.1186/s41824-019-0066-2

Review
Open Access
Published: 29 November 2019

Non-FDG PET/CT in Diagnostic Oncology: a pictorial review

European Journal of Hybrid Imaging volume 3, Article number: 20 (2019) Cite this article

202 Accesses

Abstract

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.

Radioisotopes

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.

Radiopharmaceuticals

Acetate

Names: CH₃[¹¹C]O₂, ¹¹C-acetate

Biodistribution and metabolism (Fig. 1)

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).

Scan acquisition

• Fast of 4 h is suggested

• 4 or 5 MBq\Kg of ¹¹C-acetate iv

• Uptake time 10–20 min

• Acquisition starts from the pelvis

Clinical indications in oncology (Figs. 2 and 3)

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).

FES

Names: 16α-[¹⁸F] Fluoro-17β-estradiol; 16-Fluoroestradiol, ¹⁸F-fluoroestradiol

Biodistribution and metabolism (Fig. 4)

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).

Scan acquisition

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

Clinical indications in oncology (Figs. 5 and 6)

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).

FET

Names: O-(2-[¹⁸F] Fluoroethyl)-L-tyrosine; ¹⁸F-fluoroethyltyrosine

Biodistribution and metabolism (Fig. 7)

¹⁸F-FET is an amino-acid PET tracer. After injection, the tracer is trapped into cancerous cells, though it is not incorporated into proteins (Abe et al. 2006).

Scan acquisition

• Fasting for at least 4 h is required

• 4–5 MBq\Kg of ¹⁸F-FET iv

• Dynamic one bed brain acquisition for 40 min or static one bed brain acquisitions at 10 and 40–50 min. after injection, for 10 min.

Clinical indications in oncology (Figs. 8, 9, and 10)

Diagnosis of central nervous system tumours (very low background in healthy brain) (Galldiks et al. 2015; Albert et al. 2016; Unterrainer et al. 2016; Kunz et al. 2011; Poulsen et al. 2017).

FLT

Names: 3′-deoxy-3′-[¹⁸F]-fluorothymidine; ¹⁸F-fluorothymidine

Biodistribution and metabolism (Fig. 11)

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).

Scan acquisition

• 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).

Methionine

Names: L-[methyl-¹¹C] Methionine; ¹¹C-Methionine

Biodistribution and metabolism (Fig. 15)

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).

Scan acquisition

• 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.

Choline

Names:

1.
[11C]CH, ¹¹C-choline
2.
[¹⁸F]CH, ¹⁸F-fluorocholine

Biodistribution and metabolism (Fig. 19)

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).

Scan acquisition

• 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).

PSMA

Names: [⁶⁸Ga] prostate-specific membrane antigen ligand; ⁶⁸Ga-PSMA

Biodistribution and metabolism (Fig. 25)

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).

Scan acquisition

• Fasting of 4 h is suggested

• 2 or 3 MBq\Kg of ⁶⁸Ga-PSMA iv

• Uptake time 60–100 min

• Acquisition starts from the pelvis

Clinical indications in oncology (Figs. 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, and 37)

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).

DOPA

Names: L-3,4-Dihydroxy-6-[¹⁸F] fluorophenylalanine, ¹⁸F-DOPA, ¹⁸F-Fluoro-L-DOPA

Biodistribution and metabolism (Fig. 38)

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).

Scan acquisition

• 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).

5-HTP

Names: [¹¹C] 5-hydroxytryptophan; ¹¹C-HTP

Biodistribution and metabolism (Fig. 44)

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).

Scan acquisition

• No special diet is required

• 370 MBq of ¹¹C-HTP iv

• Uptake time 1 h

Clinical indications in oncology (Fig. 45)

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).

Somatostatin analogues

Names: [⁶⁸Ga] (1,4,7,10-tetraazacyclododecane-N, N′, N″, N‴-tetraacetic acid)-1- (d)-Phe1-Thy3-octreotate (DOTATATE)- (d)-Phe1-Thy3-octreotide (DOTATOC)- NaI3-octreotide (DOTANOC)

Biodistribution and metabolism (Fig. 46)

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).

Scan acquisition

• No special diet is required

• 2–3 MBq\Kg of ⁶⁸Ga-DOTA-Peptide iv

• Uptake time 1 h

Clinical indications in oncology (Figs. 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, and 65)

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).

FMISO

Names: 1-(2-Nitro-imidazolyl)-3-[¹⁸F] fluoro-2-propanol; ¹⁸F-FMISO

Biodistribution and metabolism (Fig. 66)

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.

Scan acquisition

• Fasting for at least 2 h

• 6 MBq\Kg of ¹⁸F-FMISO iv

• Uptake time 3–4 h

Clinical indications in oncology (Fig. 67)

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).

FAZA

Names: 1-(5-[¹⁸F] Fluoro-5-deoxy-α-D-arabinofuranosyl)-2-Nitroimidazole; ¹⁸F-FAZA

Biodistribution and metabolism (Fig. 66)

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).

Scan acquisition

• No special diet is required

• 370 MBq of ¹⁸F-FAZA iv

• Uptake time 2 h

Clinical indications in oncology (Fig. 68)

The indications are similar to ¹⁸F-FMISO (Reischl et al. 2007; Wack et al. 2015; Zips et al. 2012).

NAF

Names: [¹⁸F]-Sodium fluoride; ¹⁸F-NaF

Biodistribution and metabolism (Fig. 69)

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).

Scan acquisition

• 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.).

Conclusion

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.

Availability of data and materials

Yes (own data and materials)

Abbreviations

5-HTTP:: 5-Hydroxytryptophan
BCR:: Biochemical recurrence
DOPA:: Dihydroxyphenylalanine
DOTANOC:: Tetraazacyclododecane-tetraacetic acid NaI3-octreotide
DOTATATE:: Tetraazacyclododecane-tetraacetic acid (d)-Phe1-Thy3-octreotate
DOTATOC:: Tetraazacyclododecane-tetraacetic acid (d)-Phe1-Thy3-octreotide
ER:: Oestrogen receptors
FAZA:: Fluorodeoxyarabinofuranosyl-nitroimidazole
FDG:: Fluorodeoxyglucose
FES:: Fluoroestradiol
FET:: Fluoroethyltyrosine
FLAIR:: Fluid attenuated inversion recovery
FLT:: Fluorothymidine
FMISO:: Fluoro-propanol-nitroimidazole
HCC:: Hepatocellular carcinoma
HER2:: Human epidermal growth factor receptor 2
MBq:: Megabecquerel
MIBI:: Methoxyisobutylisonitrile
MIP:: Maximum intensity projection
MRI:: Magnetic resonance imaging
MTC:: Medullary thyroid cancer
NAF:: Sodium fluoride
NET:: Neuroendocrine tumours
NSCLC:: Non-small cell lung cancer
PET/CT:: Positron emission tomography/computed tomography
PR:: Progesterone receptor
PSAdt:: Prostate-specific antigen doubling time
PSMA:: Prostate-specific antigen
PSMA:: Prostate-specific membrane antigen
SPECT:: Single-photon emission computed tomography
TTR:: Time to relapse
y.o.:: Years old

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Acknowledgements

The authors are very grateful to Pr Ora Israel and Dr Sugitha Sureshkumar for their suggestions and careful and meticulous reading of the paper.

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Department of Nuclear Sciences and Applications, International Atomic Energy Agency, Vienna, Austria
- Francesco Giammarile
- , Enrique Estrada Lobato
- , Amirreza Jalilian
- , Olivier Pellet
- & Diana Paez
Department of Nuclear Medicine, Sant’Orsola-Malpighi Hospital, 40138, Bologna, Italy
- Paolo Castellucci
Medical Imaging Center, Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, The Netherlands
- Rudi Dierckx
Department of Nuclear Medicine, Bolzano Hospital, Bolzano, Italy
- Mohsen Farsad
Department of Nuclear Medicine, CHU Liège, University of Liège, Liège, Belgium
- Roland Hustinx
Centro Uruguayo de Imagenología Molecular (CUDIM), Montevideo, Uruguay
- Susana Rossi

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Giammarile, F., Castellucci, P., Dierckx, R. et al. Non-FDG PET/CT in Diagnostic Oncology: a pictorial review. European J Hybrid Imaging 3, 20 (2019) doi:10.1186/s41824-019-0066-2

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Received
08 August 2019
Accepted
22 October 2019
Published
29 November 2019
DOI
https://doi.org/10.1186/s41824-019-0066-2

Keywords

PET/CT
Non-FDG
Pictorial

Non-FDG PET/CT in Diagnostic Oncology: a pictorial review

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Abstract

Radioisotopes

Radiopharmaceuticals

Acetate

FES

FET

FLT

Methionine

Choline

PSMA

DOPA

5-HTP

Somatostatin analogues

FMISO

FAZA

NAF

Conclusion

Availability of data and materials

Abbreviations

References

Acknowledgements

Adherence to national and international regulations

Funding

Author information

Affiliations

Department of Nuclear Sciences and Applications, International Atomic Energy Agency, Vienna, Austria

Department of Nuclear Medicine, Sant’Orsola-Malpighi Hospital, 40138, Bologna, Italy

Medical Imaging Center, Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, The Netherlands

Department of Nuclear Medicine, Bolzano Hospital, Bolzano, Italy

Department of Nuclear Medicine, CHU Liège, University of Liège, Liège, Belgium

Centro Uruguayo de Imagenología Molecular (CUDIM), Montevideo, Uruguay

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Keywords