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|Year : 2010 | Volume
| Issue : 2 | Page : 120--125
Non-FDG PET in the practice of oncology
P Caroli1, C Nanni1, D Rubello2, A Alavi3, S Fanti1,
1 Nuclear Medicine, University of Bologna, Bologna, Italy
2 Nuclear Medicine, S.Maria della Misericordia, Rovigo Hospital, Rovigo, Italy
3 Nuclear Medicine, University of Pennsylvania, Philadelphia, USA
Nuclear Medicine, University of Bologna, Bologna
Fluoro-2-deoxy-d-glucose-positron emission tomography (FDG-PET) is utilized in more than 90% of cancers in staging, re-staging, assessing therapy response and during the follow-up. However, not all tumors show significant increase of metabolic activity on FDG-PET imaging. This is particularly true for prostate cancer, neuroendocrine tumors and hepatic tumors. In this review we have considered those already used for clinical applications such as 11C- and 18F-Choline, 11C-Methionine and 18F-FET, 18F-DOPA, 68Ga-DOTA-somatostatine analogues, 11C-Acetate and 18F-FLT. Choline presents a high affinity for malignant prostate tissue, even if low grade. Choline can be labeled with either 11C or 18F, the former being the preference due to lower urinary excretion and patients exposure. The latter is more useful for possible distribution to centers lacking in on-site cyclotron. Methionine is needed for protein synthesis and tumor cells require an external supply of methionine. These tracers have primarily been used for imaging of CNS neoplasms. The most appropriate indication is when conventional imaging procedures do not distinguish between edema, fibrosis or necrosis and disease relapse. In addition, the uptake of 11C-Methionine is proportional to the tumor grade and, therefore, the maximum small unilamellar vesicles (SUV) inside the brain mass before therapy is somehow considered a prognostic value. Neuroendocrine tumors (carcinoids, pheocromocytoma, neuroblastoma, medullary thyroid cancer, microcytoma, carotid glomus tumors, and melanoma) demonstrate an increased activity of L-DOPA decarboxylase, and hence they show a high uptake of 18FDOPA. For the study of NETs, 68Ga-DOTA-TOC/DOTA-NOC has been introduced as PET tracer. This compound for PET imaging has a high affinity for sst2 and sst5 and has been used in the detection of NETs in preliminary studies; 68Ga-DOTA-NOC PET is useful before metabolic radiotherapy in order to evaluate the biodistribution of the therapeutic compound; 18F-FLT is a specific marker of cell proliferation and the most important field of application of FLT is lung cancer. Other tracers are used in PET utilized as markers of hypoxia inside big neoplastic masses include 18F-MISO, 64Cu-ATSM, 18F-EF5, which highlight the presence of hypoxic areas are useful for patients that must be treated with radiotherapy.
|How to cite this article:|
Caroli P, Nanni C, Rubello D, Alavi A, Fanti S. Non-FDG PET in the practice of oncology.Indian J Cancer 2010;47:120-125
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Caroli P, Nanni C, Rubello D, Alavi A, Fanti S. Non-FDG PET in the practice of oncology. Indian J Cancer [serial online] 2010 [cited 2021 Jun 23 ];47:120-125
Available from: https://www.indianjcancer.com/text.asp?2010/47/2/120/62998
The most generally used radiotracer in clinical practice and in the study of malignant tumors is Fluoro-Deoxy-Glucose (FDG). FDG is actively taken at the cellular level, thanks to glucose transporters, then phosphorylated and no longer metabolized. Therefore, it remains trapped within the cell. FDG-PET presents a very high sensitivity in the detection of more than 90% of cancers in staging, re-staging, assessing therapy response and during the follow-up. Moreover, FDG can be used in the recognition of non-oncology diseases like dementia and evaluation of cardiac viability. Although a wide clinical application of FDG, not all tumors show significant increase of metabolic activity on FDG PET imaging. In particular, prostate cancer, neuroendocrine tumors and hepatic tumors may be virtually invisible at PET. Further, with FDG, it is difficult to evaluate a malignant lesion in tissues with physiological uptake of FDG (such as central nervous system) or FDG excretion (as kidneys and bladder) and differentiate between inflammation and cancer. In addition to FDG, several other tracers have, therefore, been proposed, and in this review we will consider those already used for clinical applications, in particular, 11C- and 18F-Choline, 11C-Methionine and 18F-FET, 18F-DOPA, 68Ga-DOTA-somatostatine analogues, 11C-Acetate and 18F-FLT [Table 1].
11C- and 18F-Choline
Choline is a small molecule that represents a substrate for the synthesis of phosphatedylcholine, which is the major phospholipid in the cell membrane and a marker of membrane metabolism. We can use it for the study of well differentiated prostate cancer. In fact, using FDG, the frequent inflammatory processes in the prostate gland and the urinary excretion may result in difficulties during detection of primary prostate cancer and, more important, in suspicion of a local relapse of prostate cancer. Choline presents high affinity for malignant prostate tissue, even if low grade. Choline can be labeled with 11C and 18F; the former being preferable due to lower urinary excretion and patient's exposure while the latter is more useful in possible distribution to centers lacking on-site cyclotron.
Several articles in the literature evaluated the role of Choline PET/CT in prostate cancer and suggested that the most useful role is in the diagnosis of prostate cancer relapse. In patients radically treated for prostate cancer through surgery or radiotherapy with prostate specific antigen (PSA) serum level increased and negative conventional imaging (including transrectal ultrasonography, bone scintigraphy and pelvic MRI), Choline PET seems to have a high sensitivity in detection of early node involvement (sensitivity 80%; specificity 96%; accuracy 93%) and early secondary bone lesion detection. Bone lesions can be detected earlier than with bone scintigraphy since the Choline uptake occurs in metastatic cells before bone osteoblastic changes. Choline PET is also useful in local recurrence detection, however, with a lower sensitivity. ,
Several authors have recently demonstrated that the positivity of 11C-Choline PET is related to the serum levels of PSA. Castellucci et al. also establish that PSA-velocity is closely related to the probability of a positive PET scan since it expresses the malignancy of the disease relapse (the higher the PSA-velocity, the faster the prostate cancer lesion is growing).  Farsad et al. considered 11C-Choline PET efficacy for detection of intra-prostatic primary cancer and proved that it is very aspecific and must be used only for selected patients at high risk with multiple negative biopsies. In fact, every intra-prostatic focal pathology (even if benign like prostatic intraepithelial neoplasia (PIN), adenomas, intra-prostatic hyperplasia or prostatitis) shows 11C-Choline increased uptake just like prostate cancer.  In conclusion, 11C-Choline PET is a positive test to evaluate patients with radically treated prostate cancer, increasing Prostate-Specific Antigen (PSA) levels and negative conventional diagnostic flow-chart. Moreover, in the restaging of patients with only one confirmed relapse of prostate cancer, it can be useful to indicate the need of a local therapy or a systemic therapy.
11C-Methionine and 18F-FET
Magnetic resonance imaging (MRI) represents the most appropriate imaging tool to assess brain tumors, thanks to the range of sequences that can explore differences in the biophysical properties of the brain tissue and tumors. However, conventional MR presents a limitation; in particular it is not accurate enough in the detection of infiltrating gliomas cells and it is impossible to evaluate these regions during tumor resection. The radiotherapy treatment volumes must be extended to include the infiltrating cells. As the examined area includes normal brain, the total dose used has to be reduced to diminish the risk of radiation necrosis. As a consequence, gliomas recur within the treatment volume in the majority of patients. Moreover MR is limited also for the evaluation of tumors grading. The gold standard in defining brain tumors is histology but cerebral biopsies have a significant morbidity and mortality. MR can classify high grade tumor with 65% sensitivity and 95% specificity.
In patients affected by low-grade gliomas, only half could be accurately classified using MRI and one-third of non-enhancing tumors are in fact high grade gliomas. Many studies suggest that the early detection of tumor recurrence, at an asymptomatic stage, is associated with improvement in patient survival. A delay in determining the failure of a treatment may result in considering a patient too ill for second-line therapies.  Conventional imaging procedures (Contrast computerized tomography i.e. CT and MRI) are useful to discover a supposed relapse after therapy but it is sometimes very difficult or even impossible an accurate identification between post-surgical fibrosis, radionecrosis or edema (benign conditions). Glucose is the main metabolic substrate for substantia nigra pars compacta (SNC) and the brain has a physiologically intense uptake of FDG. Therefore, small malignant lesions, like in a case of disease relapse, are very difficult to detect with FDG PET as they may be masked by the hyper metabolic background. ,
Methionine and Tyrosine measure amino acid uptake and protein synthesis. Methionine is needed for protein synthesis as a precursor of S-adenosylmethionine, which is required for polyamine synthesis. Increased uptake of methionine reflects increased carrier mediated transport, increased vascular permeability and protein synthesis in malignant tissue (tumor cells require an external supply of methionine). The main limitation to Methionine use is related to 11C labeling, which implies the availability of in-site cyclotron, and therefore 18F-labeled Tyrosine has been suggested as an alternative. These agents have primarily been used for imaging of central nervous system (CNS) neoplasm. There is normally low uptake in the brain (gray matter) and in benign conditions as fibrosis, necrosis or edema. The most appropriate indication is when conventional imaging procedures do not distinguish between edema, fibrosis or necrosis and disease relapse.
In this case, PET significantly shortens the time of diagnosis, allowing a prompt second line treatment. In addition, the uptake of 11C-Methionine is proportional to the tumor grade and therefore, the maximum SUV inside the brain mass before therapy is somehow considered a prognostic value. 11C-Methionine PET has also been used to better define the radiotherapy field both for CNS tumors and H and N tumors to localize the most metabolic area inside a brain mass to guide the biopsy  or in early evaluation of radiotherapy effect on H and N cancer (as inflammation has a low 11C-Methionine uptake), and for the evaluation of patients with primary, secondary and tertiary hyperparathyroidism. 
18F-DOPA is an aromatic amino acid labeled with 18Fluore. 18F-Fluoro-L-DOPA has been used to investigate the activity of aromatic L-amino acid decarboxylase in the striatum and to assess the integrity of the dopaminergico system in vivo in patients with Parkinson's disease. Besides, 18F-DOPA has been introduced in oncologic practice, in particular, for malignant neural crest tumors. Neuroendocrine tumors (carcinoids, pheocromocytoma, neuroblastoma, medullary thyroid cancer, microcytoma, carotid glomus tumors, and melanoma) demonstrate an increased activity of L-DOPA decarboxylase, and for this reason they show a high uptake of 18FDOPA. 111In-Octreoscan SPECT or 123I-MIBG SPECT are normally used for the study of patients with specific syndromes connected to that type of neoplasia to discover primary or secondary lesions and in early evaluation of disease relapse. These tests have good sensitivity and specificity, but the spatial resolution is poor compared to what could be attained using PET scans. This means that small lesions may be missed. Thanks to its capacity to concentrate amino acids inside the cytoplasmatic space through metabolic mechanism, 18F-DOPA is considered a specific tracer and shows a very good sensitivity and specificity, probably higher than conventional imaging procedures. Unfortunately, literature is still very poor in this matter as the synthesis of this compound is difficult and neuroendocrine tumors are quite rare.
Today, the major interest in this field is represented by somatostatin analogs radio labeled with positron-emitting isotopes such as 68Ga; and the use of 18F-DOPA in oncology remains an option for medullary thyroid cancer and pheochromocytomas as these two pathologies have a variable expression of somatostatine receptors. In neurology, we can use 18F-DOPA because of L-DOPA (L-dihydroxyphenylalanine), a dopaminergic neurotrasmetitor of nigrostriatal region, and it is strongly related to neurodegenerative and movement disorders. L-DOPA is carried into the brain by the large neutral amino acid transport system, converted into dopamine by the action of L-aromatic amino acid decarboxylase (4 jnm), and then stored in intraneuronal vesicles from which it is released when the nerve cell fires. 18F-DOPA is an analogue of L-DOPA and is clinically used to trace the dopaminergic pathway and evaluate striatal dopaminergic presynaptic function (5-7 jnm).
In patients with Parkinson Disease, F-DOPA uptake in the striatum is decreased and there is an inverse correlation between the degree of motor deficit and F-DOPA uptake in the striatum, especially in the putamen. In the early phase of disease, clinical signs may be subtle or could be confused with other Parkinsonism-related disorders and the clinical diagnosis can be influenced and complicated by symptomatic medication. Considering these factors, in vivo markers of dopaminergic degeneration are important for the early diagnosis and monitoring of disease progression, and neuro imaging procedures (e.g., 18F-DOPA PET and 123I-N-(3-fluoropropyl)-2b-carbomethoxy-3b-(4-iodophenyl) nortropane [FP-CIT] SPECT for the presynaptic dopaminergic system) can help clinicians in selected cases.
68Ga-DOTA-somatostatin receptor analogues
111In-DTPA-octreotide (Octreoscan) has demonstrated high sensitivity in the detection of NETs and is classically used in the preliminary phase to evaluate the biodistribution of the therapeutic compound based on the connection to the sst2 receptor subtype. The principal treatment of this specific cancer consists of somatostatin analogues and the next step is to use radio labeled somatostatin analogues for metabolic radiotherapy in inoperable patients.
For the study of NETs, a PET tracer has been introduced - 68Ga-DOTA-NOC (tetraazacyclododecanetetraacetic acid-[1-Nal3]-octreotide). This compound for PET imaging has a high affinity for sst2 and sst5 and has been used for the detection of NETs in preliminary studies. The uptake of 68Ga-DOTA-NOC is based on a receptor mechanism and although this has not yet been adequately assessed, it seems to have higher sensitivity for NETs than Octreoscan, but could be lower than that of 18F-DOPA, which accumulates via a metabolic mechanism because some histological types express a low number of somatostatine receptors. Additionally, it has several advantages over 111In-Octreoscan for both the patient and the physician: increased spatial resolution, the possibility of performing whole-body tomography studies with a short uptake time (60 min), relatively easy synthesis and the possibility of using hybrid PET/CT scanners, thereby increasing diagnostic accuracy [20, 21ejnm]. Though 68Ga-DOTA-NOC PET is useful before metabolic radiotherapy in order to evaluate the biodistribution of the therapeutic compound, no studies have been published on this issue. The overall sensitivity and specificity of 68Ga-DOTA-NOC as compared to those of 18F-DOPA have still to be assessed, but it may be realistic to predict a complementary role for the two tracers as they explore different features of NETs.
This PET tracer is used as a precursor of membrane fatty acids but can also be transformed into Acetyl-CoA entering the tricarbossilic acid cycle. So it can be considered an intermediate molecule both in the glucose catabolism pathways and in membrane metabolism. The original application of 11C-Acetate was not in Oncology but in Cardiology because it accumulates in the myocardium proportionally to the fatty acids oxidation and is used to assess cardiac energy metabolism. In an oncological field 11C-Acetate was at first used as a Choline analogue for the detection of prostate cancer, showing a similar sensitivity and specificity.  Lately Delbeke and coll. used 11C-Acetate associated to 18F-FDG for the evaluation of liver masses. Preliminary results show that 11C-Acetate has good sensitivity for low grade hepatic cancer but not for high grade cancer, while FDG has an opposite behavior. The two radiotracers, therefore, cover the whole spectrum of hepatic cancers. ,
18F-FLT (Fluoro-levo-thymidine) was one of the most promising radiotracers synthesized for PET oncological studies. Thymidine is a Deoxyribonucleic acid (DNA) base and is actively included into DNA when it replicates. 18F-FLT is, therefore, a specific marker of cell proliferation (although, being a modified molecule compared to thymidine, it's not incorporated into DNA) and was thought to be more sensitive and specific than FDG for oncological studies in particular because it does not accumulate into inflammation and can theoretically be an optimal marker of therapy response. The most important field of application of FLT is lung cancer. Differentiating malignant from benign solitary pulmonary nodes is a very important diagnostic problem. It is known that FDG-PET has an excellent sensitivity and good specificity but false positives mainly due to granulomatous and inflammatory disease represent a big trouble. In detection of Non-small cell lung carcinoma (NSCLC), FLT seems to be appropriate but in the detection of lymph node metastases or distant metastases it is unacceptably low if compared to corresponding values of FDG PET.
Another field of application of FLT includes CNS tumors. Similarly to what was described for Methionine, FLT background uptake in normal brain tissue is low, probably owing to slow proliferation rate. FLT-PET offers images with excellent T/NT contrast, but little or no anatomical information is provided. Therefore, future research will have to answer the question of whether FLT-PET can differentiate between benign and malignant tissue and between residual tumor and radionecrosis. If FLT proves to be a sensitive and specific tracer for brain malignancies, it may be very useful (in combination with CT or MRI) in establishing the best site for tumor biopsy, to plan radiotherapy in a heterogeneous tumor or to assess an early disease relapse. However, due to the high performance of Methionine PET, this field does not seem very important for the future development of this tracer.
Other tracers are used in PET not as markers of metabolic activity but as markers of hypoxia inside big neoplastic masses. These compounds (the most important are 18F-MISO, 64Cu-ATSM, and 18F-EF5) which highlight the presence of hypoxic areas are useful for patients who must be treated with radiotherapy. In fact, it is well known that hypoxia is one the strongest factors associated to treatment resistance and hypoxic areas should be recognized and over-treated compared to non-hypoxic malignant tissues. 
FDG remains the mainly used tracer in PET, covering about 90% of PET scans in Oncology, Cardiology and Neurology. However, there are many cases in which FDG is not useful, like prostate cancer, liver cancer, CNS tumors and NET. For malignant cancer that is FDG negative, other tracers labeled with 11C, 18F and 68Ga have been synthesized and tested; these radiotracers are specific for tumors and should be taken into account when FDG negative cancers are studied. Some of these tracers are difficult to prepare or are labeled with short half-life isotopes and, therefore, only specialized PET centers endowed with cyclotrone are able to provide them. Nonetheless, some tracers have already gained significant acceptance in clinical practice. In any case, the number of these compounds will grow in order to have a wide range of injectable radiopharmaceutical drugs, sensitive and specific to each histopathological kind of cancer.
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