Principles Of

PET is a functional imaging modality that employs radiotracers to exploit altered metabolic and biochemical function in vivo. Until the early 1990s, because of a limited axial field of view within the scanner, the technique was reserved almost exclusively for neuropsychiatric and cardiac research. With the advent of a simple change in scanner design, which allowed passage of the scanning couch through the gantry, it became possible to perform whole-body PET. Subsequently oncological imaging has become the predominant clinical and research application. Recognizing its value, the expenses of 18FDG PET clinical studies are now reimbursed by health-care providers in many countries. This, together with the establishment of PET tracer distribution networks, has seen an enormous increase in the use of 18FDG PET to such an extent that it is now almost inconceivable for a cancer center not to have access to PET imaging.

It has been known for many years that many malignant tumors demonstrate enhanced glycolytic activity (1). Following the early work of Sokoloff with 14C-labeled deoxyglucose, the radiopharmaceutical 18FDG has become the most commonly used clinical PET tracer in oncology (2). Like glucose, deoxyglucose enters cancer cells via membrane glucose transporters, particularly Glut-1, and its overexpression, which is commonly seen in malignant cells, results in increased tracer uptake (3). Both glucose and deoxyglucose undergo phosphorylation by the enzyme hexokinase, which is also overexpressed in cancers. While glucose then undergoes further enzymatic reactions, deoxyglucose remains effectively trapped in the

Figure 1 Three-compartment model of glucose and FDG kinetics. Glucose and FDG enter the cell and are phosphorylated by hexokinase to glucose-6-phosphate (G-6-P) and FDG-6-phosphate (FDG-6-P), respectively. Whilst glucose-6-phosphate can undergo further enzymatic reactions, FDG-6-phosphate is effectively trapped as there is little dephosphorylation by glucose-6-phosphatase (G-6-P) in most tissues and tumors.

Figure 1 Three-compartment model of glucose and FDG kinetics. Glucose and FDG enter the cell and are phosphorylated by hexokinase to glucose-6-phosphate (G-6-P) and FDG-6-phosphate (FDG-6-P), respectively. Whilst glucose-6-phosphate can undergo further enzymatic reactions, FDG-6-phosphate is effectively trapped as there is little dephosphorylation by glucose-6-phosphatase (G-6-P) in most tissues and tumors.

intracellular compartment, a reason why this tracer is advantageous for imaging (Fig. 1). The 18FDG signal, however, also depends on a variety of other factors including blood flow and delivery, the state of tissue hypoxia as well as the number of viable tumor cells present. Furthermore, increased uptake of 18FDG can be seen following radiotherapy, due to activated inflammatory cells (4), and in granulomatous disorders (5).

A major advantage of PET is that many biological elements, including carbon, nitrogen, and oxygen, have positron emitting radionuclides, allowing substitution of a radionuclide atom for a non-radioactive atom within biological compounds of interest. New PET radiopharmaceuticals are being developed that may have more specific roles such as functional oncological imaging with 18F-fluorothymidine (a tracer for cellular proliferation) and 11C-methionine (a tracer for amino acid transport). Unfortunately, most positron emitting radionuclides have very short half-lives (Table 1) and are thus difficult to use even where there is a cyclotron available close to an imaging facility. 18F-fluorine has a half-life of approximately two hours, allowing sufficient time for radiolabeling of ligands and subsequent transfer to distant scanning facilities. It is for this reason that 18FDG-labeled biological tracers are favored in PET applications.

PET has an advantage over conventional single photon nuclear medicine imaging in that using PET it is relatively easy to measure the effects of attenuation of photons within the body and to accurately make corrections for this. Attenuation correction improves image quality for qualitative interpretation of clinical

Part II. New Imaging Technologies Table 1 Common Clinical PET Radionuclides and Radiopharmaceuticals

Radionuclide Physical half-life Example radiopharmaceuticals

110 min 20min 10 min 2 min

18FDG 18flt 11C-methionine 11C-choline 13N-ammonia

'O-water

Abbreviations: 18FLT, 18F-fluorothymidine; 18FDG, 18F-fluoro-2-deoxy -D-glucose.

scans. It also enables accurate measurement of radioactive concentrations within tissue in absolute units (MBq mL_1). With dynamic imaging, it is also possible to make measurements of rates of biological processes, e.g., metabolic rate of 18FDG, in absolute units of mL min-1 mL-1. These accurate kinetic measurements require knowledge of arterial activity concentrations, and hence arterial blood sampling. To mitigate against invasive sampling simplified semi-quantitative parameters have been developed that are more suitable for routine clinical use. The most commonly used index is the standardized uptake value (SUV) that relates the activity concentration within a lesion to the average activity concentration within the whole body [Eq. (1)], and in principle SUV can be used as an index that can be compared between different patients or to record changes in tumor activity over time to monitor therapy. There has been some controversy over the best method to measure SUV and whether corrections are required to allow for effects of different levels of plasma glucose, different body size and composition, and for the partial volume effect (6). Undoubtedly, there are some limitations in the use of SUV but in routine clinical practice, it serves as a simple, robust, and reproducible parameter that is effective for monitoring change. For more complex research applications, kinetic analyses using Patlak graphical analysis or nonlinear regression and compartmental modeling might be more appropriate but at the expense of complexity and invasiveness (7).

where SUV is the standarized uptake value, ROI is the region of interest.

Metabolic abnormalities usually precede morphological changes in malignant tumors. Diagnosis with PET relies primarily on the detection of disordered metabolic function rather than derangement of morphology, and as a result PET is more sensitive than CT and MR for detection of cancer. Lack of anatomical localization of foci of abnormal metabolism limits the value of PET for planning treatment (8). Software registration techniques have been developed to combine 18FDG PET to CT and MR (9). However, these methods are labor intensive, and unless registration of data sets is planned prospectively results are often suboptimal. Combined PET/CT scanners are now commercially available that enable accurate and seamless fusion of functional and anatomical information from PET and CT performed consecutively but within the same scanner gantry (Fig. 2). The CT data can also be used to correct the PET scan for attenuation effects thereby speeding up patient throughput such that whole-body imaging is now possible in less than 30 minutes.

injected activity (MBq)/patient wt (g)

Figure 2 Equivocal biopsy findings. (A) A patient with a lung parenchymal lesion on the left side. CT guided percutaneous biopsy did not provide a definitive result. (B) FDG PET-CT showed intense uptake within the lesion consistent with malignancy. (C) FDG PET (projection image) showed no other sites of active disease. Subsequent surgery confirmed NSCLC (T2, N0, M0). (See color insert for Fig. 2B.)

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