Composite PET/CT images provide three-dimensional whole body structural and functional information. The patient first moves through a spiral CT then a gamma camera in a single investigation. Radiotracers are used to identify the altered metabolic activity occurring within tumors. Metabolic change detectable by PET may precede anatomical changes on CT or MRI leading to greater sensitivity as compared to conventional axial imaging alone. This uptake is quantified using the standardized uptake value (SUV). Uniform radiotracer distribution throughout the body produces a SUV of 1 [
24].
18 F-Flurodeoxyglucose (18-FDG) is currently the most commonly used PET tracer in oncological imaging and has an established role in the initial staging, response assessment and recurrence detection of many cancer types [
50‐
53]. Its use is dependent on the increase glucose metabolism occurring within the tumor. However, it cannot distinguish between increased metabolic rate occurring as a result of infection, inflammation or the normal physiological activity in some organs [
24].
The use of 18-FDG-PET in staging primary bladder disease, locally recurrent and perivesical nodal disease has been difficult because the interference caused by the urinary excretion of the isotope. A number of techniques encouraging adequate washout of 18-FDG from the urinary tract have been investigated to overcome this. These include elective voiding, catheterization, bladder irrigation, and forced diuresis with intravenous frusemide prior to delayed image acquisition [
54‐
57].
Catheterization and irrigation prior to FDG-PET imaging has a reported 40% false positive rate for detection of recurrent or residual bladder cancer [
57]. These measures are invasive, making them less acceptable to patients, and continuous bladder irrigation during image acquisition increases staff exposure to radiation [
58].
In those whom FDG-urine washout was encouraged by diuretic injection, oral hydration and voiding, the sensitivity and specificity for FDG-PET CT was 86.7% and 100% respectively for detecting recurrent disease within the bladder [
56]. Further investigation is necessary however to evaluate the impact of radiotherapy, endoscopic intervention and intravesical chemotherapy on FDG-PET interpretation within the bladder. When imaging is performed after chemotherapy the sensitivity decreases to 50% and therefore 18-FDG PET results should be interpreted with caution following systemic treatment [
59].
In a meta-analysis of the overall diagnostic accuracy of 18-FDG PET in bladder cancer, 6 studies involving 203 patients were assessed. The sensitivity and specificity of 18-FDG PET or PET/CT for staging or restaging (metastatic lesions) of bladder cancer was 82% and 89% respectively. The global measure of accuracy was 0.92 [
60]. The limitations accepted by the authors include variation in the imaging technique used, one study used PET alone which meant anatomical accuracy because of the poor spatial resolution was lost, three studies were retrospective in nature and only two studies assessed detection of the primary tumor.
Although there is evidence that FDG PET-CT has a diagnostic role for identifying metastatic bladder disease, in our clinical practice it is not used as principal staging modality because of the limitations discussed above. In certain circumstances, however, it provides important contributory information when CT or MRI alone raises uncertainty regarding staging.
Alternative radiotracers that are dependent on cell proliferation, apoptosis, and angiogenesis, hypoxia and growth factors are also under investigation [
61,
62].
11C-Choline and
11C-methionine are not excreted in the urine and may have role in future imaging of bladder cancer [
24,
54,
63‐
65]. There is however limited data at present to support routine clinical use.
Choline is an essential component of cell membranes. Malignant tumors have a high turnover of cellular membranes representing their increased proliferation rate [
66]. The normal bladder has low uptake with
11C-choline [
63]. In the preoperative staging of 18 patients,
11C-choline was highly positive for primary and metastatic bladder cancer. Uptake was seen in all primary transitional cell carcinomas (mean SUV 7.3 ± 3.2 SD). In six patients,
11C-choline uptake was seen in lymph nodes as small as 5 mm; of those, four proceeded to surgery and three had pathological conformation of nodal disease [
64].
11C-Choline has also been used to detect residual disease after TURBT. In a prospective study of 27 patients prior to radical surgery,
11C-choline PET was comparable to CT alone for detecting residual cancer after TURBT but appeared to be superior for detecting nodal involvement, with reported sensitivity and specificity of 62.5% and 100% versus 50% and 68.4% for contrast-enhanced CT alone [
65].
11C-Choline has a short half-life of approximately 20 minutes. Therefore clinical use is restricted predominantly to those centers with an on-site cyclotron.
18 F-choline analogs with greater half-lives have been developed to overcome this; however, significant urinary excretion occurs as compared to
11C-choline [
67]. This represents a disadvantage for pelvic imaging as previously discussed unless adequate urinary washout can be encouraged.
11C-Methionine is a radiolabeled amino acid and is a potential tracer for visualizing protein metabolism, cellular proliferation and amino acid transport. Compared to 18-FDG PET in identifying primary tumors within the bladder, uptake is proportional to tumor stage, with a reported sensitivity of 78% in tumors greater than 1 cm but its value in local staging is not superior to conventional imaging [
54].
18 F Fluoride is a bone-seeking radiopharmaceutical that accumulates at sites of increased bone formation reflecting increased osteoblastic activity occurring within metastases. It has been shown to have increased diagnostic accuracy as compared to technetium-99 m-methylene diphosphonate (99mTc-MDP) planar or single photon emission computed tomography (SPECT) in other solid tumors [
68,
69].
Non-FDG tracers are not in widespread clinical use partly because of the lack of robust evidence supporting clinical benefit but also because of their cost and limited availability.
PET/CT: receptor specific radiopharmaceuticals
Imaging biomarkers using PET-CT and radioimmunotherapy opens the possibility of an individualized therapeutic and imaging approach. The rationale is that a tumor specific target is combined with a therapeutic radioactive agent. The selective accumulation within the target tissue can then be visualized on PET. These imaging techniques have the potential to permit an ‘image and treat approach’ by allowing tumor staging, estimation of radiation dose distribution prior to therapy, and early monitoring of treatment response [
70].
Commonly used nuclides in other tumors types include β emitters such as
131I and
90Y. They are attached to somatostatin receptor binding agents such as
90Y-DOTA-d-Phe(1)-Tyr(3)-octreotide (
90Y-DOTATOC) for the treatment of neuroendocrine tumors and to antibodies in
131I-tositumomab (Bexxar®),
90Y-rituximab (Zevalin®) to target the CD20 antigen on B cells for the treatment of lymphoma [
70,
71].
Overexpression and amplification of epidermal growth factor receptor (EGFR) (HER1 or ErdB1) and, or the HER2 gene is found in bladder cancers [
72,
73]. It therefore represents a potential target for both molecular imaging and therapy in those with known HER2-positive disease [
61]. Monoclonal antibodies for example, trastuzumab labeled with
18 F, allows
in vivo monitoring of HER2 expression by PET as well as assessing change in HER2 expression with therapy [
74,
75]. Trastuzumab has also been labeled with nucleotides suitable for therapy with the future possibility of treating metastatic disease and improving the outcome of those with HER2 bladder cancer [
70,
76,
77].