Molecular Positron Emission Tomography and PET/CT Imaging in Urological Malignancies

Transcription

1 european urology 51 (2007) available at journal homepage: Review Imaging Molecular Positron Emission Tomography and PET/CT Imaging in Urological Malignancies Tom Powles a, Iain Murray b, Cathryn Brock a, Tim Oliver a, Norbert Avril b, * a Department of Urology, Barts and the London School of Medicine, Queen Mary, University of London, London, UK b Department of Nuclear Medicine, Barts and the London School of Medicine, Queen Mary, University of London, London, UK Article info Article history: Accepted January 15, 2007 Published online ahead of print on January 23, 2007 Keywords: Diagnosis [F-18]-fluorodeoxyglucose Staging Treatment monitoring Urological tumours Abstract Objectives: Positron emission tomography (PET) provides unique insights into molecular pathways of diseases. PET using [F-18]-fluorodeoxyglucose (FDG) has gained increasing acceptance for the diagnosis, staging, and treatment monitoring of various tumour types. The aim of this review is to provide an update on the current status of molecular PET and PET/CT imaging in urological malignancies. Methods: The current literature on PET and PET/CT imaging was reviewed and summarized for prostate cancer, bladder cancer, renal cell carcinoma, and germ cell tumours. Results: Depending on the radiotracer used, PET offers diagnostic information based on glucose, choline or amino acid metabolism and has also been applied to imaging tumour cell proliferation and tissue hypoxia in urological malignancies. The diagnostic performance of FDG-PET is hampered by the renal excretion of FDG and by the low metabolic activity often seen in tumours such as prostate cancer. However, new PET tracers including radiolabelled choline and acetate may offer an alternative approach. There is consistent evidence that FDG-PET provides important diagnostic information in detecting metastatic and recurrent germ cell tumours and it might offer additional information in the staging and restaging of bladder and renal cancer. Conclusions: Although PET imaging has been shown to be a clinically useful tool, its application in urological malignancies still needs to be fully determined by larger prospective trials. The introduction of novel PET radiopharmaceuticals along with the new technology of PET/CT will likely change the future role of molecular imaging in urological malignancies. # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Nuclear Medicine, Barts and the London School of Medicine, West Smithfield (QE II), London EC1A 7BE, UK. Tel ; Fax: address: n.e.avril@qmul.ac.uk (N. Avril) /$ see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 1512 european urology 51 (2007) Introduction A spectrum of imaging techniques is currently used to diagnose and stage urological malignancies [1]. One of the most promising new techniques is positron emission tomography (PET), which provides insight into the biological behaviour of tumours rather than their morphological appearance. PET allows one to determine noninvasively various physiological and biochemical processes in vivo [2]. PET instrumentation is highly sensitive, with the capacity to detect subnanomolar concentrations of radiotracer, and it provides superior image resolution compared to conventional imaging with gamma cameras. Currently, PET can target several biological features of tumours including glucose metabolism, cell proliferation, tissue perfusion, and hypoxia [3]. Following malignant transformation, a range of tumours can be characterized by elevated glucose consumption and subsequent increased uptake of the radiolabelled glucose analogue [F-18]-fluorodeoxyglucose (FDG). The transport of FDG through the cell membrane via glucose transport proteins and subsequent intracellular phosphorylation by the enzyme hexokinase have been identified as key steps for subsequent tissue accumulation. Because FDG-6-phosphate is not further metabolized, it accumulates in cells and is visualized by PET imaging. FDG-PET has been applied to tumour imaging for more than a decade. It is generally accepted that imaging the metabolic activity of tumour tissue provides more sensitive and more specific information about the extent of disease than morphologic/anatomical imaging alone. FDG- PET is primarily used for staging different types of cancer, including head and neck cancer, lung cancer, breast cancer, colorectal cancer, lymphoma, and melanoma [3]. In addition, the quantitative assessment of changes in tumour metabolic activity provided by FDG-PET allows monitoring of response to cancer treatment [4]. Such changes are often seen before morphological changes detected by conventional imaging modalities. More recently, new PET tracers have been investigated in urological malignancies. These include [C-11]-acetate, [C-11]-methionine, [F-18]-fluorothymidine, and radiolabelled choline. The uptake of [C-11]-acetate reflects tissue metabolism through entry into catabolic or anabolic pathways mediated by acetyl-coenzyme A [2]. [C-11]-acetate is rapidly cleared from blood, and the tissue accumulation is a reflection of increased lipid synthesis. There is no excretion of the radiotracer via the urinary tract. Different natural amino acids and their analogs have been radiolabelled for PET imaging of malignant tumours [5]. Amino acids uptake is mediated by sodium-dependent and sodium-independent carrier proteins located in the cellular membrane. The increased pooling of amino acids observed in malignant tumours appears to be mainly due to increased expression of the L-type sodium-independent transporter system. [C-11]- methyl-methionine has been most extensively studied so far. Several PET tracers have been developed for imaging cell proliferation, which is an essential characteristic of malignant tumours. Fluorine-18 labelled 3-deoxy-3-[F-18]-fluorothymidine (FLT) enters the cell via transmembrane transport and is phosphorylated by cellular thymidine kinase-1 (TK-1) [6]. Because the TK-1 activity is closely related to the S-phase of the cell cycle, the intracellular accumulation of FLT reflects cellular proliferation. An indirect measure of cell proliferation is imaging the choline metabolism. Choline is a precursor of phosphatidylcholine, a major constituent of membrane phospholipids and membrane lipid synthesis, which is increased during cell proliferation. Choline has been radiolabelled with carbon-11 and fluorine-18 for PET imaging [7]. Hypoxic tumours generally respond poorly to treatment compared to normoxic tumours. Flourine-18 labelled [F-18]-misonidazole (FMISO) is a lipophilic compound which enters cells by passive diffusion [8]. In viable hypoxic cells, FMISO is reduced to a radical anion that can covalently bond to intracellular macromolecules. This trapping of FMISO does not occur in normoxic cells. One of the limitations of PET imaging using these tracers is the poor anatomical landmarks that functional PET imaging generally provides. Software fusion of PET with a previously acquired diagnostic CT often lacks precise coregistration, because patient positioning and imaging protocols are often different. Combined PET/CT is a new imaging modality that allows the acquisition of spatially registered PET and CT data in one imaging procedure [9]. PET/CT provides combined anatomical and functional imaging information and can be performed as a full diagnostic CT without compromising PET. Thus, PET/CT allows for biological characterization of morphological abnormalities seen on CT and vice versa. Combining tissue characterization and determining the exact localization and the extent of disease has been shown to result in improved sensitivity and specificity of PET/CT imaging.

3 european urology 51 (2007) Prostate cancer Studies have shown that FDG is generally not a suitable PET tracer for diagnosing prostate cancer. Unlike many other tumour types, prostate cancer often does not display increased glucose metabolism. Early studies showed little difference between FDG uptake in prostate cancer and benign prostatic hyperplasia [10,11]. In patients with rising PSA levels after prostatectomy, FDG-PET did not allow reliable differentiation between scar tissue and local recurrence [12]. Comparing FDG-PET with CT, bone scintigraphy, and clinical follow-up as reference, a total of 202 bone metastases were found in 22 untreated patients of which only 131 were detected by FDG-PET [13]. The most important factor for the low sensitivity of 65% is the low metabolic activity and hence the low FDG accumulation in prostate cancer metastases. Of note, a high positive-predictive value of 98% was obtained for metabolically active lesions. In another study, FDG-PET identified only 18% of bony lesions in 13 patients, previously classified as hormone-refractory [14]. In a recent series of 91 patients with PSA relapse following prostatectomy, FDG-PET was true-positive in 28 of 91 (31%) patients demonstrating isolated disease in the prostate bed as well as metastatic disease [15]. The studies above indicate that there is limited additional information from FDG-PET in diagnosis and staging of prostate cancer (Table 1). In 42 prostate cancer patients, FDG uptake was compared with patient outcome [16]. In the radical prostatectomy group (n = 17), patients with high FDG uptake had a significantly poorer prognosis compared to those with low FDG uptake. The same trend was observed in the endocrine therapy group (n = 25). Another study assessed the role of serial FDG-PET for prediction of outcome to chemotherapy in castrate patients with metastatic disease [17]. FDG-PET scans were performed at baseline and compared with PET at 4 and 12 wk after treatment. PET correctly identified the clinical status of 20 of 22 patients (91%) at 4 wk and of 17 of 18 patients at 12 wk (94%). FDG-PET as a single modality provided information about treatment response, otherwise assessed by a combination of PSA, bone scintigraphy, and anatomical imaging. Therefore, although FDG-PET does not appear to be useful in primary treatment decisions in hormone sensitive disease, it may have a role to play as a surrogate marker of response to chemotherapy in hormone-resistant disease. This highlights the changing characteristics of tumours as they progress and encourages further studies in different clinical settings. Several other PET tracers have been investigated in prostate cancer. As previously discussed, [C-11]- acetate uptake reflects the increased lipid synthesis of malignant tumours. In a pilot study, 22 patients underwent [C-11]-acetate-PET and 18 patients additional FDG-PET [18]. Prostate cancer showed variable Table 1 Positron emission tomography in prostate cancer Studies PET tracer Purpose Patients (n) Sensitivity (%) Specificity (%) Effert et al [10] [F-18]-FDG staging 48 N/A N/A Haseman et al [12] [F-18]-FDG staging N/A Shreve et al [13] [F-18]-FDG staging N/A Yeh et al [14] [F-18]-FDG staging 13 N/A N/A Hara et al [23] [C-11]-choline staging 10 N/A N/A Hofer et al [11] [F-18]-FDG staging 19 N/A N/A Kotzerke et al [24] [C-11]-choline staging Oyama et al [16] [F-18]-FDG treatment evaluation 42 N/A N/A Kotzerke et al [19] [C-11]-acetate staging N/A Oyama et al [18] [C-11]-acetate staging 22 N/A N/A Oyama et al [21] [C-11]-acetate staging 46 N/A N/A Fricke et al [20] [C-11]-acetate staging N/A Kotzerke et al [26] [C-11]-acetate, [C-11]-choline staging N/A Larson et al [34] [F-18]-FDHT/[F-18]-FDG staging 7 N/A N/A Morris et al [17] [F-18]-FDG treatment evaluation 22 N/A N/A Schoder et al [15] [F-18]-FDG staging N/A Yamaguchi et al [25] [C-11]-choline staging N/A Farsad et al [33] [C-11]-choline staging Kwee et al [29] [F-18]-FCh staging 17 N/A N/A Schmid et al [30] [F-18]-FCh staging 9 N/A N/A Cimitan et al [31] [F-18]-FCh staging N/A Martorana et al [32] [C-11]-choline staging N/A Sandblom et al [22] [C-11]-acetate staging N/A

4 1514 european urology 51 (2007) uptake of [C-11]-acetate but was positive in all primary prostate tumours. In patients with increasing PSA following complete prostatectomy, [C-11]- acetate-pet detected 15 of 18 cases with local recurrence [19]. [C-11]-acetate-PET also identified lymph node and bone metastases. A further study in a similar clinical setting detected metastases in 20 of 24 (83%) patients [20]. A positive correlation was observed between serum PSA levels and [C-11]-acetate uptake. Of note, [C-11]-acetate-PET detected metastases in several patients with a PSA < 5ngml 1. In another trial, 59% of [C-11]- acetate-pet studies showed positive findings, whereas only 17% of FDG-PET were positive [21]. In a recent series of 20 patients with two consecutive rising PSA measurements, the [C-11]-acetate uptake was true-positive in 11 patients and 4 patients had false-positive uptake that corresponded to other pathology [22]. As described previously, tissue uptake of radiolabelled choline corresponds to an increase in membrane lipid synthesis. In the first series of 10 patients, [C-11]-choline uptake in the prostate gland was higher compared to the uptake of FDG [23]. However, significant tracer accumulation in the normal prostate tissue did not allow for distinction of primary prostate cancer. Nevertheless, [C-11]- choline-pet was successfully used for staging of lymph node and bone metastases [24]. All metastases identified by other imaging techniques were also detected by [C-11]-choline-PET. One of 10 negative [C-11]-choline-PET studies was false-negative as a nonenlarged tumour-involved lymph node was not detected. These impressive results were confirmed in another trial, which compared [C-11]- choline-pet with MRI and MR spectroscopy [25]. [C-11]-choline-PET had a sensitivity of 100% for primary lesions, while the sensitivities of MR imaging and MR spectroscopy were 60% and 65%, respectively. Regarding the localization of primary lesions, [C-11]-choline-PET results agreed with pathological findings in 13 patients (81%). In a direct comparison between [C-11]-acetate-PET and [C-11]- choline-pet, both radiotracers detected known bone and lymph node metastases with comparable accuracy. Neither radiotracer detected small local recurrences in two patients [26]. The short half-life of [C-11]-labelled PET tracers (20 min) limits whole-body imaging as well as posing logistical problems for larger patient trials. In contrast, [F-18]- labelling, with a half-life of min, overcomes most of these limitations. Initial preclinical and clinical studies showed that [F-18]-fluorocholine is a promising tracer for the evaluation of primary and metastatic prostate cancer [7,27,28]. In 17 patients, the [F-18]-fluorocholine uptake was higher in biopsy-proven cancer compared to benign prostate hyperplasia [29]. In two patients, focally increased [F-18]-fluorocholine uptake in the abdomen corresponded to retroperitoneal lymphadenopathy on CT. However, in another prospective study, differentiation between benign hyperplasia and prostate cancer was less successful using [F-18]-fluorocholine-PET/CT [30]. The coregistered functional and anatomical information of PET/CT appears to be particularly helpful in the evaluation of PET tracers in the abdomen and pelvis. Recently, 100 patients with a persistent increase in serum PSA levels after radical prostatectomy (n = 58), radiotherapy (n = 21), or hormonal therapy (n = 21) were studied with [F-18]-fluorocholine-PET/CT [31]. Fifty-four patients with PSA levels ranging from 0.2 to 511 ng ml 1 were positive on [F-18]-fluorocholine-PET/CT. Disease was identified in the bones, abdominal lymph nodes, and pelvis. Forty-six patients with PSA levels ranging from 0.1 to 14.3 ng ml 1 were negative on [F-18]-fluorocholine-PET/CT. The authors concluded that [F-18]-fluorocholine-PET/CT might have a significant impact on management of prostate cancer patients, particularly if PSA levels increase to >4 ngml 1. Similar results regarding the role of [F-18]-fluorocholine-PET/CT for detecting local recurrence and lymph node metastases were found by others [30]. A recent study used PET/CT with [C-11]-choline in 43 patients with known prostate cancer prior to radical prostatectomy [32]. [C-11]- choline-pet/ct revealed a sensitivity of 83% for localization of nodules >5 mm, which was comparable to transrectal ultrasound-guided biopsy. The authors found no relevant information regarding the detection of extraprostatic tumour extension, which might be explained by the limited resolution of PET imaging. The same group performed a direct comparison of [C-11]-choline-PET/CT with sextant results of step-section histopathology and found a sensitivity, specificity, and accuracy of 66%, 81%, and 71%, respectively [33]. Imaging androgen receptor expression is a potential alternative approach for visualization of prostate cancer. Recently 16-b-[F-18]-fluoro-5adihydrotestosterone (FDHT) was assessed in seven patients with progressive metastatic prostate cancer and compared to the results with FDG-PET [34]. Fifty-nine metastases were identified by conventional imaging methods and a lesion-by-lesion comparison was performed between FDHT and FDG uptake. FDG-PET was positive in 57 of 59 lesions (97%) and FDHT-PET was positive in 46 of 59 lesions (78%). Treatment with testosterone resulted in

5 european urology 51 (2007) diminished FDHT uptake in metastases. Therefore, androgen receptor imaging of prostate cancer appears to be a promising area of research and may give us some insight into response to antiandrogen therapy. 3. Renal cell carcinoma The detection of renal cell carcinoma with PET imaging is hampered by the fact that most radiotracers are excreted via the kidneys. The renal elimination of FDG can in part be overcome by increasing diuresis with hydration or by administering diuretics. In an early study, 20 of 26 renal cell carcinomas were correctly identified by FDG-PET [35]. The diagnostic accuracy was found to depend on the degree of tumour differentiation. Only four of nine Fuhrman G1 tumours were detected with FDG-PET. This is in line with findings in other malignancies, where the FDG uptake was higher in dedifferentiated tumours. It is important to note that patients with angiomyolipoma, pericytoma, and pheochromocytoma were false-positive. The data regarding lymph node status was more impressive, with no false-negative findings (Table 2). In another study, FDG-PET was positive in 9 of 10 cases of renal cell carcinoma [36]. In a recent series, 53 patients underwent FDG-PET; 35 for both characterization and staging of a suspicious renal mass and 18 for staging after surgery for renal cancer [37]. In the characterization of renal masses, FDG-PET produced a high rate of false-negative results leading to a sensitivity, specificity, and accuracy of 47%, 80%, and 51% respectively. CT provided a better diagnostic performance with an accuracy of 83%. In contrast, FDG-PET detected all the sites of distant metastases revealed by CT, as well as eight additional metastatic sites, leading to an accuracy of 94% versus 89% for CT. The largest series so far included 66 patients who underwent 90 FDG-PET scans for suspected or known renal cell carcinoma [38]. FDG-PET demonstrated a sensitivity of 60% compared to 91.7% for CT and was less sensitive in detecting primary tumours, retroperitoneal lymph node metastases, or distant metastases. The specificity was 100% for both modalities. In a study evaluating FDG-PET in 24 patients with distant metastases, the overall sensitivity and specificity was 63.6% and 100%, respectively [39]. The mean size of distant metastases correctly identified by FDG-PET was 2.2 cm, while the mean size of those cancers that were missed was 1.0 cm. In summary, FDG-PET does not appear to provide additional information over CT imaging for the characterisation of renal masses. However, it may be a promising tool for the detection of distant metastasis in renal cancer. As previously discussed for prostate cancer, the use of PET/CT might improve the diagnostic performance in renal cancer as well. Few other PET radiotracers have been investigated in renal cancer. Shreve et al. [40] reported on their first experiences with [C-11]-acetate for the diagnosis of various kidney diseases. [C-11]-acetate is not eliminated via the efferent urinary tracts. However, renal cell carcinomas did not show enhanced uptake of [C-11]-acetate in comparison to the surrounding renal parenchyma, but they did have a significantly reduced clearance rate. FMISO-PET allows the assessment of hypoxia in tumours. However, only mild FMISO uptake was found in 17 patients with renal cell carcinoma where invasive measurements indicated the presence of hypoxia [61]. 4. Bladder cancer As previously discussed for prostate and renal cancer, the elimination of FDG via the efferent urinary tracts represents a significant limitation of FDG-PET for evaluation of primary bladder tumours, despite, for instance, continuous retrograde bladder irrigation. Nevertheless, initial studies using FDG-PET were promising in that 8 of 12 patients with localized bladder cancer were correctly identified [41]. In addition, 17 distant metastases were correctly identified with FDG-PET, including two of three lymph node metastases. In Table 2 Positron emission tomography in renal cell Studies PET tracer Purpose Patients (n) Sensitivity (%) Specificity (%) Shreve et al [40] [C-11]-acetate staging 18 N/A N/A Bachor et al [35] [F-18]-FDG staging N/A Goldberg et al [36] [F-18]-FDG staging Aide et al [37] [F-18]-FDG staging Majhail et al [39] [F-18]-FDG staging Kang et al [38] [F-18]-FDG staging Lawrentschuk et al [61] [F-18]-FMISO hypoxia imaging 17 N/A N/A

6 1516 european urology 51 (2007) Table 3 Positron emission tomography in bladder cancer Studies PET tracer Purpose Patients (n) Sensitivity (%) Specificity (%) Ahlstrom et al [45] [C-11]-methionine staging N/A Kosuda et al [41] [F-18]-FDG staging 12 N/A N/A Bachor et al [43] [F-18]-FDG staging Drieskens et al [42] [F-18]-FDG staging Gofrit et al [46] [C-11]-choline staging 18 N/A N/A two cases, local recurrences were visualized within radiation-induced changes. In a recent study of 55 patients, the addition of metabolic information from FDG to the anatomic information from CT yielded improved diagnostic accuracy in the preoperative staging of invasive bladder carcinoma [42]. Comparing imaging results with histopathology or clinical follow-up, the sensitivity, specificity, and accuracy were 60%, 88%, and 78%, respectively. Similar results were found in two other studies indicating that FDG-PET was better than conventional staging [43,44] (Table 3). [C-11]-methionine uptake in tissue is an indication of amino acid transport and metabolism, which is often increased in malignant tumours. An advantage of [C-11]-methionine is that it is not eliminated via the urinary tract. Twenty-three patients with biopsyproven urinary bladder carcinoma underwent [C-11]- methionine-pet, which visualized 18 of 23 primary tumours [45]. The authors concluded that [C-11]- methionine could visualize urinary bladder tumours larger than 1 cm in diameter, but its value for lesion staging is not superior to conventional methods. The use of [C-11]-choline-PET/CT was evaluated in 18 patients with advanced transitional cell carcinomas [46]. All patients had negative CT scans of the chest, abdomen, and pelvis. Increased [C-11]- choline uptake was found in all primary transitional cell carcinomas as well as in lymph nodes of six patients. Histopathology confirmed metastases in three of four cases, who underwent surgery. No additional positive lymph nodes were found on histopathology. In four patients, [C-11]-choline-PET/ CT also visualized bone metastases that were not seen on the initial CT imaging but that were later confirmed by follow-up CT. 5. Germ cell tumours An early study of FDG-PET in 11 patients with metastatic seminoma and nonseminoma germ cell tumour (NSGCT) showed increased metabolic activity in the tumour, while the FDG uptake in necrosis, fibrosis, and in mature teratoma was comparable with that of normal tissue [47]. Three patients who responded to therapy also showed a decline in metabolic tumour activity, while two nonresponders showed no change. In another study of 54 patients, FDG-PET was compared with CT, tumour markers, and histopathology obtained after primary or postchemotherapy retroperitoneal lymphadenectomy [48]. In patients with stage I seminoma, the results of FDG-PET for lymph node staging were similar to CT. In two of seven patients with stage I NSGCT, FDG-PET identified metastases that were not detected by CT, while in four of seven patients micrometastases remained undetected by PET or CT. Therefore, FDG-PET used for primary staging appears to detect some but not all metastases that are missed by conventional diagnostic procedures [49]. In further studies, FDG-PET correctly staged the retroperitoneal lymph nodes in 34 of 37 cases, as opposed to 29 of 37 using CT [50]. In addition, PET revealed 7 of 10 distant metastases, while CT identified only four of these lesions. These results have been repeated by other investigators [51] (Table 4). A recent study found that FDG-PET detected metastases in stage I NSGCT when standard staging with CT and tumour markers were negative [52]. The sensitivity, specificity, and accuracy of PET were 70%, 100%, and 93%, respectively. The sensitivity of detecting small retroperitoneal metastases was 88%. The negative and positive predictive values were 92% and 100%, respectively, whereas the negative predictive value of standard staging procedures was only 78%. In another report including 15 NSGCT patients with various stages of disease, FDG-PET detected retroperitoneal recurrence earlier than CT [53]. However, a more complete study of 50 patients with a mixture of stage I and II GCTs referred for initial staging or restaging after chemotherapy found no benefit of FDG-PET over CT for primary staging [54]. For restaging, a negative FDG-PET result correctly predicted the absence of tumour with the exception of differentiated teratoma. Similar results were found from a different group of 23 patients [55]. In a retrospective study of 55 patients who underwent a total of 70 FDG-PET scans, FDG-PET had a positive predictive value of 96% and a negative

7 european urology 51 (2007) Table 4 Positron emission tomography in germ cell tumours Studies PET tracer Purpose Patients (n) Sensitivity (%) Specificity (%) Wilson et al [47] [F-18]-FDG staging and treatment evaluation 21 N/A N/A Muller et al [48] [F-18]-FDG staging 55 N/A N/A Muller et al [48] [F-18]-FDG treatment evaluation 20 N/A N/A Ganjoo et al [59] [F-18]-FDG treatment evaluation Albers et al [50] [F-18]-FDG staging Hain et al [56] [F-18]-FDG staging Hain et al [49] [F-18]-FDG staging De Santis et al [58] [F-18]-FDG treatment evaluation Spermon et al [54] [F-18]-FDG staging 50 N/A N/A Tsatalpas et al [55] [F-18]-FDG staging 23 N/A N/A Lassen et al [52] [F-18]-FDG staging De Santis et al [57] [F-18]-FDG treatment evaluation Pfannenberg et al [60] [F-18]-FDG treatment evaluation predictive value of 90% in patients with residual masses [56]. The positive predictive value was equivalent to that of tumour markers (94%), but FDG-PET also provided the site of tumour recurrence. In 57% of cases, FDG-PET resulted in a change of patient management. FDG-PET was used to show the effect of chemotherapy in patients with metastatic NSGCT [48]. After chemotherapy, the FDG-PET correctly confirmed a complete response in 11 cases, with histopathology revealing either scar tissue or necrosis. In six patients with a negative FDG-PET scan, histopathology revealed a mature teratoma and in one other patient with active residual tumour. One false-positive FDG-PET result was caused by inflammatory changes in the histological specimen. In a direct comparison, FDG-PET had significant advantages compared to CT in the evaluation of residual masses. A prospective trial including 51 seminoma patients who underwent total of 56 scans addressed FDG-PET as a predictor for viable residual tumour after chemotherapy [57]. All 19 cases with residual lesions >3 cm on CT and 35 of 37 (95%) with residual lesions <3 cm were correctly predicted by FDG-PET. The specificity and sensitivity of FDG-PET were 100% and 80%, respectively, versus 74% and 70% for CT. Therefore the authors recommended FDG-PET as the best predictor of residual viable tumour after chemotherapy. Similar results were found in 33 patients [58]. Conversely, in another study FDG-PET had no advantage over CT in the evaluation of residual masses [59]. Several studies have addressed the role of serial FDG-PET for prediction of treatment response. In 19 patients with metastatic germ cell tumours undergoing salvage high-dose chemotherapy, FDG-PET was compared with CT and/or MRI and tumour marker [60]. Results after two or three cycles of induction chemotherapy were compared with the baseline studies. The outcome was correctly predicted by FDG-PET, CT, and tumour marker in 89%, 67%, and 88%, respectively. All patients who did not respond to chemotherapy had a positive FDG-PET scan. The sensitivities and specificities for prediction of therapy response were 100% and 67% for FDG-PET, 62% and 80% for CT and/or MRI, and 83% and 100% for normalization of tumour markers. The authors concluded that FDG-PET offers additional information to detect patients with an overall unfavourable outcome. It appears that FDG-PET may be useful very early following chemotherapy in testis cancer. As part of a phase II study, FDG-PET was performed on day 3 after single-agent carboplatin and showed a significant response to treatment, which was not seen on CT from the same patient. However, this has not been validated and further investigation is required. 6. Summary The success of molecular PET imaging depends on the level of specific tracer accumulation in tumours and sufficient target-to-background ratios at the time of imaging. Unfortunately, both conditions are difficult to achieve in urological malignancies. Due to the low metabolic activity of prostate cancer, there is no role for FDG-PET in diagnosis or staging of this malignancy. With dedifferentiation of prostate cancer in the course of disease, hormone-refractory tumours are more likely to exhibit increased FDG uptake. This scenario might represent a potential clinical application, which requires further validation. In addition, new PET tracers such as [C-11]- acetate, [C-11]-choline, and [F-18]-fluorocholine have been successfully applied to prostate cancer for both staging of primary and recurrent disease. Logistical

8 1518 european urology 51 (2007) advantages of [F-18]-fluorocholine, including the more suitable half-life, suggest this tracer as a promising candidate for evaluation in larger clinical trials. The renal excretion of FDG hampers the evaluation of primary renal and bladder cancer. However, the generally increased glucose metabolism of these tumours allows for assessment of metastatic disease. Reports regarding the diagnostic performance of FDG-PET in this setting are inconsistent. Some studies included only a limited number of patients, and others compared imaging reports retrospectively rather than providing an independent analysis. In addition, different reference standards have been used, with a potential bias when comparing FDG-PET to other imaging modalities versus histopathology. The sensitivity of FDG-PET is generally lower compared to CT for identifying small lung metastases and inferior to histopathology for identifying small tumour-involved lymph nodes. Nevertheless, the diagnostic performance of FDG-PET depends on the metabolic activity of tumour tissue, as shown for other tumour types. Therefore, FDG-PET appears to have the potential to provide additional diagnostic information over conventional imaging procedures in the staging of bladder and renal cancer. A prospective multicentre trial is needed to resolve this issue. FDG-PET seems to be particularly helpful in recurrent germ cell tumours. An important advantage of FDG-PET is the ability to detect viable tumour in residual masses after treatment, particularly in germ cell tumours. Generally, PET offers certain advantages in the evaluation of residual masses and lymph nodes. When using CT, the size of lymph nodes is of decisive importance, although even nodes that are normal in size can be tumour involved, just as nodes can be nonspecifically enlarged. Combined PET and CT imaging (PET/CT) might offer a solution to this problem. PET/CT is a new imaging modality providing coregistered metabolic and anatomic information, which has shown to result in higher sensitivity and specificity for various types of nonurological tumours. The introduction of novel PET radiopharmaceuticals along with the new technology of PET/CT will likely change the future role of molecular imaging in urological malignancies. Conflicts of interest All authors have read and approved this manuscript and agreed to publication. There is no conflict of interest involved with the presented data. References [1] Aus G, Abbou CC, Bolla M, et al. EAU guidelines on prostate cancer. Eur Urol 2005;48: [2] Phelps ME. Inaugural article: positron emission tomography provides molecular imaging of biological processes. Proc Natl Acad Sci USA 2000;97: [3] Rohren EM, Turkington TG, Coleman RE. Clinical applications of PET in oncology. Radiology 2004;231: [4] Avril NE, Weber WA. Monitoring response to treatment in patients utilizing PET. 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