BJUI. Study Type Diagnostic (case series) Level of Evidence 4 OBJECTIVES

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1 2009 THE AUTHORS. JOURNAL COMPILATION 2009 BJU INTERNATIONAL Original Articles PET/CT FOR LYMPH NODE STAGING OF PATIENTS WITH PROSTATE CANCER POULSEN ET AL. BJUI BJU INTERNATIONAL [ 18 F]-fluorocholine positron-emission/computed tomography for lymph node staging of patients with prostate cancer: preliminary results of a prospective study Mads H. Poulsen, Kirsten Bouchelouche*, Oke Gerke*, Henrik Petersen*, Birgitte Svolgaard, Niels Marcussen, Niels Svolgaard, Mattias Ögren*, Werner Vach, Poul F. Høilund-Carlsen*, Ulla Geertsen and Steen Walter Departments of Urology, *Nuclear Medicine, Radiology, and Pathology, Odense University Hospital, and Department of Statistics, University of Southern Denmark, Odense, Denmark Accepted for publication 6 November 2009 Study Type Diagnostic (case series) Level of Evidence 4 OBJECTIVES To evaluate prospectively [ 18 F]-fluorocholine positron-emission/computed tomography (FCH PET/CT) for lymph node staging of prostate cancer before intended curative therapy, and to determine whether imaging 15 or 60 min after radiotracer injection is preferable. PATIENTS AND METHODS In all, 25 consecutive patients with newly diagnosed prostate cancer (Gleason score >6, and/or a prostate-specific antigen level of >10 ng/ml, and/or T3 cancer) were scanned before lymphadenectomy. Each patient was assessed twice with imaging, at 15 and 60 min after the injection with FCH. Images were compared with the results of histopathological examination of the surgically removed lymph nodes. Maximum standardized uptake values (SUV max ) at 15 and 60 min were also compared. RESULTS Histopathologically, metastases were present in removed lymph nodes from three patients. FCH PET/CT showed a high radiotracer uptake in four patients, the former three and a fourth. The sensitivity, specificity, positive and negative predictive value of FCH PET/CT for patient based lymph node staging of prostate cancer were 100%, 95%, 75% and 100%, respectively; the corresponding 95% confidence intervals were %, %, % and %, respectively. Values of SUV max at early and late imaging were not significantly different. CONCLUSIONS This small series supports the use of FCH PET/ CT as a tool for lymph node staging of patients with prostate cancer. Values of SUV max at early and late imaging did not differ. However, larger prospective studies are needed to validate these findings. KEYWORDS prostate cancer, lymph node staging, [ 18 F]-fluorocholine, PET/CT INTRODUCTION Primarily, prostate cancer is staged on the basis of a clinical examination, the patient s Gleason score, PSA level and T stage according to the TNM classification. In patients with a high risk of disseminated disease, the N and M stages are further evaluated. Traditionally, the lymph nodes are examined by lymphadenectomy. Currently, 30 50% of patients who receive intended curative therapy have a recurrence [1,2], one of the reasons being undetected lymph node involvement [3]. As lymphadenectomy and subsequent intended curative therapy are associated with morbidity and mortality [3,4], methods to more precisely reveal lymph node involvement are being sought. Trials on lymph node staging of patients with traditional CT or MRI have been disappointing in showing a low sensitivity with both methods [5 7]. Studies of positron-emission tomography (PET)/CT show that this method, with newer radiotracer molecules like choline, might have a potential role in both N and M staging of prostate cancer, and would be preferable because it is a noninvasive whole-body examination [8,9]. The most commonly used PET radiotracer, [ 18 F]-fluorodeoxyglucose, is not ideal in prostate cancer due to the generally low metabolism of prostate adenocarcinomas [10]. However, [ 18 F]- fluorocholine (FCH) is a radiotracer that has shown promising results for staging prostate cancer [11 13]. The optimal distribution time for the FCH radiotracer is still to be established. If FCH PET/CT can detect lymph node metastases better than conventional imaging methods, staging might improve and more patients would avoid the surgical trauma of lymphadenectomy, while achieving a more accurate staging of their disease and a more optimal treatment. We present pilot data from a recently started prospective trial on the value of FCH PET/CT for lymph node staging of prostate cancer, using histopathological examination of JOURNAL COMPILATION 2010 BJU INTERNATIONAL 106, doi: /j x x 639

2 POULSEN ET AL. surgically removed lymph nodes as the reference. The objective of this prospective trial was to assess the value of FCH PET/CT for the initial detection of regional and distal lymph node metastases from prostate cancer. We undertook this pilot study to determine whether early or late imaging after radiotracer injection is preferable, and to get an initial impression of the accuracy of FCH PET/CT imaging for lymph node staging. PATIENTS AND METHODS Between January and July 2008, 25 consecutive patients with a newly diagnosed prostate cancer were assessed using FCH PET/ CT scanning before lymphadenectomy. All patients met the following inclusion criteria: (i) Gleason score >6; and/or (ii) a PSA level of >10 ng/ml; and/or (iii) a T3 cancer. All patients had a γ-camera whole-body bone scan, with no metastases, and all were scheduled for intended curative therapy, i.e. radical prostatectomy (RP) or external beam radiotherapy. The study was approved by The Regional Ethics Committee. All patients had given oral and written informed consent to participate. FCH was synthesised using a robotic system, as described by Kryza et al. [14]. PET/CT data were acquired on a Discovery VCT PET/CT scanner (GE Healthcare, UK) [15]. A helical diagnostic CT scan (64-slice helical, 120 kv, smart ma maximum 400 ma, pitch : 1, rotation time s) was acquired with in vivo contrast medium (Ultravist, Bayer Healthcare, Montville NJ, USA; 370 mg iodine/ ml, 0.8 ml/kg body weight i.v., delay time 70 s, and E-Z-cat orally) using a standard CT protocol with a scan field of view of 70 cm. The first CT scan at 15 min was done as a high-dose and the second at 60 min as a lowdose scan. Data were reconstructed with a standard filter into transaxial slices with a field of view of 50 cm, matrix size of (pixel size 0.98 mm) and a slice thickness of 3.75 mm. The CT scan was followed immediately by a three-dimensional static PET scan using a standard whole-body acquisition protocol with six or seven bed positions, a slice overlap of 7 and an acquisition time of 2.5 min per bed position. No dynamic PET imaging was used. The scan field of view was 70 cm. Attenuation correction was based on the CT scan. The PET data were reconstructed into transaxial slices with a matrix size of (pixel size 5.47 mm) and a slice thickness of 3.75 mm using iterative threedimensional ordered-subset expectation maximization (two iterations, 28 subsets). Corrections for attenuation, random, dead time, and normalization were done inside the iterative loop. CT, PET and fused PET/CT data were analysed on a GE Healthcare Advantage Workstation 4.4. FCH PET/CT scans were interpreted by both a nuclear medicine specialist and an onco-radiologist, considering regional and distant metastases, and were assessed both as PET/CT and CT scans, but data in the study were based solely on the FCH PET/CT data, whereas the CT scan was used for clinical purposes. Patients fasted for 6 h before the i.v. injection with radiotracer, each receiving 4 MBq per kg body weight [13,16]. After injection, all patients received an early PET/CT scan after 15 min and a delayed scan after 60 min. All CT scans were from the base of the skull to mid thigh, whereas all PET scans were done in the opposite direction. The change in FCH uptake from 15 min to 60 min after acquisition was examined by comparing respective maximum standardized uptake values (SUV max ), calculated using a standard formula, considering body weight and injected dose of radioactivity within a region of interest of 1 cm in diameter [17]. The results of the FCH PET/CT scans were not divulged to the surgeon and the pathologist, and the histopathological results were not communicated to the experts reading the FCH PET/CT scans. A standard open retroperitoneal bilateral lymphadenectomy was undertaken through a midline incision, with dissection and removal of the regional lymph nodes of the prostate, lymphatic nodes of the external iliac, located between the ramus superior ossis pubis, the external iliac vein, and the internal iliac vein. The specimens from each side were handled separately and placed in individual containers. The specimens were processed according to standard protocols. The lymph nodes were counted; small lymph nodes were divided in two whereas the larger ones were cut into more slices to allow all lymph node tissue to be embedded and included. The tissue was cut into 3 4 μm thick sections that were stained with haematoxylin and eosin. In unclear cases, the sections were stained immunohistochemically for pan-cytokeratin. The binary outcome variable metastases in the regional lymph nodes (yes/no) was used FIG. 1. Images of patient no. 5 with a histopathologically verified lymph node metastasis within the external iliac lymph nodes, on the left side. In A, conventional CT, there was an unenlarged lymph node of 7 mm. In B, the corresponding FCH PET/CT scan, there was a pathological high tracer uptake at the same unenlarged lymph node. to estimate the diagnostic usefulness of FCH PET/CT. Sensitivity, specificity, positive (PPV) and negative predictive value (NPV) were calculated, with two-sided 95% Clopper- Pearson CIs [18]. RESULTS The characteristics of and findings from the 25 patients are shown in Table 1. The FCH PET/CT scans were made a mean (range) of 3.7 (1 16) days before lymphadenectomy, where a mean of 5.0 (2 11) lymph nodes were removed in total. The mean (range) age of the patients was 66.2 (62 75) years, the mean PSA level 20.1 (6 60) ng/ml, the Gleason score 7.1 (5 9), and four patients (16%) were T1, five (20%) T2, and 16 (64%) T3. The histopathological examination of the removed lymph nodes showed metastases in three patients; two had a single node with metastases, and the third had three nodes with metastases. FCH PET/CT showed a high radiotracer uptake in four patients, including these three. In the two patients with singlenode metastases FCH PET/CT identified the correct node. An example of this is shown in Fig. 1. In the patient with three lymph nodes with metastases, PET/CT identified these three nodes, but also additional lymph nodes that 640 JOURNAL COMPILATION 2010 BJU INTERNATIONAL

3 PET/CT FOR LYMPH NODE STAGING OF PATIENTS WITH PROSTATE CANCER TABLE 1 The characteristics of the patients Patient/age, years Initial TNM stage PSA level, ng/ml Gleason score Biopsies positive/ total Total cancer length in biopsies, mm LNs resected, n LNs with metastases, n; size, mm PET positive LNs 1/67 T2c,N0,M / /61 T3a,N0,M / /69 T3b,N0,M / ; 8, 10,11 Multiple 4/69 T3a,N0,M / /75 T3a,N0,M / ; 7 1 6/70 T2a,N0,M /6 2 7 LN 7/69 T3b,N0,M / /53 T3a,N0,M / LN 9/71 T1c,N0,M / /68 T3a,N0,M / LN 11/62 T1c,N0,M / /71 T2b,N0,M / /62 T3a,N0,M / LN 14/64 T1c,N0,M / /68 T1c,N0,M / /62 T3a,N0,M / LN 17/68 T3a,N0,M / ; /67 T3a,N0,M / /62 T3a,N0,M / /64 T3a,N0,M / LN 21/71 T3b,N0,M / /68 T2c,N0,M / /69 T2c,N0,M / /58 T3b,N0,M / /67 T3b,N0,M /6 5 5 LN Other PET findings LNs, lymph nodes; LN, lymph node(s) in lower abdomen or pelvis with a high tracer uptake. TABLE 2 Prostate cancer by FCH PET/CT compared with histopathological results Histopathological examination, n (%) FCH PET/CT + Metastases Metastases + Metastases 3/25 (12) 1/25 (4) Metastases 0/25 21/25 (84) were PET-positive, and in these the histopathological examination showed inflammation. The histopathological examination in this fourth patient showed conical inflammation in the PET-positive lymph node. In all patients, there was a high radiotracer uptake in the prostate gland, consistent with their biopsy-confirmed prostate cancers; Table 2 outlines the results. The sensitivity, specificity, PPV and NPV of FCH PET/CT for patient-based lymph node staging of prostate cancer were 100%, 95%, 75% and 100%, respectively; the corresponding 95% CIs were %, %, % and %, respectively. In the three patients with histologically confirmed prostate metastases within their lymph nodes, the mean SUV max of the affected lymph nodes was 4.5 ( ) and 3.6 ( ) at 15 and 60 min after injection, respectively, the difference being statistically insignificant. Seven other patients had a high radiotracer uptake in lymph nodes in the lower abdomen and pelvis. However, these lymph nodes were all outside the region of the lymphadenectomy. Nine patients had other additional findings, primarily within their lungs or in the mediastinum. All patients with suspected malignancy other than prostate cancer were referred to assisting departments for further evaluation. The assisting departments did not detect any malignancies. None of the patients had complications in relation to the PET/CT scan or the operation. DISCUSSION Prostate cancer is the second most frequently diagnosed cancer and the third most common cause of death from cancer in European men [4,19]; it has a recurrence rate of 30 50% after intended curative therapy. Together, these facts call for improvements in staging and therapy of prostate cancer [1,2]. Lymph node staging remains a cornerstone in staging prostate cancer, but it is debated whether to use a standard or extended lymphadenectomy. The standard procedure is less sensitive, whereas the extended lymphadenectomy has more complications. The debate is ongoing and consensus on standardization or the extent of lymphadenectomy has not yet been reached [3,20]. JOURNAL COMPILATION 2010 BJU INTERNATIONAL 641

4 POULSEN ET AL. Standard imaging with CT or MRI appears to be insufficient for lymph node staging of prostate cancer [7,21]. Therefore, MRI with contrast and PET/CT are being studied to improve staging [8,22]. The advantage of PET/ CT is the fusion of functional PET imaging to detect the cancer and precise anatomical localization by CT, potentially leading to a higher diagnostic value than offered by individual CT, MRI or PET. If PET/CT is shown to be equal to or better than lymphadenectomy, this imaging method might improve the mortality and morbidity rates. The capability of PET depends on the radiotracer; FCH is an 18 F-labelled analogue of choline, which is a substrate for the synthesis of phosphatidylcholine, a major constituent of the cell membrane. The first step in this synthesis is phosphorylation by choline kinase, the activity of which is often upregulated in cancer, inducing accumulation of choline in several neoplasms, e.g. those of the breast, liver, prostate, and brain. Furthermore, FCH is rapidly and extensively cleared from the blood after i.v. injection, allowing a good tumour-to-background contrast. Clearing of FCH from the blood is primarily by the choline transport system in prostate cancer and certain normal tissues [12]. In 2001 DeGrado et al. [12] reported on the synthesis and evaluation of FCH, concluding that FCH might serve as a radiotracer for prostate cancer, within both the gland and its metastases. During recent years, several reports on the clinical use of FCH have been published. The first evaluation of FCH PET/CT for lymph-node staging of prostate cancer was by Schmid et al. [23], who examined nine patients and obtained concordant results, in that neither lymphadenectomy nor FCH PET/CT found evidence of lymph node metastases in any of the patients. Häcker et al. [24] included 20 intermediate- and high-risk patients for FCH PET/CT followed by sentinel node and extended pelvic lymph node dissection. Ten of the patients had histologically verified lymph node metastases, but the results were disappointing because FCH PET/CT detected lymph node metastases in only one patient. Husarik et al. [25] used FCH PET/CT in addition to lymphadenectomy in 25 patients; in three, lymph node metastases were verified histologically, but FCH PET/CT only detected one of these. [ 11 C]-choline is a related PET radiotracer, and two promising larger studies on lymph node staging of prostate cancer by this radiotracer have been published. Schiavian et al. [26] prospectively evaluated 57 patients and reported sensitivity, specificity, PPV and NPV of 60%, 98%, 90% and 87%, respectively, in a patient-based analysis. de Jong et al. [27] prospectively included 67 patients and found a sensitivity of 80% and a specificity of 96% for lymph node staging of prostate cancer. There are no clinical studies comparing directly [ 11 C]-choline PET/CT and FCH PET/CT for imaging prostate cancer, but in vitro studies of FCH reveal that it closely mimics the natural processes of both [ 11 C]-choline and choline [12,28], suggesting that [ 11 C]- choline and FCH might perform similarly for detecting prostate cancer cells. Compared to [ 11 C]-choline, FCH has the advantage of having a longer physical half-life (109 vs 20 min) which allows for transportation and for delayed imaging, enhancing bone metastases. However, FCH has a higher urinary excretion rate, making it less suitable for imaging of the prostate gland. In the present series, FCH PET/CT had a high sensitivity and a high NPV for detecting lymph node metastases; the specificity and the PPV were lower. The high sensitivity was consistent with our finding that all three patients with metastases were detected by FCH PET/CT. The specificity and PPVs were suboptimal because one patient had a positive FCH PET/CT finding caused by inflammation and another had a high choline uptake in multiple lymph nodes, of which only three harboured metastases (Table 1), suggesting that FCH PET/CT had a tendency to overestimate the number of patients and lymph nodes with metastases [12]. No patient with metastases was overlooked by FCH PET/ CT, consistent with a NPV in our small sample of 100% for detecting lymph node metastases. When comparing our series with the three existing studies on lymph node staging of prostate cancer, there were variations in the populations examined and the doses of FCH, but otherwise the studies were fairly comparable. The results differ in that both Häcker et al. [24] and Husarik et al. [25] concluded that FCH PET/CT is not suitable for initial staging of prostate cancer, while Schmid et al. [23] had no conclusions on lymph node staging, whereas in our limited series FCH PET/CT seemed promising for initial lymph node staging due to a high sensitivity and a high NPV. The reason for the reported differences might be random variations due to the few patients studied and the few verified metastases, as also reflected by wide CIs [23 25]. However, comparing the existing studies on FCH-PET/CT for lymph node staging of prostate cancer, there is an apparent improvement in sensitivity over time, whereas the specificity remained high. This might reflect progress in handling and interpreting the PET/CT scans. Thus, larger prospective studies are needed to clarify the true value of FCH PET/CT for initial lymph node staging of prostate cancer. The results of our entire study scheduled to include 205 patients will hopefully make a significant contribution. Lymph node metastases outside the standard lymphadenectomy region might also be detected by FCH PET/CT. In cases where FCH PET/CT performs well within this standard region, one can argue that FCH PET/CT will perform equally well in the adjacent regions, given that the pathophysiology is comparable [29]. The lymph of the prostate gland is drained through a net of nodes, part of which are included in the region of standard lymphadenectomy, whereas others are in adjacent regions. Thus, the lymph nodes in the standard and adjacent regions might be comparable, and it is fair to anticipate that FCH PET/CT could detect lymph node metastases with similar accuracy within the adjacent regions [3,30]. Seven patients in our study had lymph nodes with a high radiotracer uptake in the adjacent regions. Imaging at 15 min and 60 min were not associated with different detection rates. Similar findings were reported by Husarik et al. [25], whereas Cimitan et al. [13] noted in a study of 100 patients that bone metastases were enhanced by delayed imaging. Because of the latter we tend to recommend delayed imaging. The present patients correspond to those with intermediate- and high-risk disease according to the criteria of D Amico et al. [31] and we foresee that FCH PET/CT imaging for lymph node staging of patients with prostate cancer could be of value for these categories of patients. Depending on the outcome of the whole study, FCH PET/CT might replace lymphadenectomy, thus potentially improving lymph node staging of patients with prostate cancer. The primary limitations of our study were the few patients and regional lymph node metastases, and that the few patients had metastases of 7 mm, whereas no micrometastases were found by histology. 642 JOURNAL COMPILATION 2010 BJU INTERNATIONAL

5 PET/CT FOR LYMPH NODE STAGING OF PATIENTS WITH PROSTATE CANCER In conclusion, our series supports the use of FCH PET/CT as a tool for lymph node staging of prostate cancer. Values of SUV max at early and late imaging did not differ. However, larger prospective studies are needed to validate these findings. CONFLICT OF INTEREST None declared. Source of funding: departmental. REFERENCES 1 Freedland SJ, Moul JW. Prostate specific antigen recurrence after definitive therapy. J Urol 2007; 177: Poppel H, Joniau S. An analysis of radical prostatectomy in advanced stage and high-grade prostate cancer. Eur Urol 2008; 53: Sivalingam S, Oxley J, Probert JL, Stolzenburg JU, Schwaibold H. Role of pelvic lymphadenectomy in prostate cancer management. Urology 2007; 69: Damber JE, Aus G. Prostate cancer. Lancet 2008; 371: Heidenreich A, Bolla M, Joniau S et al. EAU Guidelines on Prostate Cancer. Eur Urol 2008; 53: Wang L, Hricak H, Kattan MW et al. 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6 POULSEN ET AL. EDITORIAL COMMENT The authors are to be congratulated for providing new and exciting prospective data on combined PET/CT in urological oncology. For many years we have had to be content with retrospective series using only the functional method of pure PET, whereas the technology has advanced now with PET/CT, allowing functional and anatomical alignment, further enhancing the accuracy and diagnostic capabilities. FCH is one of the newer radiotracers that focus on different aspects of tumour biology (in this case the construction of cell membranes, which is typically increased in malignancy) rather than simply glucose metabolism, that has been the mainstay of PET with 18Ffluorodeoxyglucose. What is particularly encouraging was that despite the few positive nodes, those that were positive were all Gleason 7, and no higher. This is exactly the group where we are unsure as to the benefit of nodal dissection, even with the assistance of nomograms. A tool that can direct us accurately is desirable. Clearly larger series with more events will be needed to establish FCH as the radiotracer of choice with PET/CT, but it is a promising start. The practical question of how long to allow for the radiotracer to biodistribute after injection is clinically relevant, and the authors show that there is no benefit to allowing a longer time of distribution. This will allow increased turnover of resources and more flexibility with using FCH. Nathan Lawrentschuk Uro-Oncologist, University of Melbourne, Austin Hospital, Australia, and University of Toronto, Princes Margaret Hospital, Canada 644 JOURNAL COMPILATION 2010 BJU INTERNATIONAL