EURURO-6606; No. of Pages 5 EUROPEAN UROLOGY XXX (2016) XXX–XXX

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Brief Correspondence 68

Ga-PSMA Positron Emission Tomography/Computed Tomography Provides Accurate Staging of Lymph Node Regions Prior to Lymph Node Dissection in Patients with Prostate Cancer Annika Herlemann a, Vera Wenter b, Alexander Kretschmer a, Kolja M. Thierfelder c, Peter Bartenstein b,d, Claudius Faber e, Franz-Josef Gildehaus b, Christian G. Stief a,d, Christian Gratzke a,d, Wolfgang P. Fendler b,* a

Department of Urology, Ludwig-Maximilians-University of Munich, Munich, Germany; b Department of Nuclear Medicine, Ludwig-Maximilians-University

of Munich, Munich, Germany; c Department of Clinical Radiology, Ludwig-Maximilians-University of Munich, Munich, Germany;

d

Comprehensive Cancer

Centre, Ludwig-Maximilians-University of Munich, Munich, Germany; e Institute of Pathology, Ludwig-Maximilians-University of Munich, Munich, Germany

Article info

Abstract

Article history: Accepted December 29, 2015

We evaluated the accuracy of 68Ga-prostate-specific membrane antigen-HBED-CC (68Ga-PSMA) positron emission tomography/computed tomography (PET/CT) for nodal staging prior to lymph node dissection (LND) in patients with prostate cancer (PCa). Thirty-four patients with histologically proven PCa underwent 68Ga-PSMA-HBED-CC PET/CT prior to radical prostatectomy with primary LND (pLND; n = 20) and PET/CT prior to secondary LND (sLND; n = 14). Accuracy of PET and CT were analysed separately for staging of the following 71 lymph node (LN) regions: pelvic left (n = 30), pelvic right (n = 31), presacral (n = 3), and para-aortic (n = 7). Postoperative histopathology was taken as a reference standard. Thirty-seven of 71 (52%) regions showed LN metastases on histopathology. Sensitivity, specificity, positive predictive value, and negative predictive value for detection of LN metastases were 84%, 82%, 84%, and 82% for PET criteria and 65%, 76%, 75%, and 67% for CT criteria. PET was more accurate for nodal staging compared with CT both at pLND (88% vs 75%) and sLND (77% vs 65%). Overall, 68Ga-PSMA PET/CT provides accurate nodal staging prior to pLND and sLND for PCa. Patient summary: 68Ga-PSMA positron emission tomography/computed tomography is accurate in detecting tumour spread to lymph nodes before patients undergo surgery for prostate cancer. # 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Associate Editor: Giacomo Novara Keywords: Prostate cancer PSMA PET/CT Positron emission tomography Lymph node dissection

* Corresponding author. Department of Nuclear Medicine, Marchioninistrasse 15, 81377 Munich, Germany. Tel. +49 89 4400 7 4646; Fax: +49 89 4400 7 7646. E-mail address: [email protected] (W.P. Fendler).

Preoperative staging is generally recommended in patients with biochemical persistence or recurrence and in patients with high risk prostate cancer (PCa), as defined by a prostate specific antigen (PSA) level > 20 ng/ml, Gleason score  8 or clinical stage  T3a [1]. To date, pelvic lymph node dissection (LND) is considered the most accurate for assessment of nodal involvement [1,2]. However, preoperative evaluation

of lymph node (LN) metastasis even by more advanced imaging techniques such as choline-based combined positron emission tomography and computed tomography (PET/ CT) has demonstrated limited sensitivity and specificity [3–5], particularly in patients with low PSA level [6,7]. PET/CT using the radiolabelled prostate-specific membrane antigen (PSMA) ligand 68Ga-PSMA-HBED-CC has the potential to

http://dx.doi.org/10.1016/j.eururo.2015.12.051 0302-2838/# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Please cite this article in press as: Herlemann A, et al. 68Ga-PSMA Positron Emission Tomography/Computed Tomography Provides Accurate Staging of Lymph Node Regions Prior to Lymph Node Dissection in Patients with Prostate Cancer. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2015.12.051

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EUROPEAN UROLOGY XXX (2016) XXX–XXX

overcome this limitation; however, there is little evidence for its value in terms of preoperative staging [8–12]. Given the importance of nodal staging for surgery planning, more studies with adequate histopathological (HP) confirmation in this setting are urgently needed. We hypothesized that 68GaPSMA PET/CT provides accurate preoperative LN staging. To test this hypothesis we aimed to evaluate the performance of 68 Ga-PSMA PET/CT for region-based nodal staging prior to primary LND (pLND) and secondary LND (sLND) in patients with PCa. Thirty-four consecutive patients were enrolled and analysed according to the following inclusion criteria: (1) PCa proven by histopathology, (2) risk for LN metastases as characterized by Gleason  7, 50% positive biopsy cores, or PSA  10 ng/ml at pLND [1], biochemical persistence or recurrence at sLND, (3) 68Ga-PSMA PET/CT less than 50 d before pLND (n = 20) or sLND (n = 14) at our department. Four (20%) patients had intermediate risk, 16 (80%) patients had high risk PCa at pLND [1]. pLND patients with any prior local LN treatment were excluded. Patients underwent surgery between January 2014 and August 2015. All patients gave written consent to undergo the procedures. The requirement to obtain informed consent for inclusion in the retrospective analysis was waived by the local ethics committee. Patient characteristics are given in Supplementary Table 1. Previous and concomitant therapy is given in Supplementary Table 2. 68 Ga-PSMA was radiolabelled with 68Ga3+ from a 68 Ge/68Ga generator system (GalliaPharm, Eckert & Ziegler AG, Berlin, Germany) using an automated synthesis module (GRP, Scintomics GmbH, Fu¨rstenfeldbruck, Germany) and prepacked cassettes (ABX GmbH, Radeberg, Germany) as described by Weineisen et al [13]. Whole body 68Ga-PSMA PET/CT images were acquired using a Siemens Biograph 64 TruePoint PET/CT scanner (n = 27; 79%; Siemens Medical Solutions, Erlangen, Germany) or a GE Discovery 690 (n = 7; 21%; General Electric, Essen, Germany). PET/CT scan was obtained with intravenous injection of iodine-containing contrast agent following 60 min after almost simultaneous intravenous administration of 20 mg furosemide and 68Ga-PSMA. All patients underwent open retropubic or robotassisted radical prostatectomy with simultaneous bilateral pelvic pLND. If preoperative staging showed any suspicious LN outside the pelvis, pLND was extended to these regions. For patients with sLND an open approach through a midline incision was performed. All suspicious LNs detected using 68 Ga-PSMA PET/CT imaging were dissected and classified accordingly by anatomic region for evaluation. Following regions as defined by [14] were analysed for the presence or absence of LN metastases by HP and PET/CT: pelvic left (n = 30) and pelvic right (n = 31) nodes, each including common iliac, external iliac, internal iliac, and obturator nodes; presacral nodes (n = 3); para-aortic nodes (n = 7). PET/CT analysis was performed by W.P.F. and K.M.T. together with each more than 5 yr experience in clinical and scientific interpretation of CT and PET/CT scans for tumour staging. Location of nodes was each determined with CT. PET positive nodes were identified by 68Ga-PSMA

uptake visually above background. CT positive nodes were defined by either short axis  15 mm or short axis  8 mm together with loss of fatty hilum, focal necrosis, penetration of the capsule, or increased contrast enhancement. PET/CT findings were validated by systematic HP performed by a uropathologist (C.F.) with more than 5 yr experience, who was blinded to PET/CT data. The histopathological results were compared with findings on 68Ga-PSMA PET and CT. Sensitivity (SE), specificity (SP), positive predictive value (PPV), negative predictive value (NPV), and accuracy (ACC) were calculated for detection of HP positive regions. k coefficient was calculated to determine the level of agreement of PET with CT. Overall, 484 nodes were resected from 71 regions. One hundred and thirty two nodes from 37 regions (52%) were HP proven metastases. LN yield was not significantly different in regions with +/- HP proven metastases according to Mann–Whitney test (p = 0.297). The average number of LN metastases per diseased LN region was 3.6  4.6 (range, 1–22). The average maximum standardised uptake value of PET positive LNs was 8.5  6.9 (range, 2.0– 40.0). The performance of PET and CT for detection of diseased LN regions is given in Table 1. Diagnostic performance was different at pLND versus sLND. At pLND 23 of 26 regions were correctly identified as not-diseased (SP 88%), whereas at sLND only five of eight true negative regions were correctly diagnosed by PET (SP 63%). NPV was also lower at sLND versus pLND (56% vs 92%) based on four versus two false negative (FN) findings. Para-aortic region was PET positive in seven patients at sLND and six of these seven patients (86%) had HP proven LN involvement. PET SE and PPV were high both at pLND (86% and 80%) and sLND (83% and 86%). The average CT short axis diameter of PET positive LN was 0.8  0.4 cm (range, 0.0–2.6 cm). A considerable portion of

Table 1 – Performance of 68Ga-PSMA positron emission tomography versus computed tomography for nodal staging by region. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy are each given in percent based on true positive, true negative, false positive, and false negative findings for detection of diseased lymph node regions. Results are given separately for lymph node dissection during primary surgery, for secondary, and for lymph node dissection at any time point

TP TN FP FN SE SP PPV NPV ACC

LND (n = 71)

pLND (n = 40)

sLND (n = 31)

PET

CT

PET

CT

PET

CT

31 28 6 6 84 82 84 82 83

24 26 8 13 65 76 75 67 70

12 23 3 2 86 88 80 92 88

9 21 5 5 64 81 64 81 75

19 5 3 4 83 63 86 56 77

15 5 3 8 65 63 83 38 65

ACC = accuracy; CT = computed tomography; FN = false negative; FP = false positive; LND = lymph node dissection; NPV = negative predictive value; PET = positron emission tomography; pLND = primary lymph node dissection; PPV = positive predictive value; SE = sensitivity; sLND = secondary lymph node dissection; SP = specificity; TN = true negative; TP = true positive.

Please cite this article in press as: Herlemann A, et al. 68Ga-PSMA Positron Emission Tomography/Computed Tomography Provides Accurate Staging of Lymph Node Regions Prior to Lymph Node Dissection in Patients with Prostate Cancer. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2015.12.051

EURURO-6606; No. of Pages 5 EUROPEAN UROLOGY XXX (2016) XXX–XXX

PET true positive LN was  0.5 cm by CT short axis diameter (43 of 108, 40%; Fig. 1) or by both CT diameters (10 of 108, 9%). The average short axis diameter of CT positive LN was 1.2  0.5 cm (range, 0.8–2.6 cm). SE, SP, PPV, and NPV was lower for CT compared with PET, resulting in lower ACC of 75% versus 88% for pLND, 65% versus 77% for sLND, and 70% versus 83% for the entire group. There was moderate agreement

3

between PET and CT for the entire group (k = 0.58). Examples for false PET or CT findings are given in Supplementary Figure 1. The performance of PET and CT for detection of N stage on a patient basis is given in Table 2. Our analysis of 71 LN regions from 34 patients demonstrates a superior performance of PET compared with CT for the correct identification of the presence or absence of LN

Fig. 1 – Lymph node metastases with varying size on PET/CT. Fused 68Ga-PSMA PET/CT (A,C,E) and CT (B,D,F) images were taken from iliac left regions with hisopathologically proven disease. CT short axis diameters of PET positive LN were 10 mm (E,F).

Please cite this article in press as: Herlemann A, et al. 68Ga-PSMA Positron Emission Tomography/Computed Tomography Provides Accurate Staging of Lymph Node Regions Prior to Lymph Node Dissection in Patients with Prostate Cancer. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2015.12.051

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Table 2 – Accuracy of 68Ga-PSMA positron emission tomography for nodal staging on a patient basis. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy are each given in percent for detection of diseased lymph node regions in patients with prostate cancer verified by histopathology n = 34

PET positive (n = 24) PET negative (n = 10)

HP positive (n = 22)

HP negative (n = 12)

20 2 SE 91%

4 8 SP 67%

PPV 83% NPV 80% ACC 82%

ACC = accuracy; HP = histopathology; NPV = negative predictive value; PET = positron emission tomography; PPV = positive predictive value; SE = sensitivity; SP = specificity.

metastases (SE 84% vs 65%; SP 82% vs 76%). We were able to confirm recent findings in pLND [12] and histologically verify the accuracy of 68Ga-PSMA PET/CT in patients undergoing sLND. False CT findings occurred in case of enlarged LN after prior inflammation (false positive [FP]; Supplementary Fig. 1C) or nonenlarged micrometastases (FN; Supplementary Fig. 1D). The challenge of identifying micrometastases is well-known. Small LN metastases (

Computed Tomography Provides Accurate Staging of Lymph Node Regions Prior to Lymph Node Dissection in Patients with Prostate Cancer.

We evaluated the accuracy of 68Ga-prostate-specific membrane antigen-HBED-CC (68Ga-PSMA) positron emission tomography/computed tomography (PET/CT) for...
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