EURURO-6193; No. of Pages 5 EUROPEAN UROLOGY XXX (2015) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Case Series of the Month
Prostate-specific Membrane Antigen–radioguided Surgery for Metastatic Lymph Nodes in Prostate Cancer Tobias Maurer a,*, Gregor Weirich b, Margret Schottelius c, Martina Weineisen d, Benjamin Frisch e, Asli Okur d,e, Hubert Ku¨bler a, Mark Thalgott a, Nassir Navab e, Markus Schwaiger d, Hans-Ju¨rgen Wester c, Ju¨rgen E. Gschwend a, Matthias Eiber d a
Department of Urology, Technische Universita¨t Mu¨nchen, Klinikum rechts der Isar, Munich, Germany;
b
Institute of Pathology, Technische Universita¨t
Mu¨nchen, Klinikum rechts der Isar, Munich, Germany; c Pharmaceutical Radiochemistry, Technische Universita¨t Mu¨nchen, Klinikum rechts der Isar, Munich, Germany;
d
Department of Nuclear Medicine, Technische Universita¨t Mu¨nchen, Klinikum rechts der Isar, Munich, Germany;
e
Computer Aided Medical
Procedures, Technische Universita¨t Mu¨nchen, Klinikum rechts der Isar, Munich, Germany
Article info
Abstract
Article history: Accepted April 22, 2015
With the advent of 68Ga-labeled prostate-specific membrane antigen-N,N0 -bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N0 -diacetic acid (68Ga-PSMA-HBEDCC) positron emission tomography (PET) hybrid imaging in prostate cancer (PCa), even small metastatic lymph nodes (LNs) can be visualized. However, intraoperative detection of such LNs may not be easy owing to their inconspicuous morphology and/or atypical localization. The aim of our feasibility study was to evaluate PSMA-radioguided surgery for detection of metastatic LNs. One patient with primary PCa and evidence of LN metastases and four PCa patients with evidence of recurrent disease to regional LNs on 68 Ga-PSMA-HBED-CC PET hybrid imaging received an intravenous injection of an 111InPSMA investigation and therapy agent 24 h before surgery. Metastatic LNs were tracked intraoperatively using a gamma probe with acoustic and visual feedback. All radioactivepositive LN specimens detected in vivo were confirmed by ex vivo measurements and corresponded to PSMA-avid metastatic disease according to histopathology analysis. Intraoperative use of the gamma probe detected all PSMA-positive lesions identified on preoperative 68Ga-PSMA-HBED-CC PET. Detection of small subcentimeter metastatic LNs was facilitated, and PSMA-radioguided surgery in two patients revealed additional lesions close to known tumor deposits that were not detected by preoperative 68Ga-PSMAHBED-CC PET. However, greater patient numbers and long-term follow-up data are needed to determine the future role of PSMA-radioguided surgery. # 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Editor: Matthew Cooperberg Keywords: Prostate-specific membrane antigen Positron emission tomography Radioguided Prostate cancer
* Corresponding author. Department of Urology, Technische Universita¨t Mu¨nchen, Klinikum rechts der Isar, Ismaninger Strasse 22, 81671 Munich, Germany. Tel. +49 89 41405521; Fax: +49 89 41404818. E-mail address: [email protected] (T. Maurer).
1.
Case series
This feasibility study included one patient with primary prostate cancer (PCa) and evidence of lymph node (LN)
metastases, and four patients with biochemical-recurrent PCa and evidence of metastatic disease solely to regional LNs on 68Ga-labeled prostate-specific membrane antigen-N,N0 bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,
http://dx.doi.org/10.1016/j.eururo.2015.04.034 0302-2838/# 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Maurer T, et al. Prostate-specific Membrane Antigen–radioguided Surgery for Metastatic Lymph Nodes in Prostate Cancer. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.04.034
EURURO-6193; No. of Pages 5 2
EUROPEAN UROLOGY XXX (2015) XXX–XXX
Table 1 – Patient characteristics and results of PSMA-ligand–radioguided surgery Patient Age (yr) Primary treatment Initial histological classification Further treatment
1 64 – –
PSA at examination (ng/ml) Suspicious lesions on PSMA-ligand PET imaging Resected tissue specimens a
244 5
PSMA-ligand RGS positive PSMA-ligand RGS negative Histological classification Location of positive LN fields (size of largest positive LN within field)
–
Histology – + 6 0 0 4 pT4 pN1 (6/25) cM0 GS10 Right side: obturator fossa (6 mm) external iliac (12 mm) internal iliac (4 mm) common iliac (2 mm) Left side: obturator fossa (8 mm) external iliac (5 mm)
2 75 RP (Jan 2010) pT2c pN0 cM0 R0 GS7 Salvage PLND (Nov 2010) RTX (May–Aug 2012_ 0.46 1
3 69 RP (Sept 2013) pT3a pN0 cM0 R0 GS7b –
4 75 RP (Feb 2006) pT3b pN0 cM0 R0 GS8 RTX (Aug 2006)
5 75 HIFU + TURP (2007) cT2 cN0 cM0 GS6
0.42 1
4.36 4
2.45 2
Histology + 1 0 pN1 (1/2)
Histology + – 1 0 0 6 pN1 (1/1)
Histology + – 5b 0 0 2 pN1 (10/20)*
Histology + 2 0 pN1 (2/2)
Paravesical right (6 mm)
Left side: obturator fossa (8 mm) external iliac (3 mm) internal iliac (9 mm) common iliac (5 mm) pararectal (11 mm)
Pararectal right (10 mm) presacral (7 mm)
– 0 1
Paravesical left (10 mm)
RTX (2009)
– 0 0
RP = radical prostatectomy; HIFU = high-intensity focused ultrasound; TURP = transurethral resection of the prostate; GS = Gleason score; PLND = pelvic lymph node dissection; RTX = radiotherapy of the prostate bed; PSA = prostate-specific antigen; PSMA = prostate-specific membrane antigen; RGS = radioguided surgery. a LNs found in tissue specimens varied in number (0–5). b Five different resected tissue specimens rated positive contained a total of ten histology-proven LN metastases.
Fig. 1 – Example results for a patient with recurrent prostate cancer to pelvic lymph nodes (patient 4). (A) Axial T2-weighted magnetic resonance imaging (MRI) shows a small (6 mm) lymph node in left the obturator fossa (arrow). (B) Axial 68Ga-labeled prostate-specific membrane antigen (PSMA)-ligand positron emission tomography (PET) and (C) axial 68Ga-PSMA-N,N0 -bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N0 -diacetic acid (HBED-CC) PET/MRI fusion images show a distinct signal for this lymph node that is highly suspicious for metastasis, subsequently confirmed by histology after radioguided surgery using an 111In-PSMA investigation and therapy agent. Note the susceptibility artifacts in the region of the hip joints caused by bilateral hip prostheses, as well as the activity of excreted 68Ga-PSMA-HBED-CC in the bladder.
N0 -diacetic acid (68Ga-PSMA-HBED-CC) positron emission tomography (PET) hybrid imaging (Table 1; Fig. 1). All patients were treated only after providing consent once they had been informed of the experimental nature of PSMA-radioguided surgery as an individual treatment concept. For PSMA-radioguided surgery, a gamma-emitting 111Inlabeled PSMA ligand was used as a radiotracer because of its favorable half-life of 2.8 d. However, owing to the instability of 111In-PSMA-HBED-CC, a 1,4,7,10-tetraazacyclododececane,1-(glutaric acid)-4,7,10-triacetic acid (DOTAGA)-conjugated peptide-based ligand targeting PSMA (PSMA-I&T; investigation and therapy) was used for 111In labeling and PSMA-radioguided surgery [1]. At 24 h before surgery,
patients received an intravenous injection of 146 MBq (mean; range 110–169 MBq) 111In-PSMA-I&T. Intraoperatively, metastatic LNs were detected using a gamma probe (Crystal Probe CXS-SG603; Crystal Photonics, Berlin, Germany) with live acoustic and visual feedback of the count rate; a higher rate indicates the presence of a radioactive hotspot (Fig. 2). In this technique the surgeon cognitively maps the count information onto the surgical field, without the possibility of image guidance. This approach was improved by the use of a freehand single-photon emission computed tomography system (declipseSPECT; SurgicEye, Munich, Germany) that allows visualization of radioactivity within a reconstructed three-dimensional (3D) image. The
Please cite this article in press as: Maurer T, et al. Prostate-specific Membrane Antigen–radioguided Surgery for Metastatic Lymph Nodes in Prostate Cancer. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.04.034
EURURO-6193; No. of Pages 5 EUROPEAN UROLOGY XXX (2015) XXX–XXX
3
Fig. 2 – (A) Intraoperative set-up for prostate-specific membrane antigen (PSMA)-radioguided surgery. (B) A gamma probe is connected to (C) a gamma counter (Crystal Probe CXS-SG603) providing acoustic and visual feedback of the count rate. The gamma probe is also equipped with spheroid optical markers (Ilumark, Feldkirchen, Germany) for three-dimensional (3D) tracking with a freehand single-photon emission computed tomography system (declipseSPECT) allowing (D) visual feedback including (E) overlay of reconstructed 3D nuclear images showing the position of hotspots corresponding to 111In-PSMA accumulation in the surgical field.
position of the gamma probe is recorded by an optical tracking system simultaneously with the count rate. Once sufficient information about the spatial distribution of the radioactivity has been acquired, a 3D image is reconstructed. This image is then co-registered with a live video stream of the surgical field to provide an augmented reality display during PSMA-radioguided surgery showing the position of hotspots corresponding to 111In-PSMA-I&T accumulation (Fig. 2). Resected tissue fractions from different anatomic sites according to preoperative 68Ga-PSMA-HBED-CC PET findings (eg, paracaval, pararectal, or internal iliac node specimen) were analyzed as separate tissue specimens. Fatty tissue from the patient served as a background reference for these measurements ex vivo. The count rate for the background reference typically ranged between 0 and 5 counts/s. Each of these tissue specimens was measured ex vivo and subsequently underwent pathologic evaluation to allow exact matching. The reference tissue was also histologically evaluated to ensure that it contained no metastatic PCa deposits. We defined tissue specimens
that showed a count rate at least double the background reference count as being radioactive-positive. Most radioactive-positive tissue specimens had count rates between 30 and 80 counts/s. Besides conventional hematoxylin-eosin staining, histologic analysis also included PSMA immunohistochemistry with a monoclonal murine PSMA antibody (clone 3E6; Dako, Hamburg, Germany) (Fig. 3). Results for gamma probe measurements (background signal [negative] vs signal above background [positive]) in resected tissue specimens ex vivo were compared to postoperative histology findings (Table 1). PSMA-radioguided surgery after administration of 111 In-labeled PSMA-I&T increased surgeon confidence in intraoperative detection and complete dissection of small metastatic lesions seen in preoperative 68Ga-PSMA-HBED-CC PET hybrid imaging. PSMA-radioguided surgery detected all PET-positive lesions in vivo that were first observed by preoperative imaging. Histologic analysis confirmed that all resected tissue specimens exhibiting positive measurements in vivo and ex vivo had PSMA-avid metastatic disease analysis (Table 1). Furthermore, PSMA-radioguided surgery
Please cite this article in press as: Maurer T, et al. Prostate-specific Membrane Antigen–radioguided Surgery for Metastatic Lymph Nodes in Prostate Cancer. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.04.034
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Fig. 3 – Example of two representative lymph node specimens from patient 4 rated as (A) strong or (B) weakly positive by ex vivo acoustic measurement during 111In-prostate-specific membrane antigen (PSMA)-radioguided surgery. Corresponding histological analysis (PSMA immunohistochemistry) revealed (C) a macrometastasis and (D) a micrometastasis of PSMA-expressing adenocarcinoma of the prostate. The macrometastasis was detected by preoperative 68Ga-PSMA-N,N0 -bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N0 -diacetic acid positron emission tomography/magnetic resonance imaging, but the micrometastasis was only detected intraoperatively by 111In-PSMA-radioguided surgery.
after 111In-PSMA-I&T administration detected additional lesions close to known tumor deposits in two of the five patients (patients 1 and 4; Table 1). These lesions corresponded to very small metastatic deposits of 2–4 mm (Fig. 3). No patient experienced complications related to intravenous administration of 111In-PSMA-I&T. 2.
Discussion
Systemic medical therapy currently represents the standard of care for patients with metastatic disease after local curative treatment for PCa. However, in patients with minimal or localized metastatic disease burden and good clinical status, salvage concepts as individual treatment regimens might represent a valid option favoring progression-free survival [2,3]. A prerequisite for these therapies is reliable and early detection of disease recurrence. For this purpose, morphologic imaging procedures such as computed tomography and magnetic resonance imaging or functional PET imaging, mostly using radiolabeled-choline derivatives, are of limited value and often underestimate the extent of metastatic spread [4,5]. 68Ga-PSMA-HBED-CC PET hybrid
imaging was recently introduced in PCa staging with promising results [6,7], and higher detection rates have been observed in patients with biochemical recurrence after radical prostatectomy compared to results with currently used tracers such as 18F-choline [8], especially for low PSA values [9]. Thus, local treatment strategies might attract even more attention in the future. Early recurrence with small metastatic deposits within fatty tissue or LNs and atypical localization might impede intraoperative detection and resection. Use of nearinfrared-fluorescence or radioguided surgery after injection of indigocyanine green or 99mTc-nanocolloid into the prostate has been proposed for guiding sentinel LN dissection in patients with primary PCa [10]. However, lymph drainage might be altered in recurrent disease and the site of tracer injection remains unclear. We described for the first time a method for direct detection of metastatic PCa lesions via molecular targeting of PSMA using 111In-labeled PSMA-I&T. Comparable to medical targeted therapies, PSMA-radioguided surgery facilitates targeted molecular surgery, as it allows specific intraoperative detection of PSMA-expressing PCa deposits. Especially for intraoperative detection of small
Please cite this article in press as: Maurer T, et al. Prostate-specific Membrane Antigen–radioguided Surgery for Metastatic Lymph Nodes in Prostate Cancer. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.04.034
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EUROPEAN UROLOGY XXX (2015) XXX–XXX
subcentimeter metastatic LNs and atypically located lesions, 111In-PSMA-I&T-radioguided surgery showed promising results in this feasibility study. However, larger patient cohorts and long-term follow-up are needed to confirm these initial encouraging results and to determine the possible role of this technique in clinical routine. In addition, the extent of LN dissection necessary during PSMA-radioguided surgery needs to be clarified for patients with recurrent prostate cancer. However, adequate patient selection on the basis of PSMA-targeted PET hybrid imaging, and dedicated and subtle tissue resection during 111In-PSMAI&T-radioguided surgery are mandatory.
[4] Umbehr MH, Muntener M, Hany T, Sulser T, Bachmann LM. The role of 11C-choline and 18F-fluorocholine positron emission tomography (PET) and PET/CT in prostate cancer: a systematic review and metaanalysis. Eur Urol 2013;64:106–17. [5] Evangelista L, Guttilla A, Zattoni F, Muzzio PC. Utility of choline positron emission tomography/computed tomography for lymph node involvement identification in intermediate- to high-risk prostate cancer: a systematic literature review and meta-analysis. Eur Urol 2013;63:1040–8. [6] Schafer M, Bauder-Wust U, Leotta K, et al. A dimerized urea-based inhibitor of the prostate-specific membrane antigen for
68
Ga-PET
imaging of prostate cancer. EJNMMI Res 2012;2:23. [7] Maurer T, Beer AJ, Wester HJ, Kubler H, Schwaiger M, Eiber M. Positron emission tomography/magnetic resonance imaging with
Conflicts of interest: The authors have nothing to disclose.
68
Gallium-labeled ligand of prostate-specific membrane antigen:
promising novel option in prostate cancer imaging? Int J Urol
References
2014;21:1286–8. [8] Afshar-Oromieh A, Zechmann CM, Malcher A, et al. Comparison of
[1] Weineisen M, Schottelius M, Simecek J, Eiber M, Schwaiger M, Wester HJ. Development and first in human evaluation of PSMA I&T—a ligand for diagnostic imaging and endoradiotherapy of prostate cancer. J Nucl Med 2014;55:1083. [2] Suardi N, Gandaglia G, Gallina A, et al. Long-term outcomes of salvage lymph node dissection for clinically recurrent prostate cancer: results of a single-institution series with a minimum follow-up of 5 years. Eur Urol 2015;67:299–309. [3] Abdollah F, Briganti A, Montorsi F, et al. Contemporary role of salvage lymphadenectomy in patients with recurrence following
PET imaging with a
68
Ga-labelled PSMA ligand and
18
F-choline-
based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging 2014;41:11–20. [9] Eiber M, Maurer T, Souvatzoglou M, et al. Evaluation of hybrid 68
Ga-PSMA ligand PET/CT in 248 patients with biochemical
recurrence after radical prostatectomy. J Nucl Med 2015;56: 668–74. [10] KleinJan GH, van den Berg NS, Brouwer OR, et al. Optimisation of fluorescence guidance during robot-assisted laparoscopic sentinel node biopsy for prostate cancer. Eur Urol 2014;66:991–8.
radical prostatectomy. Eur Urol 2015;67:839–49.
Please cite this article in press as: Maurer T, et al. Prostate-specific Membrane Antigen–radioguided Surgery for Metastatic Lymph Nodes in Prostate Cancer. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.04.034
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Case Series of the Month
Prostate-specific Membrane Antigen–radioguided Surgery for Metastatic Lymph Nodes in Prostate Cancer Tobias Maurer a,*, Gregor Weirich b, Margret Schottelius c, Martina Weineisen d, Benjamin Frisch e, Asli Okur d,e, Hubert Ku¨bler a, Mark Thalgott a, Nassir Navab e, Markus Schwaiger d, Hans-Ju¨rgen Wester c, Ju¨rgen E. Gschwend a, Matthias Eiber d a
Department of Urology, Technische Universita¨t Mu¨nchen, Klinikum rechts der Isar, Munich, Germany;
b
Institute of Pathology, Technische Universita¨t
Mu¨nchen, Klinikum rechts der Isar, Munich, Germany; c Pharmaceutical Radiochemistry, Technische Universita¨t Mu¨nchen, Klinikum rechts der Isar, Munich, Germany;
d
Department of Nuclear Medicine, Technische Universita¨t Mu¨nchen, Klinikum rechts der Isar, Munich, Germany;
e
Computer Aided Medical
Procedures, Technische Universita¨t Mu¨nchen, Klinikum rechts der Isar, Munich, Germany
Article info
Abstract
Article history: Accepted April 22, 2015
With the advent of 68Ga-labeled prostate-specific membrane antigen-N,N0 -bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N0 -diacetic acid (68Ga-PSMA-HBEDCC) positron emission tomography (PET) hybrid imaging in prostate cancer (PCa), even small metastatic lymph nodes (LNs) can be visualized. However, intraoperative detection of such LNs may not be easy owing to their inconspicuous morphology and/or atypical localization. The aim of our feasibility study was to evaluate PSMA-radioguided surgery for detection of metastatic LNs. One patient with primary PCa and evidence of LN metastases and four PCa patients with evidence of recurrent disease to regional LNs on 68 Ga-PSMA-HBED-CC PET hybrid imaging received an intravenous injection of an 111InPSMA investigation and therapy agent 24 h before surgery. Metastatic LNs were tracked intraoperatively using a gamma probe with acoustic and visual feedback. All radioactivepositive LN specimens detected in vivo were confirmed by ex vivo measurements and corresponded to PSMA-avid metastatic disease according to histopathology analysis. Intraoperative use of the gamma probe detected all PSMA-positive lesions identified on preoperative 68Ga-PSMA-HBED-CC PET. Detection of small subcentimeter metastatic LNs was facilitated, and PSMA-radioguided surgery in two patients revealed additional lesions close to known tumor deposits that were not detected by preoperative 68Ga-PSMAHBED-CC PET. However, greater patient numbers and long-term follow-up data are needed to determine the future role of PSMA-radioguided surgery. # 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Editor: Matthew Cooperberg Keywords: Prostate-specific membrane antigen Positron emission tomography Radioguided Prostate cancer
* Corresponding author. Department of Urology, Technische Universita¨t Mu¨nchen, Klinikum rechts der Isar, Ismaninger Strasse 22, 81671 Munich, Germany. Tel. +49 89 41405521; Fax: +49 89 41404818. E-mail address: [email protected] (T. Maurer).
1.
Case series
This feasibility study included one patient with primary prostate cancer (PCa) and evidence of lymph node (LN)
metastases, and four patients with biochemical-recurrent PCa and evidence of metastatic disease solely to regional LNs on 68Ga-labeled prostate-specific membrane antigen-N,N0 bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,
http://dx.doi.org/10.1016/j.eururo.2015.04.034 0302-2838/# 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Maurer T, et al. Prostate-specific Membrane Antigen–radioguided Surgery for Metastatic Lymph Nodes in Prostate Cancer. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.04.034
EURURO-6193; No. of Pages 5 2
EUROPEAN UROLOGY XXX (2015) XXX–XXX
Table 1 – Patient characteristics and results of PSMA-ligand–radioguided surgery Patient Age (yr) Primary treatment Initial histological classification Further treatment
1 64 – –
PSA at examination (ng/ml) Suspicious lesions on PSMA-ligand PET imaging Resected tissue specimens a
244 5
PSMA-ligand RGS positive PSMA-ligand RGS negative Histological classification Location of positive LN fields (size of largest positive LN within field)
–
Histology – + 6 0 0 4 pT4 pN1 (6/25) cM0 GS10 Right side: obturator fossa (6 mm) external iliac (12 mm) internal iliac (4 mm) common iliac (2 mm) Left side: obturator fossa (8 mm) external iliac (5 mm)
2 75 RP (Jan 2010) pT2c pN0 cM0 R0 GS7 Salvage PLND (Nov 2010) RTX (May–Aug 2012_ 0.46 1
3 69 RP (Sept 2013) pT3a pN0 cM0 R0 GS7b –
4 75 RP (Feb 2006) pT3b pN0 cM0 R0 GS8 RTX (Aug 2006)
5 75 HIFU + TURP (2007) cT2 cN0 cM0 GS6
0.42 1
4.36 4
2.45 2
Histology + 1 0 pN1 (1/2)
Histology + – 1 0 0 6 pN1 (1/1)
Histology + – 5b 0 0 2 pN1 (10/20)*
Histology + 2 0 pN1 (2/2)
Paravesical right (6 mm)
Left side: obturator fossa (8 mm) external iliac (3 mm) internal iliac (9 mm) common iliac (5 mm) pararectal (11 mm)
Pararectal right (10 mm) presacral (7 mm)
– 0 1
Paravesical left (10 mm)
RTX (2009)
– 0 0
RP = radical prostatectomy; HIFU = high-intensity focused ultrasound; TURP = transurethral resection of the prostate; GS = Gleason score; PLND = pelvic lymph node dissection; RTX = radiotherapy of the prostate bed; PSA = prostate-specific antigen; PSMA = prostate-specific membrane antigen; RGS = radioguided surgery. a LNs found in tissue specimens varied in number (0–5). b Five different resected tissue specimens rated positive contained a total of ten histology-proven LN metastases.
Fig. 1 – Example results for a patient with recurrent prostate cancer to pelvic lymph nodes (patient 4). (A) Axial T2-weighted magnetic resonance imaging (MRI) shows a small (6 mm) lymph node in left the obturator fossa (arrow). (B) Axial 68Ga-labeled prostate-specific membrane antigen (PSMA)-ligand positron emission tomography (PET) and (C) axial 68Ga-PSMA-N,N0 -bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N0 -diacetic acid (HBED-CC) PET/MRI fusion images show a distinct signal for this lymph node that is highly suspicious for metastasis, subsequently confirmed by histology after radioguided surgery using an 111In-PSMA investigation and therapy agent. Note the susceptibility artifacts in the region of the hip joints caused by bilateral hip prostheses, as well as the activity of excreted 68Ga-PSMA-HBED-CC in the bladder.
N0 -diacetic acid (68Ga-PSMA-HBED-CC) positron emission tomography (PET) hybrid imaging (Table 1; Fig. 1). All patients were treated only after providing consent once they had been informed of the experimental nature of PSMA-radioguided surgery as an individual treatment concept. For PSMA-radioguided surgery, a gamma-emitting 111Inlabeled PSMA ligand was used as a radiotracer because of its favorable half-life of 2.8 d. However, owing to the instability of 111In-PSMA-HBED-CC, a 1,4,7,10-tetraazacyclododececane,1-(glutaric acid)-4,7,10-triacetic acid (DOTAGA)-conjugated peptide-based ligand targeting PSMA (PSMA-I&T; investigation and therapy) was used for 111In labeling and PSMA-radioguided surgery [1]. At 24 h before surgery,
patients received an intravenous injection of 146 MBq (mean; range 110–169 MBq) 111In-PSMA-I&T. Intraoperatively, metastatic LNs were detected using a gamma probe (Crystal Probe CXS-SG603; Crystal Photonics, Berlin, Germany) with live acoustic and visual feedback of the count rate; a higher rate indicates the presence of a radioactive hotspot (Fig. 2). In this technique the surgeon cognitively maps the count information onto the surgical field, without the possibility of image guidance. This approach was improved by the use of a freehand single-photon emission computed tomography system (declipseSPECT; SurgicEye, Munich, Germany) that allows visualization of radioactivity within a reconstructed three-dimensional (3D) image. The
Please cite this article in press as: Maurer T, et al. Prostate-specific Membrane Antigen–radioguided Surgery for Metastatic Lymph Nodes in Prostate Cancer. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.04.034
EURURO-6193; No. of Pages 5 EUROPEAN UROLOGY XXX (2015) XXX–XXX
3
Fig. 2 – (A) Intraoperative set-up for prostate-specific membrane antigen (PSMA)-radioguided surgery. (B) A gamma probe is connected to (C) a gamma counter (Crystal Probe CXS-SG603) providing acoustic and visual feedback of the count rate. The gamma probe is also equipped with spheroid optical markers (Ilumark, Feldkirchen, Germany) for three-dimensional (3D) tracking with a freehand single-photon emission computed tomography system (declipseSPECT) allowing (D) visual feedback including (E) overlay of reconstructed 3D nuclear images showing the position of hotspots corresponding to 111In-PSMA accumulation in the surgical field.
position of the gamma probe is recorded by an optical tracking system simultaneously with the count rate. Once sufficient information about the spatial distribution of the radioactivity has been acquired, a 3D image is reconstructed. This image is then co-registered with a live video stream of the surgical field to provide an augmented reality display during PSMA-radioguided surgery showing the position of hotspots corresponding to 111In-PSMA-I&T accumulation (Fig. 2). Resected tissue fractions from different anatomic sites according to preoperative 68Ga-PSMA-HBED-CC PET findings (eg, paracaval, pararectal, or internal iliac node specimen) were analyzed as separate tissue specimens. Fatty tissue from the patient served as a background reference for these measurements ex vivo. The count rate for the background reference typically ranged between 0 and 5 counts/s. Each of these tissue specimens was measured ex vivo and subsequently underwent pathologic evaluation to allow exact matching. The reference tissue was also histologically evaluated to ensure that it contained no metastatic PCa deposits. We defined tissue specimens
that showed a count rate at least double the background reference count as being radioactive-positive. Most radioactive-positive tissue specimens had count rates between 30 and 80 counts/s. Besides conventional hematoxylin-eosin staining, histologic analysis also included PSMA immunohistochemistry with a monoclonal murine PSMA antibody (clone 3E6; Dako, Hamburg, Germany) (Fig. 3). Results for gamma probe measurements (background signal [negative] vs signal above background [positive]) in resected tissue specimens ex vivo were compared to postoperative histology findings (Table 1). PSMA-radioguided surgery after administration of 111 In-labeled PSMA-I&T increased surgeon confidence in intraoperative detection and complete dissection of small metastatic lesions seen in preoperative 68Ga-PSMA-HBED-CC PET hybrid imaging. PSMA-radioguided surgery detected all PET-positive lesions in vivo that were first observed by preoperative imaging. Histologic analysis confirmed that all resected tissue specimens exhibiting positive measurements in vivo and ex vivo had PSMA-avid metastatic disease analysis (Table 1). Furthermore, PSMA-radioguided surgery
Please cite this article in press as: Maurer T, et al. Prostate-specific Membrane Antigen–radioguided Surgery for Metastatic Lymph Nodes in Prostate Cancer. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.04.034
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EUROPEAN UROLOGY XXX (2015) XXX–XXX
Fig. 3 – Example of two representative lymph node specimens from patient 4 rated as (A) strong or (B) weakly positive by ex vivo acoustic measurement during 111In-prostate-specific membrane antigen (PSMA)-radioguided surgery. Corresponding histological analysis (PSMA immunohistochemistry) revealed (C) a macrometastasis and (D) a micrometastasis of PSMA-expressing adenocarcinoma of the prostate. The macrometastasis was detected by preoperative 68Ga-PSMA-N,N0 -bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N0 -diacetic acid positron emission tomography/magnetic resonance imaging, but the micrometastasis was only detected intraoperatively by 111In-PSMA-radioguided surgery.
after 111In-PSMA-I&T administration detected additional lesions close to known tumor deposits in two of the five patients (patients 1 and 4; Table 1). These lesions corresponded to very small metastatic deposits of 2–4 mm (Fig. 3). No patient experienced complications related to intravenous administration of 111In-PSMA-I&T. 2.
Discussion
Systemic medical therapy currently represents the standard of care for patients with metastatic disease after local curative treatment for PCa. However, in patients with minimal or localized metastatic disease burden and good clinical status, salvage concepts as individual treatment regimens might represent a valid option favoring progression-free survival [2,3]. A prerequisite for these therapies is reliable and early detection of disease recurrence. For this purpose, morphologic imaging procedures such as computed tomography and magnetic resonance imaging or functional PET imaging, mostly using radiolabeled-choline derivatives, are of limited value and often underestimate the extent of metastatic spread [4,5]. 68Ga-PSMA-HBED-CC PET hybrid
imaging was recently introduced in PCa staging with promising results [6,7], and higher detection rates have been observed in patients with biochemical recurrence after radical prostatectomy compared to results with currently used tracers such as 18F-choline [8], especially for low PSA values [9]. Thus, local treatment strategies might attract even more attention in the future. Early recurrence with small metastatic deposits within fatty tissue or LNs and atypical localization might impede intraoperative detection and resection. Use of nearinfrared-fluorescence or radioguided surgery after injection of indigocyanine green or 99mTc-nanocolloid into the prostate has been proposed for guiding sentinel LN dissection in patients with primary PCa [10]. However, lymph drainage might be altered in recurrent disease and the site of tracer injection remains unclear. We described for the first time a method for direct detection of metastatic PCa lesions via molecular targeting of PSMA using 111In-labeled PSMA-I&T. Comparable to medical targeted therapies, PSMA-radioguided surgery facilitates targeted molecular surgery, as it allows specific intraoperative detection of PSMA-expressing PCa deposits. Especially for intraoperative detection of small
Please cite this article in press as: Maurer T, et al. Prostate-specific Membrane Antigen–radioguided Surgery for Metastatic Lymph Nodes in Prostate Cancer. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.04.034
EURURO-6193; No. of Pages 5 5
EUROPEAN UROLOGY XXX (2015) XXX–XXX
subcentimeter metastatic LNs and atypically located lesions, 111In-PSMA-I&T-radioguided surgery showed promising results in this feasibility study. However, larger patient cohorts and long-term follow-up are needed to confirm these initial encouraging results and to determine the possible role of this technique in clinical routine. In addition, the extent of LN dissection necessary during PSMA-radioguided surgery needs to be clarified for patients with recurrent prostate cancer. However, adequate patient selection on the basis of PSMA-targeted PET hybrid imaging, and dedicated and subtle tissue resection during 111In-PSMAI&T-radioguided surgery are mandatory.
[4] Umbehr MH, Muntener M, Hany T, Sulser T, Bachmann LM. The role of 11C-choline and 18F-fluorocholine positron emission tomography (PET) and PET/CT in prostate cancer: a systematic review and metaanalysis. Eur Urol 2013;64:106–17. [5] Evangelista L, Guttilla A, Zattoni F, Muzzio PC. Utility of choline positron emission tomography/computed tomography for lymph node involvement identification in intermediate- to high-risk prostate cancer: a systematic literature review and meta-analysis. Eur Urol 2013;63:1040–8. [6] Schafer M, Bauder-Wust U, Leotta K, et al. A dimerized urea-based inhibitor of the prostate-specific membrane antigen for
68
Ga-PET
imaging of prostate cancer. EJNMMI Res 2012;2:23. [7] Maurer T, Beer AJ, Wester HJ, Kubler H, Schwaiger M, Eiber M. Positron emission tomography/magnetic resonance imaging with
Conflicts of interest: The authors have nothing to disclose.
68
Gallium-labeled ligand of prostate-specific membrane antigen:
promising novel option in prostate cancer imaging? Int J Urol
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