Radioguidance for LN dissection in BCR 1

JNM Hot topics 1

Entering the era of molecular-targeted precision surgery in 2

recurrent prostate cancer 3

4

Tobias Maurer1,2, Fijs W. B. van Leeuwen3,4, Margret Schottelius5, 5

Hans-Jürgen Wester5, Matthias Eiber6 6

7

1 Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, 8

Germany 9

2 Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, 10

Hamburg, Germany 11

3 Interventional Molecular Imaging Laboratory, department of Radiology, Leiden 12

University Medical Centre, Leiden, the Netherlands. 13

4 Department of Urology, Antoni van Leeuwenhoek Hospital – the Netherlands 14

Cancer Institute, Amsterdam, the Netherlands. 15

5 Pharmaceutical Radiochemistry, Technical University of Munich, Munich, 16

Germany 17

6 Department of Nuclear Medicine, Technical University of Munich, Munich, 18

Germany 19

Journal of Nuclear Medicine, published on December 20, 2018 as doi:10.2967/jnumed.118.221861

Radioguidance for LN dissection in BCR 2

Corresponding author: 20

PD Dr. med. Tobias Maurer 21

Martini-Klinik, Prostate-Cancer Center, University Hospital Hamburg-Eppendorf, 22

Martinistraße 52 Gebäude Ost 46 23

20246 Hamburg 24

Germany 25

t.maurer@uke.de 26

www.martini-klinik.de 27

www.martini-klinik.de/dr-maurer 28

Tel.: +49-40-7410-51300 29

FAX: +49-40-7410-51323 30

e-mail: t.maurer@uke.de 31

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Word count: 763 33

34

Keywords: radioguided surgery, PSMA, salvage surgery, fluorescence, hybrid tracer 35

36

Abbreviations: 37

PET: positron emission tomography 38

PSA: prostate-specific antigen 39

PSMA: prostate-specific membrane antigen 40

41

Conflict of Interest: 42

All authors declare no conflict of interest. 43

Radioguidance for LN dissection in BCR 3

Precision medicine is currently entering the surgical theater with PSMA-radioguided 44

surgery representing an excellent example combining the expertise of 45

radiopharmacists, nuclear medicine imaging specialists and uro-oncological 46

surgeons. 47

In recent years novel techniques and tracer concepts in nuclear medicine 48

have had tremendous impact on prostate cancer imaging (1). In particular, PET 49

imaging utilizing agents targeting the prostate-specific membrane antigen (PSMA) 50

for the detection of prostate cancer lesions has clearly emerged as the preferred 51

imaging standard in patients with rising prostate-specific antigen (PSA) values after 52

primary curative treatment (2,3). Especially in early biochemical recurrent prostate 53

cancer bot, patients and treating physicians, face the difficult decision whether 54

secondary local therapy promising potential cure is feasible or if systemic treatment 55

needs be initiated. Here, PSMA-ligand PET enables detection of prostate cancer 56

lesions even at low PSA values below 1ng/mL in 52 - 64% of patients (4,5). With the 57

information obtained by PSMA-ligand PET at hand, the treatment plan changed in 58

62% of patients in comparison to conventional imaging as demonstrated by a recent 59

prospective Australian study in 260 men (6). Moreover, in a recent meta-analysis by 60

Han and colleagues comprising 15 studies with 1163 patients (primarily patients with 61

biochemical recurrence) the treatment management was also modified in 54% of 62

cases by the results of PSMA-ligand PET, with a clear shift toward targeted therapy 63

options (7). However, if salvage surgery is considered, the successful detection and 64

removal of cancerous lesions with a minimum of side effects is crucial. As these 65

mostly small and often atypically located metastatic lymph nodes are difficult to 66

identify within a surgically pretreated or pre-irradiated region, surgical guidance is 67

highly appreciated. 68

In the past, surgical guidance by radioguided approaches have been 69

successfully implemented in the treatment of prostate cancer (8). Wawroschek and 70

colleagues were the first to introduce the concept of sentinel lymph node dissection 71

using 99mTc-nanocolloid (9). After local injection within the prostate 99mTc-nanocolloid 72

follows the lymphatic drainage and intraoperative gamma probe tracing help to 73

identify radioactive lymph nodes. These first draining (sentinel) lymph nodes 74

Radioguidance for LN dissection in BCR 4

represent the first sites that may harbor metastatic prostate cancer cells. The 75

surgical guidance aspects of this procedure were extended with intraoperative 76

fluorescence imaging following the development of so-called hybrid-tracers that not 77

only contain a radiolabel, but also contain a fluorescent label (e.g. indocyanine-78

green-99mTc-nanocolloid) (10). However, lymphatic mapping, although able to 79

identify < 2mm micrometastases, is not targeting a specific biomarker expressed by 80

tumor cells. Furthermore, after previous surgery, in contrast to the primary setting, 81

the lymphatic drainage is altered and may interfere with procedures relying on intact 82

lymphatic vessel architecture. 83

Based on its excellent specificity for prostate cancer tissue, PSMA represents 84

an ideal molecular target in metastatic prostate cancer – not only for imaging, but 85

also for systemic therapy using targeted tracers labeled with beta- or alpha-emitting 86

nuclides. The previously mentioned need for surgical guidance has triggered the 87

subsequent development of gamma-emitting agents for targeted surgical 88

interventions (11). The concept of PSMA-radioguided surgery utilizing 111Indium- or 89 99mTc-labeled PSMA-ligands has been successfully introduced into clinical practice 90

(12-15). Briefly, after preoperative intravenous injection metastatic lesions 91

(previously identified using PSMA-PET) can be detected by intraoperative gamma 92

probe measurements during salvage surgery procedures (Fig. 1). This intraoperative 93

guidance is not only of use to identify lesions in situ, but also for immediate 94

confirmation of successful removal by ex vivo gamma probe measurements at the 95

operating room table. Furthermore, it can guide the surgeon with respect to the 96

extent of the surgical dissection by intraoperative detection of additional small-sized 97

lesions. First results indicate that such a targeted approach is superior to 98

conventional salvage surgery (16). However, microscopic disease, which is both 99

negative on preoperative PSMA-ligand PET as well as not detectable during PSMA-100

radioguided surgery, still remains a challenge. 101

Recent innovative developments in PSMA-targeted surgical approaches 102

focus on hardware as well as tracer design. Just recently tethered DROP-IN gamma 103

probes that facilitate radioguided robot-assisted surgery have found their way to the 104

clinic (17). This enables minimal-invasive and potentially less harmful surgical 105

Radioguidance for LN dissection in BCR 5

interventions. Additionally, hybrid PSMA-targeted tracers bearing both a radioactive 106

label and a fluorescent dye are currently under investigation (18). It is anticipated 107

that this refinement further enhances the sensitivity and accuracy of prostate cancer 108

targeted surgical interventions (19). The surgeon is able not only to track prostate 109

cancer-infested lymph nodes via nuclear medicine modalities, but additionally 110

receives direct visual feed-back of prostate cancer-infested lymph nodes upon 111

further preparation. 112

In conclusion, although long-term outcome data is still being acquired, 113

molecular-targeted precision surgery in recurrent prostate cancer utilizing PSMA has 114

the potential to further refine and improve the armentarium in our fight against 115

prostate cancer. 116

Radioguidance for LN dissection in BCR 6

References: 117

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1. De Visschere PJL, Standaert C, Futterer JJ, et al. The role of imaging in 119 patients with early recurrent prostate cancer: systematic review. Eur Urol Oncol. in 120 press. 121 122 2. Maurer T, Eiber M, Schwaiger M, Gschwend JE. Current use of PSMA-PET 123 in prostate cancer management. Nat Rev Urol. 2016;13:226-235. 124 125 3. Li R, Ravizzini GC, Gorin MA, et al. The use of PET/CT in prostate cancer. 126 Prostate Cancer Prostatic Dis. 2018;21:4-21. 127 128 4. Rauscher I, Duwel C, Haller B, et al. Efficacy, Predictive Factors, and 129 Prediction Nomograms for (68)Ga-labeled Prostate-specific Membrane Antigen-130 ligand Positron-emission Tomography/Computed Tomography in Early 131 Biochemical Recurrent Prostate Cancer After Radical Prostatectomy. Eur Urol. 132 2018;73:656-661. 133 134 5. Afshar-Oromieh A, Holland-Letz T, Giesel FL, et al. Diagnostic performance 135 of (68)Ga-PSMA-11 (HBED-CC) PET/CT in patients with recurrent prostate cancer: 136 evaluation in 1007 patients. Eur J Nucl Med Mol Imaging. 2017;44:1258-1268. 137 138 6. Roach PJ, Francis R, Emmett L, et al. The Impact of (68)Ga-PSMA PET/CT 139 on Management Intent in Prostate Cancer: Results of an Australian Prospective 140 Multicenter Study. J Nucl Med. 2018;59:82-88. 141 142 7. Han S, Woo S, Kim YJ, Suh CH. Impact of (68)Ga-PSMA PET on the 143 Management of Patients with Prostate Cancer: A Systematic Review and Meta-144 analysis. Eur Urol. 2018;74:179-190. 145 146 8. van Leeuwen FWB, Winter A, van der Poel HG, et al. Image guided surgery 147 technologies for lymphatic metastases in prostate cancer. Nat Rev Urol. in press. 148 149 9. Wawroschek F, Vogt H, Weckermann D, Wagner T, Harzmann R. The 150 sentinel lymph node concept in prostate cancer - first results of gamma probe-151 guided sentinel lymph node identification. Eur Urol. 1999;36:595-600. 152 153 10. van den Berg NS, Valdes-Olmos RA, van der Poel HG, van Leeuwen FW. 154 Sentinel lymph node biopsy for prostate cancer: a hybrid approach. J Nucl Med. 155 2013;54:493-496. 156 157 11. Eiber M, Fendler WP, Rowe SP, et al. Prostate-Specific Membrane Antigen 158 Ligands for Imaging and Therapy. J Nucl Med. 2017;58:67s-76s. 159 160

Radioguidance for LN dissection in BCR 7

12. Schottelius M, Wirtz M, Eiber M, Maurer T, Wester HJ. [(111)In]PSMA-I&T: 161 expanding the spectrum of PSMA-I&T applications towards SPECT and 162 radioguided surgery. EJNMMI Res. 2015;5:68. 163 164 13. Maurer T, Weirich G, Schottelius M, et al. Prostate-specific membrane 165 antigen-radioguided surgery for metastatic lymph nodes in prostate cancer. Eur 166 Urol. 2015;68:530-534. 167 168 14. Robu S, Schottelius M, Eiber M, et al. Preclinical Evaluation and First 169 Patient Application of 99mTc-PSMA-I&S for SPECT Imaging and Radioguided 170 Surgery in Prostate Cancer. J Nucl Med. 2017;58:235-242. 171 172 15. Maurer T, Robu S, Schottelius M, et al. (99m)Technetium-based Prostate-173 specific Membrane Antigen-radioguided Surgery in Recurrent Prostate Cancer. Eur 174 Urol. 2018. 175 176 16. Knipper S, Tilki D, Mansholt J, et al. Metastases-yield and Prostate-specific 177 Antigen Kinetics Following Salvage Lymph Node Dissection for Prostate Cancer: A 178 Comparison Between Conventional Surgical Approach and Prostate-specific 179 Membrane Antigen-radioguided Surgery. Eur Urol Focus. 2018. 180 181 17. Meershoek P, van Oosterom MN, Simon H, et al. Robot-assisted 182 laparoscopic surgery using DROP-IN radioguidance: first-in-human translation. Eur 183 J Nucl Med Mol Imaging. 2018. 184 185 18. Schottelius M, Wurzer A, Wissmiller K, et al. Synthesis and preclinical 186 characterization of the PSMA-targeted hybrid tracer PSMA-I&F for nuclear and 187 fluorescence imaging of prostate cancer. J Nucl Med. 2018. 188 189 19. Baranski AC, Schafer M, Bauder-Wust U, et al. PSMA-11-Derived Dual-190 Labeled PSMA Inhibitors for Preoperative PET Imaging and Precise Fluorescence-191 Guided Surgery of Prostate Cancer. J Nucl Med. 2018;59:639-645. 192

Radioguidance for LN dissection in BCR 8

Figure 1 193

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Radioguided surgery after injection of 99mTc-labeled PSMA tracer in a patient with 195

recurrent prostate cancer: Preoperative 68Ga-PSMA-11 PET/MR fusion image (A) 196

shows an intense signal projecting on a subcentimer presacral lymph node (B). 197

Intraoperative measurements with a wireless gamma probe detects distinct 99mTc-198

PSMA tracer accumulation confirmed by ex vivo measurement (C). 199