Accepted Article. Runninghead: 68 Ga-PSMA PET/CT for recurrent prostate cancer

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1 Received Date : 28-Sep-2016 Revised Date : 19-Nov-2016 Accepted Date : 01-Dec-2016 Article type : Original Article Article Category: Urological Oncology Clinical impact of 68 Ga-PSMA PET/CT in prostate cancer patients with rising PSA after treatment with curative intent: preliminary analysis of a multidisciplinary approach Albisinni S, 1 Artigas C, 2 Aoun F, 1 Biaou I, 1 Grosman J, 1 Gil T, 3 Hawaux E, 1 Limani K, 1 Otte F, 4 Peltier A, 1 Sideris S, 3 Sirtaine N, 5 Flamen P 2 and van Velthoven R 1 1 Department of Urology, Institut Jules Bordet, UniversitéLibre de Bruxelles, Brussels, Belgium 2 Department of Nuclear Medicine, Institut Jules Bordet, UniversitéLibre de Bruxelles, Brussels, Belgium 3 Department of Oncology, Institut Jules Bordet, UniversitéLibre de Bruxelles, Brussels, Belgium 4 Department of Radiation Oncology, Institut Jules Bordet, UniversitéLibre de Bruxelles, Brussels, Belgium 5 Department of Pathology, Institut Jules Bordet, UniversitéLibre de Bruxelles, Brussels, Belgium Runninghead: 68 Ga-PSMA PET/CT for recurrent prostate cancer Corresponding Author: Simone Albisinni Department of Urology Jules Bordet Institute Université Libre de Bruxelles Boulevard de Waterloo 121 Brussels, Belgium Tel Fax albisinni.simone@gmail.com This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: /bju.13739

2 ABSTRACT Background: To assess the impact of 68 Ga-(HBED-CC)-PSMA (Prostate Specific Membrane Antigen) PET/CT in the clinical management of PCa patients with rising PSA after treatment with curative intent. 68 Ga-PSMA PET/CT scan is a novel molecular imaging technique in the field of prostate cancer (PCa). Methods: 131 consecutive patients were referred to our center for a 68 Ga-PSMA PET/CT in the setting of recurring prostate cancer. 11/131(8%) presented persistent PSA after radical prostatectomy, while 120/131 (92%) were referred for biochemical recurrence after surgery, radiotherapy or both. Images where performed 1 hour post-injection of 2MBq/Kg of 68 Ga- (HBED-CC)-PSMA ligand. All exams were interpreted by two experienced nuclear medicine specialists. With the results of the exam, a multidisciplinary oncology committee (MOC) reported on the treatment strategy. A positive impact in clinical management was considered if the exam determined a modification in the treatment strategy compared to MOC decision prior to PSMA. Results: All patients completed the exam with no adverse reactions. Median PSA at the time of the exam was 2.2ng/ml (range ). Overall, 68 Ga-PSMA PET/CT detected at least one lesion suspicious of PCa in 98/131 (75%) patients. An impact in management was found in 99/131patients (76%).Main modifications included continuing surveillance (withholding hormonal therapy), hormonal manipulations, stereotaxic radiotherapy, salvage radiotherapy, salvage node dissection or salvage local treatment (prostatectomy, HIFU). Conclusion: Our preliminary experience suggests that performing 68 Ga-PSMA PET/CT in PCa patients with rising PSA after treatment with curative intent can be clinically useful as it changes the treatment strategy in a significant percentage of patients. However, larger prospective trials are needed to validate our findings. Keywords: Prostate cancer, recurrence, PET, PSMA, diagnostics INTRODUCTION Prostate cancer is the most common malignancy in men and accounts for over deaths yearly in the United States (1). Although the majority of patients present with organconfined disease, about 21% of them will develop a biochemical recurrence after primary treatment (2). To date, although PSA remains an extremely accurate biomarker for recurrence, its values cannot determine the recurrence location and burden of recurrent

3 disease. Clearly, these findings are crucial in defining the management of recurrent prostate cancer: while local relapses and oligometastatic states can be targeted by focal treatment, including stereotaxic radiotherapy, salvage surgery or High Intensity Focal Ultrasound (HIFU), high volume metastases require systemic treatment via hormonal manipulations or chemotherapy(3). To date, conventional imaging studies such as CT scan, bone scintigraphy and MRI have a low diagnostic yield in patients with biochemical recurrence, especially those with low PSA levels (<20ng/ml), which represent the vast majority of cases (4). 11 C- Choline PET has been deeply investigated in this scenario with variable results, but its sensitivity is strongly dependent on the PSA level and kinetics with low detection rates for PSA values <1ng/ml (5). 68 Ga-(HBED-CC)-PSMA (Prostate Specific Membrane Antigen) PET/CT scan is a novel molecular imaging technique in the field of prostate cancer (PCa), and is currently being tested in different clinical scenarios (6 8).The test relies on the overexpression of PSMA by PCa cells. PSMA is a transmembrane type II glycoprotein, also called folate hydrolase I or glutamate carboxipeptidase II, found both in local and metastatic PCa cells (9,10).Recently, Schwenck et al. compared 68 Ga-(HBED-CC)-PSMA to 11 C-Choline PET in 67 men with recurrent PCa: the authors reported a higher sensitivity of the former exam, especially at low PSA levels, for both lymph node and bone metastases detection(11). In our tertiary referral center 68 Ga-PSMA PET/CT has been recently introduced, being the first center in Belgium and we are performing this test in patients presenting with a biochemical recurrence after primary treatment of PCa with curative intent. The aim of the current manuscript was to retrospectively evaluate the clinical impact of 68 Ga-PSMA PET/CT in these patients, according to the influence of the test on the treatment decision-making in the setting of recurrent PCa. As in our center decisions on every cancer patient are made by a multidisciplinary oncologic committee (MOC), we decided to explore the impact of the

4 results of 68 Ga-PSMA PET/CT on management strategy and treatment modifications based on this multidisciplinary approach. PATIENTS AND METHODS Beginning in January 2015 to December 2015, 154 patients referred to our tertiary center to perform a 68 Ga-PSMA PET/CT were retrospectively analyzed. The study was approved by the ethics committee of the Jules Bordet Institute, Bruxelles, Belgium and received institutional review board approval. We excluded from our analysis 20 patients in whom the exam was performed for initial local staging, 2 in whom the exam was done following treatment of castration resistant PCa and 1 in whom the test was used to characterize a lymphadenopathy (ultimately revealed as bladder cancer origin). This resulted in a cohort of 131 for final analysis. All patients underwent 68 Ga-PSMA PET/CT because of a biochemical recurrence (BCR) or disease progression of PCa after local treatment with curative intent. General characteristics of the cohort are illustrated in table 1. 11/131 (8%) patients had persistent PSA after radical prostatectomy, while 120/131 (92%) had BCR after surgery, radiotherapy, HIFU or a combination of treatments. BCR after surgery was defined by a PSA levels > 0.2 ng/ml and subsequent rise (3). After radiotherapy, HIFU or brachytherapy the Phoenix criteria (nadir + 2ng/ml) were used to define BCR (12). PSA was measured prior to PSMA PET/CT testing and had a median value of 2.2ng/ml (IQR ). The vast majority of patients had undergone radical prostatectomy as primary treatment (106/131, 81%), followed by external beam radiation therapy (17/131, 13%). 26/131 patients had already undergone a 11 C-Choline PET in another institution in the 6 months prior to 68 Ga- PSMA PET/CT: in these cases the images of the two scans were compared by our Nuclear Medicine specialists at the moment of the PSMA PET exam. The patient s case was discussed in a MOC only after 68 Ga-PSMA-PET/CT results were available. At least one

5 urologist, one medical oncologist, one pathologist, one radiation oncologist and one nuclear medicine specialist were always present during such meetings. 68 Ga-PSMA PET/CT was considered of clinical utility when its results, positive or negative, determined a modification of a preplanned therapeutic strategy or the addition of a new therapy. This includes focal treatment of oligometastases, continuing surveillance withholding ADT, early chemotherapy in high volume metastatic disease. 68 Ga-PSMA PET/CT details and interpretation Images were acquired at the Jules Bordet Institute using a General Electric (GE) Discovery 690 time of flight (TOF) PET system, 60 min after injection (range: min) of 2 MBq/kg of 68 Ga-labeled HBED-CC (with a maximum of 200 MBq). 68 Ga was obtained after elution from a 68Ge/68Ga radionuclide generator (IGG100, Eckert & Ziegler). All PET scans were acquired in three-dimensional mode with an acquisition time of 120 seconds per bed position with an overlap of 23.4 %. PET images were reconstructed with the built-in GE VUE Point Fx algorithm, a sharper resolution recovery algorithm, an ordered subset expectation maximization algorithm with three iterations and 18 subsets, and were postfiltered with a 6.8-mm full-width at half-maximum (FWHM) Gaussian function. The images were corrected for attenuation and for scatter using the CT data. CT was performed with 64 slices helical scanner (VCT; GE Medical Systems). The tension was 120 kv, and the current was modulated by the Auto-mA software with a noise index of 30 (range: ma) and ASIR. The other CT acquisition parameters were 0.5 s per CT rotation and a pitch of The CT images were reconstructed with the ASIR algorithm set at 40 %, with a matrix of ( mm pixel size) and a slice thickness of 2.5 mm. The PET matrix was pixels of mm with a slice thickness of 3.27 mm.

6 Two experienced nuclear medicine physicians (CA, PF) read independently all PSMA PET-CT images on a dedicated workstation (Advantage Workstation; GE Healthcare) using the commercial PET VCAR software AW Server 3.2. Any focal uptake of 68 Ga-PSMA ligand at least 2 times higher than the surrounding background and not associated with physiologic uptake was considered suggestive for malignancy. Statistical analysis Descriptive statistics were used to analyze our outcome data. Differences in positive exam rates across various PSA values were explored via χ 2 test. Difference in median PSA value across groups in whom 68 Ga-PSMA PET/CT did and did not modify treatment strategy was explored with Mann-Whitney test. All analyses and graphics were performed using the Stata software version 12. A two-sided p < 0.05 defined statistical significance. RESULTS All 131 men completed the exam with no adverse events being recorded. Globally, 68 Ga-PSMA PET/CT was positive for at least 1 lesion suspect of PCa metastasis in 98/131 patients (75%). As shown in graph 1, PSMA results were significantly more likely to be positive with increasing values of PSA (p<0.001), and in all patient with PSA values 10ng/ml at least one lesion was detected. Indeed, 68 Ga-PSMA PET/CT was found to be positive in 45% of patients with PSA<0.5ng/ml, in 75% of men with PSA 0.5-1ng/ml, in 83% for PSA values ng/ml and in 95% of those men with PSA ng/ml (Figure 1). 68 Ga-PSMA PET/CT discussed in the MOC determined modification in treatment strategy in 99/131 (76%) men, modifying the first proposed therapeutic approach. Of these 99 patients, 68 had a positive while 31 had a negative 68 Ga-PSMA PET/CT scan. Such

7 modifications are illustrated in table 2: indeed the most common decision was to avoid androgen deprivation therapy (ADT) (63/99, 64%) and undergo clinical surveillance (22/99, 22%), stereotaxic radiotherapy (12/99, 12%) or salvage radiotherapy (11/99, 11%). Salvage radiotherapy was avoided in 22/99 (22%) men, in favor of surveillance, ADT or salvage node dissection (table 2). ADT was instead implemented in 13/99 (13%) patients initially planned for local treatment or surveillance. Treatment of oligometastatic disease was proposed and performed in 34 men (14 men underwent stereotaxic radiotherapy, 10 salvage lymph node dissection, 8 salvage HIFU and 2 salvage prostatectomy). Concerning the 32/131 (24%) ( patients in whom the PSMA PET/CT did not modify the planned treatment, this group included 11/32 (34%) men in whom pelvic irradiation was already planned; in these patients PSMA PET/CT confirmed the local recurrence which was either already seen on MRI or suspected according to predictive factors (3). In 16/32 (50%) men, a complete androgen blockage was already planned given a rapidly ascending PSA, and confirmed by the PSMA PET/CT due to detection of multiple metastases or because of patient being unfit for focal treatment of oligometastases. Finally, in 2 patients in whom a stereotaxic radiotherapy was proposed, the dosimetric CT was unable to identify the target lesion and as such it was not possible to deliver the treatment. Of note, PSA level did not differ significantly (p=0.14) across patients in whom PSMA PET/CT did or did not modify treatment strategy. DISCUSSION Biochemical recurrence can occur in over one third of the patients after primary treatment for PCa (13), with most of these men then developing clinical metastases within 5-8 years. As to date most imaging exams are unable to identify the lesion responsible for the PSA recurrence at an early stage with low PSA values, men are frequently treated by systemic hormonal castration, with heavy metabolic consequences, reduced quality of life,

8 and possibly increased cardiovascular mortality (14). Moreover, the identification of a low volume metastatic state, or oligometastases, may prompt the use of focal treatments (15), reducing morbidity, delaying hormone treatment and possibly improving oncologic outcomes. In this scenario, an accurate diagnostic tool, capable of guiding treatment, is of crucial importance and can significantly modify our conception and management of recurrent PCa (16). In the current study we evaluated the real life, clinical utility of performing a 68 Ga- PSMA PET/CT in patients with biochemical recurrence after primary treatment of prostate cancer. The test was useful in 76% of patients, determining an impact on therapeutic decision-making. Moreover, even in those patients in whom the results of the imaging test did not modify the management, they frequently confirmed the decided strategy, supporting the multidisciplinary decision-making process. 68 Ga-PSMA PET/CT is a novel molecular imaging technique currently explored in the field of prostate cancer. Fendler et al. evaluated the test in the local staging of prostate cancer, and found that 68 Ga-PSMA PET detected seminal vesicle invasion with a 86% accuracy and extracapsular extension with a 71% accuracy (17). Moreover, 68 Ga-PSMA PET/CT may be used in combination with multi-parametric MRI in the local staging of PCa, increasing specificity and positive predictive value for significant cancer, as reported by Rhee et al (18). Concerning clinical management and decision making, Dewes et al. analyzed 15 patients who were scheduled to undergo definitive local radiotherapy (19). They reported a change in clinical TNM stage in over 50 of patients, and a modification of irradiation plan in one third, mainly concerning lymph node irradiation. Morigi et al. performed a prospective trial on 38 men who underwent both 68 Ga-PSMA and 18 F-fluoromethylcholine PET in the setting of PSA recurrence after primary treatment of PCa. In patients with low PSA values (0.5-2ng/ml), detection rate was 69% for 68 Ga-PSMA versus 31% for 18 F-fluoromethylcholine. Moreover, the authors reported an impact of the tests on clinical management in 63% of patients, mainly

9 due to the results of 68 Ga-PSMA PET(20). Rauscher et al. evaluated the accuracy of 68 Ga- PSMA PET compared to morphological imaging to assess lymph node metastases in patients with recurrent prostate cancer(21). 48 men underwent preoperative 68 Ga-PSMA PET and then salvage lymphadenectomy: 68 Ga-PSMA PET detected lymph node metastases in in 53/68 pathologically proven metastatic lymph node fields (77.9%) while morphological imaging was positive in only 18/67 (26.9%). Moreover, the lymph nodes detected by 68 Ga-PSMA PET were smaller (mean 8.3mm) compared to those detected by conventional CT or MRI (mean 13mm).Similarly, Giesel et al reported a significant increase in detection of pathologic pelvic lymph nodes in patients with recurrent PCa via a 68 Ga-PSMA PET exam compared to conventional imaging: 66% of patients identified by 68 Ga-PSMA PET in fact were negative on conventional imaging modalities (22). In the setting of recurrent PCa, the largest studies to date have been published by Afshar et al and by Eiber et al, reporting promising results in 319 and 248 men, respectively. In the first study, the investigators retrospectively analyzed 68 Ga-PSMA PET results in 319 men with recurrent PCa: the exam detected at least one lesion in 83% of cases and, in the subset for which histology was available, the authors described a sensitivity of 77% and a specificity of 100%(23). Lesion detection was correlated to PSA level at the moment of the exam. Eiber et al. retrospectively evaluated 248 men with PCa recurrence after radical prostatectomy (24); 90% had at least one suspicious lesion and a positive correlation with serum PSA was also found, as in the current study. In addition, multiple case reports are documenting the utility of 68 Ga-PSMA PET/CT in the identification of oligometastatic PCa (25,26); nonetheless, different pathologic conditions can present with PSMA uptake leading to false positives (27). Finally, Pyka et al. compared PSMA PET to bone scintigraphy in the detection of bone metastases. In their study examining 126 men (of which 76 were diagnosed with metastatic bone disease), PSMA PET

10 significantly outperformed bone scintigraphy, with overall sensitivity and specificity of % and %, compared to % sensitivity and a % specificity of bone scintigraphy (p<0.001) (28). In the present study 68 Ga-PSMA PET/CT detected at least one lesion suspected of PCa recurrence in 75% of our patients. This is in line with previously reported data in men with recurrent PCa, with detection rates ranging from 71% to 89.5%[17, 18], although detection remains dependent on PSA levels at the time of PET examination (29,30). Of note, 20% of our patients had PSA levels <0.5ng/ml, and half of those who overall presented a negative scan where within this group. It remains poorly understood why some patients have negative PSMA exams, as nearly all PCas express PSMA(31): different hypotheses include dedifferentiated neuroendocrine cancers, recurrences situated close to the urinary tract and millimetric recurrences below the resolution of the PET scans(23).in the present study we focused our efforts in exploring the clinical impact PSMA PET/CT had in the real life scenario of recurrent PCa patients. Indeed, an exam is useful if its performance modifies patient management, possibly with an amelioration of his clinical condition and outcome. We found a modification of clinical management in 76% of the men who underwent PSMA PET/CT. Clearly, the long-term impact of the clinical decision made for our patients remains to be demonstrated. Nonetheless, in 57/131 (44%) we have been able to withhold or delay androgen blockage, probably ameliorating their quality of life and not endangering their oncologic outcomes (14). Moreover, although the exam did not literally change the therapeutic strategy in other patients, as in those who were already scheduled for prostatic fossa irradiation (11/131), we believe it is reassuring to confirm the decided attitude and target lesion with an imaging exam. This is also helpful in counseling the patient and may reduce useless irradiations or hormonal treatments. A radiotherapy boost to the PSMA positive lesion could also be administered(32).

11 Our study is not devoid of limitations. Indeed one could argue that the treatment of oligometastatic disease has not yet proven to yield favorable long-term outcomes for PCa (33). Nonetheless, delaying hormone therapy is crucial in order to reduce cardiovascular morbidity and mortality(14). Moreover, the study is retrospective in nature, thus its results must be interpreted with caution. Although MOC members were blinded to the results of the 68 Ga-PSMA PET/CT when giving the primary treatment choice, the fact of knowing that an additional potentially game-changing test had been performed may have biased our results and increased our rates of treatment modifications. Finally, our cohort was not homogeneous, as patients underwent different types of primary cancer treatment (surgery, radiotherapy, HIFU); nonetheless, this represents a real life situation in which every day clinical choices are always applied to a heterogeneous cohort of patients. Adapting our therapeutic decisions according to a more sensitive and specific imaging technique seems the right step for a better personalized therapeutic approach. However, if this approach of treatment decision based on 68 Ga-PSMA PET/CT is beneficial for the patient in terms of overall and progression-free survival is something that needs to be addressed in further large prospective trails. Conclusions In this retrospective study, the use of 68 Ga-PSMA PET/CT in the setting of recurrent PCa after local treatment with curative intent determined a modification of planned medical/surgical therapeutic strategy in 76% of patients. These modifications mainly regarded surveillance, hormonal manipulations, stereotaxic radiotherapy and salvage treatments. Further larger and prospective studies are necessary to confirm our findings. ACKNOWLEDGMENTS None

12 COI statement The authors declare no conflict of interest Funding None REFERENCES 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016.CA Cancer J Clin Jan;66(1): van den Bergh RCN, van Casteren NJ, van den Broeck T, Fordyce ER, Gietzmann WKM, Stewart F, et al. Role of Hormonal Treatment in Prostate Cancer Patients with Nonmetastatic Disease Recurrence After Local Curative Treatment: A Systematic Review. Eur Urol Dec 12; 3. Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol Feb;65(2): Beresford MJ, Gillatt D, Benson RJ, Ajithkumar T. A systematic review of the role of imaging before salvage radiotherapy for post-prostatectomy biochemical recurrence.clinoncol R CollRadiol G B Feb;22(1): Treglia G, Ceriani L, Sadeghi R, Giovacchini G, Giovanella L. Relationship between prostatespecific antigen kinetics and detection rate of radiolabelled choline PET/CT in restaging prostate cancer patients: a meta-analysis. ClinChem Lab Med May;52(5): van Leeuwen PJ, Stricker P, Hruby G, Kneebone A, Ting F, Thompson B, et al. 68Ga-PSMA has high detection rate of prostate cancer recurrence outside the prostatic fossa in patients being considered for salvage radiation treatment. BJU Int Dec 18; 7. Maurer T, Gschwend JE, Rauscher I, Souvatzoglou M, Haller B, Weirich G, et al. Diagnostic Efficacy of (68)Gallium-PSMA-PET compared to Conventional Imaging in Lymph Node Staging of of 130 consecutive Patients with Intermediate to High-Risk Prostate Cancer. J Urol Dec 9; 8. Verburg FA, Pfister D, Heidenreich A, Vogg A, Drude NI, Vöö S, et al. Extent of disease in recurrent prostate cancer determined by [(68)Ga]PSMA-HBED-CC PET/CT in relation to PSA levels, PSA doubling time and Gleason score. Eur J Nucl Med Mol Imaging Nov 12; 9. Mannweiler S, Amersdorfer P, Trajanoski S, Terrett JA, King D, Mehes G. Heterogeneity of prostate-specific membrane antigen (PSMA) expression in prostate carcinoma with distant metastasis. PatholOncol Res POR Jun;15(2):

13 10. Horoszewicz JS, Kawinski E, Murphy GP. Monoclonal antibodies to a new antigenic marker in epithelial prostatic cells and serum of prostatic cancer patients. Anticancer Res Oct;7(5B): Schwenck J, Rempp H, Reischl G, Kruck S, Stenzl A, Nikolaou K, et al. Comparison of (68)Galabelled PSMA-11 and (11)C-choline in the detection of prostate cancer metastases by PET/CT. Eur J Nucl Med Mol Imaging Aug 24; 12. Roach M, Hanks G, Thames H, Schellhammer P, Shipley WU, Sokol GH, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J RadiatOncol Jul;65(4): Teeter AE, Presti JC, Aronson WJ, Terris MK, Kane CJ, Amling CL, et al. Do nomograms designed to predict biochemical recurrence (BCR) do a better job of predicting more clinically relevant prostate cancer outcomes than BCR? A report from the SEARCH database group.urology Jul;82(1): Hershman DL, Unger JM, Wright JD, Ramsey S, Till C, Tangen CM, et al. Adverse Health Events Following Intermittent and Continuous Androgen Deprivation in Patients With Metastatic Prostate Cancer. JAMA Oncol Dec 23; Aoun F, Peltier A, van Velthoven R. A comprehensive review of contemporary role of local treatment of the primary tumor and/or the metastases in metastatic prostate cancer.biomed Res Int. 2014;2014: Aoun F, Kourie HR, Artigas C, Roumeguère T. Next revolution in molecular theranostics: personalized medicine for urologic cancers. Future OncolLond Engl. 2015;11(15): Fendler WP, Schmidt DF, Wenter V, Thierfelder KM, Zach C, Stief C, et al. 68Ga-PSMA-HBED-CC PET/CT detects location and extent of primary prostate cancer. J Nucl Med Off PublSocNucl Med Jun 3; 18. Rhee H, Thomas P, Shepherd B, Greenslade S, Vela I, Russell PJ, et al. PSMA PET May Improve the Diagnostic Accuracy of mpmri in Localised Prostate Cancer as Confirmed by Whole-Mount Histopathology. J Urol May 21; 19. Dewes S, Schiller K, Sauter K, Eiber M, Maurer T, Schwaiger M, et al. Integration of (68)Ga- PSMA-PET imaging in planning of primary definitive radiotherapy in prostate cancer: a retrospective study. RadiatOncolLond Engl. 2016;11(1): Morigi JJ, Stricker PD, van Leeuwen PJ, Tang R, Ho B, Nguyen Q, et al. Prospective Comparison of 18F-Fluoromethylcholine Versus 68Ga-PSMA PET/CT in Prostate Cancer Patients Who Have Rising PSA After Curative Treatment and Are Being Considered for Targeted Therapy. J Nucl Med Off PublSocNucl Med Aug;56(8): Rauscher I, Maurer T, Beer AJ, Graner F-P, Haller B, Weirich G, et al. Value of 68Ga-PSMA HBED-CC PET for the assessment of lymph node metastases in prostate cancer patients with biochemical recurrence: comparison with histopathology after salvage lymphadenectomy. J Nucl Med Off PublSocNucl Med Jun 3;

14 22. Giesel FL, Fiedler H, Stefanova M, Sterzing F, Rius M, Kopka K, et al. PSMA PET/CT with Gluurea-Lys-(Ahx)-[ 68 Ga(HBED-CC)] versus 3D CT volumetric lymph node assessment in recurrent prostate cancer. Eur J Nucl Med Mol Imaging Nov;42(12): Afshar-Oromieh A, Avtzi E, Giesel FL, Holland-Letz T, Linhart HG, Eder M, et al. The diagnostic value of PET/CT imaging with the (68)Ga-labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging Feb;42(2): Eiber M, Maurer T, Souvatzoglou M, Beer AJ, Ruffani A, Haller B, et al. Evaluation of Hybrid 68 Ga-PSMA Ligand PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy. J Nucl Med Off PublSocNucl Med May;56(5): O Kane DB, Lawrentschuk N, Bolton DM. Prostate cancer nodal oligometastasis accurately assessed using prostate-specific membrane antigen positron emission tomography-computed tomography and confirmed histologically following robotic-assisted lymph node dissection. Urol Ann Jun;8(2): Queiroz MA, Viana P, Santos A, Bastos D, Etchebehere E, Cerri G. Clinical Impact of 68Ga-PSMA PET/CT in a Patient With Biochemical Recurrence of Prostate Cancer. ClinNucl Med Jun 6; 27. Artigas C, Alexiou J, Garcia C, Wimana Z, Otte F-X, Gil T, et al. Paget bone disease demonstrated on (68)Ga-PSMA ligand PET/CT. Eur J Nucl Med Mol Imaging Jan;43(1): Pyka T, Okamoto S, Dahlbender M, Tauber R, Retz M, Heck M, et al. Comparison of bone scintigraphy and 68Ga-PSMA PET for skeletal staging in prostate cancer. Eur J Nucl Med Mol Imaging [Internet] Jun 12 [cited 2016 Jun 15]; Available from: Sachpekidis C, Eder M, Kopka K, Mier W, Hadaschik BA, Haberkorn U, et al. (68)Ga-PSMA-11 dynamic PET/CT imaging in biochemical relapse of prostate cancer. Eur J Nucl Med Mol Imaging Jan 12; 30. Ceci F, Uprimny C, Nilica B, Geraldo L, Kendler D, Kroiss A, et al. (68)Ga-PSMA PET/CT for restaging recurrent prostate cancer: which factors are associated with PET/CT detection rate? Eur J Nucl Med Mol Imaging Jul;42(8): Ross JS, Sheehan CE, Fisher HAG, Kaufman RP, Kaur P, Gray K, et al. Correlation of primary tumor prostate-specific membrane antigen expression with disease recurrence in prostate cancer. Clin Cancer Res Off J Am Assoc Cancer Res Dec 15;9(17): Shakespeare TP. Effect of prostate-specific membrane antigen positron emission tomography on the decision-making of radiation oncologists. RadiatOncolLond Engl. 2015;10(1): Ost P, Bossi A, Decaestecker K, De Meerleer G, Giannarini G, Karnes RJ, et al. Metastasisdirected therapy of regional and distant recurrences after curative treatment of prostate cancer: a systematic review of the literature. EurUrol May;67(5): Figure Legends. Figure 1. 68Ga PSMA PET/CT results according to PSA value

15 Table 1. General characteristics of the population Total number of patients 131 Age (years) PSA (ng/ml) BMI (kg/m 2 ) Median (IQR) Mean±SD Median (IQR) Mean±SD Median (IQR) Mean±SD ADT at time of PSMA No Yes Reason for PSMA Persistent Post-operative PSA BCR after Surgery BCR after Surgery and Radiotherapy BCR after Radiohormonotherapy BCR after HIFU/brachytherapy Primary treatment for PCa Radical Prostatectomy EBRT HIFU/Brachytherapy TNM Gleason Score Previous Salvage treatment Time to BCR (months) ct1 ct2 ct3 ct4 pt1 pt2 pt3 pt4 68 (62-75) 69±8 2.2 ( ) 5.4± ( ) 26.5± (8%) 37 (28%) 61 (47%) 14 (11%) 8 (6%) 106 (81%) 17 (13%) 8 (6%) 8 (6%) 4 (3%) 4 (3%) 2 (2%) 3 (2%) 31 (24%) 56 (42%) 1 (1%) Unknown 22 (17%) Unknown No Yes Median (IQR) Mean±SD 19 (15%) 40 (31%) 19 (15%) 29 (22%) 24 (18%) 59 (45%) 72 (55%) 50 (30-87) 66±57

16 Table 2. Treatment modifications according to 68 Ga-PSMA PET/CT results in 99 patients Planned treatment (n) Modification according to PSMA Total N patients ADT (22) Salvage radiotherapy (7) Surveillance 29 Salvage radiotherapy (7) 13 Salvage HIFU (3) ADT Antiandrogen monotherapy (1) Stereotaxic radiotherapy (1) Surveillance (1) ADT (12) 14 2 nd line hormonal therapy* (1) Stereotaxic radiotherapy Stereotaxic radiotherapy on incorrect site (1) ADT (8) 13 Antiandrogen monotherapy (1) Salvage radiotherapy Salvage HIFU (1) ADT (5) Salvage pelvic node dissection 10 Salvage radiotherapy (5) ADT (8) Salvage HIFU 8 ADT (2) ADT+Chemotherapy 4 2 nd line hormonal therapy* (2) ADT (2) Salvage prostatectomy 2 Salvage radiotherapy (3) Modification in radiotherapy target 3 or addition stereotaxic boost 2 nd line hormonal therapy* (1) Radium Surveillance (1) 2 nd line hormonal therapy* 1 ADT (1) ADT+Vertebral fixation and palliative radiotherapy 1 *Abiraterone, Enzalutamide; ADT: Androgen deprivation therapy; HIFU: High Intensity Focal Ultrasound.

17 Table 3. Patients (n=32) in which PSMA did NOT modify preplanned therapeutic strategy Complete androgen blockage 16 administered anyway* Salvage radiotherapy already 11 planned according to MRI/predictive factors 3 Oligometastasis on PSMA not 2 visualized on imaging techniques used for radiotherapy planing Lesion seen on MRI and Bone 1 scan, PSMA only confirmed planned stereotaxic radiotherapy Other ** 2 3 Cfr reference 3 *Rapidly progressing PSA or patient unfit for focal treatment **Patient treated for other malignancy; discordance between PSMA and MRI

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