The Prostate

Prostate-Specific Membrane Antigen-Based Imaging in Prostate Cancer: Impact on Clinical Decision Making Process Mehmet Onur Demirkol,1,2 Ömer Acar,3* Burcu Uçar,2 Sultan Rana Ramazano glu,4 5 3,6 YeSsim Sa glıcan, and Tarık Esen 1

Koc University, School of Medicine, Department of Nuclear Medicine and Molecular Imaging, Istanbul, Turkey 2 VKF American Hospital, Department of Nuclear Medicine and Molecular Imaging, Istanbul, Turkey 3 Koc University, School of Medicine, Department of Urology, Istanbul, Turkey 4 VKF American Hospital, Department of Pathology, Istanbul, Turkey 5 Acıbadem University, School of Medicine, Department of Pathology, Istanbul, Turkey 6 VKF American Hospital, Department of Urology, Istanbul, Turkey

BACKGROUND. There is an ongoing need for an accurate imaging modality which can be used for staging purposes, metastatic evaluation, predicting biologic aggresiveness and investigating recurrent disease in prostate cancer. Prostate specific membrane antigen, given its favorable molecular characteristics, holds a promise as an ideal target for prostate cancer-specific nuclear imaging. In this study, we evaluated our initial results of PSMA based PET/CT imaging in prostate cancer. METHODS. A total of 22 patients with a median age and serum PSA level of 68 years and 4.15 ng/ml, respectively underwent Ga-68 PSMA PET/CT in our hospital between Februrary and August 2014. Their charts were retrospectively reviewed in order to document the clinical characteristics, the indications for and the results of PSMA based imaging and the impact of Ga-68 PSMA PET/CT findings on disease management. RESULTS. The most common indications were rising PSA after local  adjuvant treatment followed by staging and metastatic evaluation before definitive or salvage treatment. All except 2 patients had prostatic  extraprostatic PSMA positive lesions. For those who had a positive result; treatment strategies were tailored accordingly. Above the PSA level of 2 ng/ ml, none of the PSMA based nuclear imaging studies revealed negative results. CONCLUSIONS. PSMA based nuclear imaging has significantly impacted our way of handling patients with prostate cancer. Its preliminary performance in different clinical scenarios and ability to detect lesions even in low PSA values seems fairly promising and deserves to be supplemented with further clinical studies. Prostate # 2015 Wiley Periodicals, Inc.

KEY WORDS:

prostate; cancer; nuclear imaging; ligand

INTRODUCTION Prostate cancer (Pca) is a major health concern, especially in developed countries with their greater proportion of elderly men in the general population. The incidence is highest in Northern and Western Europe (>200 per 100,000), while rates in Eastern and Southern Europe have showed a continuous increase [1]. ß 2015 Wiley Periodicals, Inc.

Conflict of interest: The authors have nothing to disclose. 

Correspondence to: Ömer Acar, M.D, F.E.B.U, Koc University, School of Medicine, Department of Urology, Istanbul, Turkey. E-mail: [email protected] Received 16 October 2014; Accepted 1 December 2014 DOI 10.1002/pros.22956 Published online in Wiley Online Library (wileyonlinelibrary.com).

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There is a considerable interest in developing an accurate noninvasive imaging biomarker that will accurately stage the primary disease, evaluate recurrent disease, detect metastatic lesions and predict the aggressiveness of the disease. Given the lack of specificity in conventional imaging techniques, one possible solution is to screen for Pca specific antigenic targets and develop agents capable of specific binding. Prostate-specific membrane antigen (PSMA) is a highly specific prostate epithelial cell membrane antigen [2–6]. Based on the data gathered by histopathological studies, almost all Pca cells are capable of expressing PSMA [7–10]. The expression of PSMA increases progressively in higher-grade cancers, metastatic disease, and castration-resistant Pca [11–13]. Unlike other prostate specific antigens like PSA, PSMA is not secreted and is membrane bound [14]. The unique functional characteristics, Pca specificity and antigenic access, make PSMA an ideal extracellular target for various imaging methods and therapeutic options. Early clinical results suggest that PET/CT using PSMA-targeted agents will make valuable contributions to the daignosis and management of Pca. In this paper, we are going to review our initial experience with Gallium-68 (Ga-68) PSMA PET/CT imaging in Pca. MATERIALS AND METHODS Between February and August 2014, a total of 22 patients with Pca have been investigated by Ga-68-labelled PSMA ligand PET/CT imaging in our Nuclear Medicine and Molecular Imaging Department. After obtaining their informed consent, a retrospective chart review was conducted. Demographic information, clinical characteristics, the indication for Ga-68 PSMA PET/CT study, imaging findings and the impact of these findings on disease management were recorded and discussed. Median patient age was 68  10.07 (range ¼ 43–86) years. Median serum PSA level at the time of imaging was 4.15  40 (range ¼ 0.2–191.5) ng/ml. The indication for Ga-68 PSMA PET/CT imaging was; failure to achieve PSA nadir after local treatment for curative intent (n ¼ 1), staging and metastatic evaluation after the initiation of definitive treatment (n ¼ 1), rising PSA despite systemic therapy in a patient who presented with metastatic disease (n ¼ 1), staging and metastatic evaluation before treatment in high risk prostate cancer (n ¼ 7), symptomatic progression despite hormonal therapy in a patient with locally-advanced high risk prostate cancer (n ¼ 1) and eventually rising PSA after local  adjuvant treatment (n ¼ 11). Those who were imaged due to rising PSA, The Prostate

had inconclusive findings on conventional imaging studies, including F-18 FDG and F-18 NaF PET/CT. SYNTHESIS AND IMAGING The Germanium-68/Gallium-68 generator used for radionuclide production was purchased from IDB-Holland BV (The Netherlands). Gallium-68 (half life ¼ 68.3 min; bþ, max. 1.9 MeV) is a positron-emitting isotope and radionuclide that can be obtained by extracting Gallium-68 from the parent isotope Germanium-68 (physical half time: 271 days). A fully automated synthesis module (Scintomics GRP, Germany) and its control center and GRP-Interface software were used to transfer the radiosynthesis of [Ga-68] Ga-PSMA-HBED-CC into an environment suitable for clinical application using cationic purification method [15]. Disposable casette kits and chemicals including the precursors PSMA-HBED-CC (DKFZ-PSMA-11) in GMP-complaint grade used for the radiosynthesis were obtained from ABX advanced biochemical compounds. Analysis of the synthesized molecule and determination of the radiochemical purity were performed using High Performance Liquid Chromatography (HPLC, Knauer, Germany). [Ga-68] Ga-PSMA-HBED-CC was obtained in >99% radiochemical purity with an average standart deviation of 0.67%. The Ga-68 PSMA complex solution was administered via an intravenous bolus dose of 166  17 MBq. Images were taken, 45 and 90 min after the injection with Phillips Gemini/TF PET/CT scanner (The Netherlands). The imaging protocol was the same for every patient. Images were interpreted visually. First, physiologic accumulation in the lacrimal and salivary glands, nasal mucosa, liver, spleen, bowel, kidneys and bladder was noted. Focal and/or diffuse accumulation outside the normal biodistribution areas and focal accumulation in liver were considered abnormal. RESULTS A total of 18 patients had extraprostatic  prostatic PSMA positive lesions (median serum PSA ¼ 7.05  43.8, range 0.2–191.5 ng/ml) and despite all being theoretically eligible, only 7 of them were referred to theranostic application with Lutetium-177/ Yttrium-90 labelled PSMA. Systemic therapies of the rest (n ¼ 10) were modified and depending on their progress, the decision to proceed with theranostics would be reconsidered. Two patients, who only had prostatic PSMA positive lesion(s) but not elsewhere in the body (PSA ¼ 4 and 3.7 ng/ml, respectively) were scheduled for local treatment with curative intent.

Prostate-Specific Membrane Antigen-Based Imaging Remaining two patients, whose PSA could not reach a nadir and started to rise (2 and 0.3 ng/ml, respectively) following radical prostatectomy, had completely negative imaging results. One last patient who had an isolated PSMA positivity at the bladder neck following radical prostatectomy is being followed-up with serial PSA measurements without any active change in the treatment plan. These results are summarized in Figure 1 and Table I. The lowest and highest PSA values which were associated with PSMA positivity were 0.2 and 191.5 ng/ml, respectively. Above the PSA threshold level of 2 ng/ml, none of the Ga-68 PSMA based imagings revealed negative findings. We have utilized Ga-68 PSMA PET/CT for a variety of indications and except two completely negative results, PSMA based imaging had a significant impact on the management strategy in each clinical setting. Staging and Metastatic Evaluation Two patients with high volume, Gleason 4 þ 3 disease and serum PSA levels of 4.7 and 3, respectively were staged with PSMA based imaging. Apart from multifocal prostatic PSMA positivities, both were devoid of systemic metastases and they were scheduled for local definitive treatment. Five patients with high volume, high grade (Gleason pattern 4 and 5) disease whose median serum PSA level was 19.7  2.2 ng/ml (range 15–20) were also staged with Ga-68 PSMA PET/CT. Eventually, two of them were found to have lymphatic and bony metastases (Fig. 2) whereas the remaining three had

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only lymph node involvement. Based on these findings they initially received hormonal treatment and for those who had only pelvic lymph node positivity (n ¼ 2 out of 5), radiotherapy would be considered depending on the magnitude of PSA decline after androgenic deprivation. Rising PSA A total of 14 patients who had rising PSA after local and/or systemic treatment for prostate cancer [brachytherapy (n ¼ 1), radiotherapy þ hormonotherapy (n ¼ 2), radical prostatectomy  adjuvant radio-hormonotherapy (n ¼ 9), hormonotherapy (n ¼ 2)] were evaluated by Ga-68 PSMA PET/CT. One interesting patient in this category was a morbidly obese (Body mass index ¼ 47.6 kg/m2), 54 year-old gentleman who has undergone major abdominal surgeries, systemic chemotherapy, hepatic radiofrequency ablation and pulmonary metastasectomy for stage IV rectal cancer after being treated with brachytherapy due to prostate cancer. He had a steadily increasing PSA level after the stabilization of rectal cancer. Systematic, random TRUS-guided biopsy revealed normal histologic findings. Multiparametric prostate MRI discovered a suspicious lesion in the right basal part of the gland and Ga-68 PSMA PET/CT confirmed the PSMA reactivity in that region. Visual registration biopsy documented the presence of Gleason 4 þ 3 recurrent disease in close proximity with the brachy seeds (Fig. 3). All treatment options (salvage prostatectomy, androgenic deprivation, systemic chemotherapy, radiotherapy, including re-brachytherapy) were discussed in a multidiscipli-

Fig. 1. Diagram summarizing the nuclear imaging findings and individualized management strategies. The Prostate

The Prostate

Others

Staging and metastatic evaluation

Rising PSA

Indication

86

75

64

65 66 76

60

85 43

68 76

2

3

5

6 7 12

14

16 17

18 20

72

54

15

22

68

68

13

19

57 69 68 72 58

4 8 9 10 11

65

54

1

21

Age (years)

Patient number

0,2

19,7

20

15

0,3 16,8 19,9 4,7 3

29

2 1,85

9,7 0,3

12,9

3,9 0,3 3

1,8

1,35

191,5

4,4

Serum PSA value (ng/ml)

Symptomatic progression despite hormonotherapy for locally advanced prostate cancer

Staging (pre-treatment)

Staging (pre-treatment)

Staging (pre-treatment)

Metastatic CRPC þ rising PSA despitesystemictreatment Rising PSA after RP andadjuvanttreatment Rising PSA after RP andadjuvanttreatment PSA failingtoreach nadir after RP Rising PSA after RP Rising PSA after RP andadjuvanttreatment Metastatic CRPC þ rising PSA despitesystemictreatment Rising PSA afterradiotheraphy (IMRT) Rising PSA after RP andadjuvanttreatment Rising PSA after RP Rising PSA after RP andadjuvanttreatment Rising PSA after RP andadjuvanttreatment Staging (early post-RP period) Staging (pre-treatment) Staging (pre-treatment) Staging (pre-treatment) Staging (pre-treatment)

Rising PSA after brachytherapy

Indication

Multifocal prostatic lesions, metastatic right obturator lymphadenopathy Multifocal prostatic lesions with an extraprostatic infiltration on the right side, multiple metastatic lymph nodes Multifocal prostatic lesions, extracapsular extension, probable bladder necki nvasion, metastatic bilateral external iliac and presacral metastatik lymphadenopathies Multifocal prostatic lesions with an extraprostatic infiltration on the right side, metastatic right external iliac lymphadenopathy

Multipl bony metastasis, metastatic presacral lymphadenopathy Metastatic left obturator lympadenopathy Multiple lymph node and bony metastases Multiple lymph node and bony metastases Multifocal prostatic lesions, no metastasis Multifocal prostatic lesions, no metastasis

No PSMA positivity Subpleuralandmediastinal PSMA positivelesions

Multiplebonyandsofttissuemetastases Metastaticrightinternaliliaclymphadenopathy

Multiplebonyandsofttissuemetastases

Residualprostatictissue at thebladderneck No PSMA positivity Multiplebonymetastases

Metastaticleftobturatorlympadenopathy

Multiplebonymetastases

Recurrent disease in the right basal part of the prostate Multiplebonymetastases

Findings

TABLE I. Summary of the Ga-68 PSMA PET/CT Indications, Nuclear Imaging Findings and the Individualized Treatment Decisions

Theranostic application

Systemictreatment

Systemic treatment

Systemic treatment

Systemic treatment Systemic treatment Systemic treatment Local definitive treatment Local definitive treatment

Systemictreatment

Serial PSA measurements Theranosticapplication

Systemictreatment Theranosticapplication

Theranosticapplication

Serial PSA measurements Serial PSA measurements Theranosticapplication

Systemictreatment

Systemictreatment

Theranosticapplication

Theranostic application

Clinical implication/decision

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Fig. 2. (A) Images of a patient (]9) showing multipl lymph node and bone metastases. (B) Metastatic right retrocrural lymph node, measuring 2 mm in its maximal dimension.

nary setting and considering his uneligibility for the above-mentioned alternatives he was offered theranostic application with Lutetium-177 labelled PSMA. Another case worth mentioning would be a 76 year-old man, who was initially managed with robotassisted radical prostatectomy. He had pT3a, Gleason 4 þ 3 disease with a focal tertiary pattern 5 differ-

entiation. Additionally, he had surgical margin positivity and malignant infiltration in the pelvic lymph nodes. Interestingly, his PSA remained stable and low for 4 years after which it reached the level of 0.2 ng/ml. Further PSA increase led to the initiation of total androgenic blockage despite negative pelvic MRI and bone scintigraphy. PSA increased up to The Prostate

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Fig. 3. (A) Ga-68 PSMA PET/CT image of patient ]1. Clearly visible pathological radiotracer uptake in right basal part of prostate. (B1) Prostate cancer glands showing radiation changes with cytoplasmic vacuolation and nuclear hyperchromasia. (B2) Antibodies to basal cells (p53, HMWCK) are negative, AMACR is positive by immunohistochemistry, confirming the diagnosis of malignancy.

Fig. 4. (A) Ga-68 PSMA PET/CT demonstrating a patient (]20) representative for mediastinal lymph node and lung metastases of prostate cancer. (B) and (C) Hematoxylene and eosin sections of the cell block containing tumor cells. (D and E) Immunocytochemical staining revealed prostatic acid phosphotase (PAP) positivity in favor of prostate primary. Tumor cells were TTF-1 negative. The Prostate

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Fig. 5. (A) Ga-68 PSMA PET/CT of a patient (]21) with multiple bone metastases of prostate cancer. (B) Intense accumulation of radiolabeled PSMA in a milimetric foci in left scapula.

1.8 ng/ml while he was on hormonal treatment and this time we conducted Ga-68 PSMA PET/CT. Abdominal and pelvic regions were free of PSMA positivity. However, to everyone’s surprise, there were mediastinal and parenchymal PSMA positive deposits in the thorax (Fig. 4). Due to the rarity of such a finding, we sampled the mediastinal mass via FNAB and confirmed the presence of metastatic prostate cancer. Another challenging case was a 65 year-old male, who had undergone radical prostatectomy and adjuvant radiotheraphy for his locally advanced disease.

Despite these efforts he had a continously rising PSA and all of the conventional imaging modalities revealed inconclusive findings. Whereas, Ga-68 PSMA PET/CT demonstrated multiple metastatic bone and bone marrow lesions in addition to a presacral lymphadenopathy (Fig. 5). Others In this cohort, a 68-year old patient underwent Ga-68 PSMA PET/CT due to de-novo lower urinary The Prostate

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tract symptoms (LUTS) while being followed up under antiandrogenic treatment due to high-risk locally advance prostate cancer. Despite a stable and low PSA (0.2 ng/ml), PSMA based imaging revealed multifocal prostatic lesions with a probable extraprostatic extension on the right side, and a metastatic right external iliac lymphadenopathy. Due to the discordance between biochemical findings and imaging results, we decided to take samples from the prostate. Histopathological assesment confirmed the presence of Gleason 4 þ 5 ¼ 9 adenocarcinoma with diffuse (>80%) neuroendocrine differentiation. DISCUSSION Prostate-specific membrane antigen is a transmembranous, cell surface protein with a significantly increased expression in prostate cancer cells when compared to other PSMA-expressing tissues such as kidney, small intestine or salivary glands [16–18]. Additional advantages of PSMA are its large extracellular domain and enzymatic activity which allows for development of specific inhibitors and their internalization after ligand binding [19]. Therefore, this protein may serve as a promising target for prostate cancer-specific imaging and therapy. Recently, methods have been developed to label PSMA ligands with Ga-68, F-18, Tc-99m and I-123/ 124/131 enabling their use for PET imaging, scintigraphy options and radioligand therapy [20–23]. Afshar-Oromieh et al. confirmed the ability of Ga-68 PSMA PET/CT to detect prostate cancer relapses and metastases with high contrast by targeting the extracellular domain of PSMA [24]. Nodal staging in prostate cancer should be performed only when the findings will directly influence a treatment decision. The measurement of PSA level alone is unhelpful in predicting the presence of lymph node metastases for an individual patient. Abdominal CT and MRI have similar performances in prostate cancer nodal staging. They indirectly assess nodal invasion by measuring lymph node diameter. As a consequence, their sensitivity is low and microscopic invasions cannot be detected. Using a 10 mm threshold, CT or MR sensitivity is 2 ng/ ml. Those two patients who were free of PSMA positivity had serum PSA levels of 2 and 0.3 ng/ml, respectively. The lowest PSA value which had been associated with PSMA positive lesions was 0.2 ng/ ml in our series and this particular case underwent Ga-68 PSMA PET/CT due to new onset LUTS despite his low and stable PSA. Although it is hard to correlate his LUTS with PSMA positivity, the messag would be the weakness of PSA-only based monitorization after treatment for prostate cancer and the idea of combining several factors (clinical, biochemical, radiological and nuclear-imaging based) for a more trustworthy follow-up. Although PSMA-negative prostate cancer seems to be rare [29,30], we cannot exclude the possibility of false-negative PET/CT imaging in patients without

Prostate-Specific Membrane Antigen-Based Imaging pathological findings. The positive correlation between PSMA based imaging and histopathological results is not uniform in our cohort. Only three patients had complementary biopsy findings after Ga-68 PSMA PET/CT raised suspicion. However, the histopathological proof of local disease recurrence and metastatic spread in those extraordinary cases should be regarded as a justifiable reason for not sampling all the others. Yet, to our knowledge, these represent the first documented examples of a positive correlation between histopathological results and Ga-68 PSMA PET/CT findings. According to their unpublished data, Afshar-Oromieh et al. have reported that among their patients who have been further investigated by histology there were no false-negative or false-positive findings indicating a high sensitivity and specificity of the PSMA ligand. CONCLUSIONS Our preliminary data support the versatile utility of Ga-68 PSMA based imaging in prostate cancer. It might provide valuable information for the clinician in various clinical scenarios especially; staging and metastatic evaluation, rising PSA after treatment for curative intent. PSMA based nuclear imaging can detect milimetric metastatic deposits even at low PSA levels some of which might be associated with poorly differentiated disease. Hence, this imaging modality might be useful to reduce multiple investigations. Undoubtedly, there is a need for further analyses to confirm these findings and to define sensitivity and specificity in subgroups. Additionally, PSMA based imaging findings should ideally be further supported with histopathological documentation and/or follow-up imaging results in order to confirm the nature of detected lesions. Nevertheless, Ga-68 PSMA PET-CT seems to be a promising tool in the diagnostic armamentarium of prostate cancer. REFERENCES

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29. Mannweiler S, Amersdorfer P, Trajanoski S, Terrett JA, King D, Mehes. Heterogeneity of prostate-specific membrane antigen (PSMA) expression in prostate carcinoma with distant metastasis. Pathol Oncol Res 2009;15:167–172.

Prostate-specific membrane antigen-based imaging in prostate cancer: impact on clinical decision making process.

There is an ongoing need for an accurate imaging modality which can be used for staging purposes, metastatic evaluation, predicting biologic aggresive...
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