Maurer T, Gschwend JE, Rauscher I, Souvatzoglou M, Haller B, Weirich G, Wester HJ, Heck M, Kübler H, Beer AJ, Schwaiger M, Eiber M.

09.12.2015 [Original Artikel]

Current standard imaging techniques are insufficient to reliably detect lymph node metastases in prostate cancer. Recently ligands of PSMA (prostate specific membrane antigen) were introduced in PET (positron emission tomography) of prostate cancer. Thus the aims of this retrospective analysis were to 1) investigate the diagnostic efficacy of (68)Ga-PSMA-PET imaging for lymph node staging in patients with prostate cancer scheduled for radical prostatectomy and 2) compare it to morphological imaging (computerized tomography and magnetic resonance tomography) with histopathological evaluation as the standard of reference. A total of 130 patients with intermediate to high risk prostate cancer were staged with (68)Ga-PSMA-PET/magnetic resonance tomography or PET/computerized tomography from December 2012 to November 2014 before radical prostatectomy and template pelvic lymph node dissection. Histopathological findings of resected tissue were statistically correlated with the results of (68)Ga-PSMA-PET and morphological imaging in a patient and template based manner. Lymph node metastases were found in 41 of 130 patients (31.5%). On patient based analysis the sensitivity, specificity and accuracy of (68)Ga-PSMA-PET were 65.9%, 98.9% and 88.5%, and those of morphological imaging were 43.9%, 85.4% and 72.3%, respectively. Of 734 dissected lymph node templates 117 (15.9%) showed metastases. On template based analysis the sensitivity, specificity and accuracy of (68)Ga-PSMA-PET were 68.3%, 99.1% and 95.2%, and those of morphological imaging were 27.3%, 97.1% and 87.6%, respectively. On ROC analysis (68)Ga-PSMA-PET performed significantly better than morphological imaging alone on patient and template based analyses (p = 0.002 and <0.001, respectively). In patients with intermediate to high risk prostate cancer preoperative lymph node staging with (68)Ga-PSMA-PET proved to be superior to standard routine imaging. Thus it has the potential to replace current standard imaging for this indication if confirmed by prospective studies.

Schottelius M, Wirtz M, Eiber M, Maurer T, Wester HJ.

25.11.2015

The relevance of prostate-specific membrane antigen (PSMA) targeting in the clinical management of prostate cancer (PCa) is continually increasing, entailing the development of PSMA-targeted molecular probes. Recently, a first PSMA-targeted theranostic concept has been successfully implemented by [(68)Ga/(177)Lu]PSMA-I&T. To further exploit the excellent PSMA-targeting characteristics and in vivo performance of the PSMA-I&T platform, [(111)In]PSMA-I&T was evaluated as a complementary probe for radioguided surgery and SPECT imaging. Compared to [(68)Ga/(177)Lu]PSMA-I&T, [(111)In]PSMA-I&T showed unchangedly high PSMA-affinity and enhanced internalization into PSMA-expressing LNCaP PCa cells. Biodistribution studies in LNCaP xenograft-bearing mice (1 h p.i.) revealed slightly reduced background accumulation of [(111)In]PSMA-I&T compared to [(177)Lu]PSMA-I&T and identical tumor uptake of both compounds, leading to increased tumor/background ratios for [(111)In]PSMA-I&T. An exemplary patient with metastatic PCa underwent preoperative [(68)Ga]HBED-CC-PSMA PET/CT (1 h p.i.) and [(111)In]PSMA-I&T SPECT/CT (4 h p.i.), followed by prostatectomy and radioguided extended pelvic lymphadenectomy (24 h p.i.). In [(111)In]PSMA-I&T SPECT/CT, the previously identified PCa lesions ([(68)Ga]HBED-CC-PSMA PET/CT) showed high tracer accumulation and were also detectable using planar scintigraphy. The intraoperative use of a hand-held gamma probe allowed detection and resection of all [(111)In]PSMA-I&T-accumulating lesions. The presence of PSMA-positive tumor tissue in the resected specimens was confirmed histopathologically and via [(111)In]PSMA-I&T autoradiography. [(111)In]PSMA-I&T shows efficient PSMA targeting in vitro and in vivo, combined with low background accumulation. In an exemplary PCa patient, [(111)In]PSMA-I&T was successfully applied for preoperative SPECT/CT visualization and radioguided resection of PSMA-positive lesions, hinting towards a high value of [(111)In]PSMA-I&T as a complementary tool to [(68)Ga/(177)Lu]PSMA-I&T in the clinical management of prostate cancer.

Eiber M, Nekolla SG, Maurer T, Weirich G, Wester HJ, Schwaiger M.

01.08.2015 [Original Artikel]

Current imaging procedures for prostate cancer including positron emission tomography (PET) exhibit considerable limitations and are not always able to meet the diagnostic needs. Recently, a (68)Gallium-labeled ligand of the prostate-specific membrane antigen ((68)Ga-PSMA) has been introduced in PET-imaging of prostate cancer with first promising results. Due to relatively exclusive expression of PSMA in prostatic tissue as well as increased expression in prostate cancer, 68 Ga-PSMA was reported to exhibit a favorable lesion to background ratio. Together with the novel development of combined PET/MRI, the combination of excellent morphological detail, multiparametric functional information, and molecular PET data might lead to a significant improvement in detection of prostate cancer. We present an exemplarily case of primary staging using multiparametric (68)Ga-PSMA PET/MR by combining molecular and structural information.

Weineisen M, Schottelius M, Simecek J, Baum RP, Yildiz A, Beykan S, Kulkarni HR, Lassmann M, Klette I, Eiber M, Schwaiger M, Wester HJ.

18.06.2015 [Original Artikel]

On the basis of the high and consistent expression of prostate-specific membrane antigen (PSMA) in metastatic prostate cancer (PC), the goal of this study was the development, preclinical evaluation, and first proof-of-concept investigation of a PSMA inhibitor for imaging and therapy (PSMA I&T) for (68)Ga-based PET and (177)Lu-based endoradiotherapeutic treatment in patients with metastatic and castration-resistant disease. PSMA I&T was synthesized in a combined solid phase and solution chemistry strategy. The PSMA affinity of (nat)Ga-/(nat)Lu-PSMA I&T was determined in a competitive binding assay using LNCaP cells. Internalization kinetics of (68)Ga- and (177)Lu-PSMA I&T were investigated using the same cell line, and biodistribution studies were performed in LNCaP tumor-bearing CD-1 nu/nu mice. Initial human PET imaging studies using (68)Ga-PSMA I&T, as well as endoradiotherapeutic treatment of 2 patients with metastatic PC using (177)Lu-PSMA I&T, were performed. PSMA I&T and its cold gallium and lutetium analog revealed nanomolar affinity toward PSMA. The DOTAGA (1,4,7,10-tetraazacyclododecane-1-(glutamic acid)-4,7,10-triacetic acid) conjugate PSMA I&T allowed fast and high-yield labeling with (68)Ga(III) and (177)Lu(III). Uptake of (68)Ga-/(177)Lu-PSMA I&T in LNCaP tumor cells is highly efficient and PSMA-specific, as demonstrated by competition studies both in vitro and in vivo. Tumor targeting and tracer kinetics in vivo were fast, with the highest uptake in tumor xenografts and kidneys (both PSMA-specific). First-in-human (68)Ga-PSMA I&T PET imaging allowed high-contrast detection of bone lesions, lymph node, and liver metastases. Endoradiotherapy with (177)Lu-PSMA I&T in 2 patients was found to be effective and safe with no detectable side effects. (68)Ga-PSMA I&T shows potential for high-contrast PET imaging of metastatic PC, whereas its (177)Lu-labeled counterpart exhibits suitable targeting and retention characteristics for successful endoradiotherapeutic treatment. Prospective studies on larger cohorts of patients are warranted and planned.

Maurer T, Weirich G, Schottelius M, Weineisen M, Frisch B, Okur A, Kübler H, Thalgott M, Navab N, Schwaiger M, Wester HJ, Gschwend JE, Eiber M.

06.05.2015 [Original Artikel]

With the advent of (68)Ga-labeled prostate-specific membrane antigen-N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid ((68)Ga-PSMA-HBED-CC) 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 (111)In-PSMA investigation and therapy agent 24h before surgery. Metastatic LNs were tracked intraoperatively using a gamma probe with acoustic and visual feedback. All radioactive-positive 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 (68)Ga-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 (68)Ga-PSMA-HBED-CC PET. However, greater patient numbers and long-term follow-up data are needed to determine the future role of PSMA-radioguided surgery.

Herrmann K, Bluemel C, Weineisen M, Schottelius M, Wester HJ, Czernin J, Eberlein U, Beykan S, Lapa C, Riedmiller H, Krebs M, Kropf S, Schirbel A, Buck AK, Lassmann M.

16.04.2015 [Original Artikel]

Prostate-specific membrane antigen (PSMA) is a promising target for diagnosis and treatment of prostate cancer. EuK-Subkff-(68)Ga-DOTAGA ((68)Ga-PSMA Imaging & Therapy [PSMA I&T]) is a recently introduced PET tracer for imaging PSMA expression in vivo. Whole-body distribution and radiation dosimetry of this new probe were evaluated. Five patients with a history of prostate cancer were injected intravenously with 91-148 MBq of (68)Ga-PSMA I&T (mean ± SD, 128 ± 23 MBq). After an initial series of rapid whole-body scans, 3 static whole-body scans were acquired at 1, 2, and 4 h after tracer injection. Time-dependent changes of the injected activity per organ were determined. Mean organ-absorbed doses and effective doses were calculated using OLINDA/EXM. Injection of 150 MBq of (68)Ga-PSMA I&T resulted in an effective dose of 3.0 mSv. The kidneys were the critical organ (33 mGy), followed by the urinary bladder wall and spleen (10 mGy each), salivary glands (9 mGy each), and liver (7 mGy). (68)Ga-PSMA I&T exhibits a favorable dosimetry, delivering organ doses that are comparable to (kidneys) or lower than those delivered by (18)F-FDG.

Eiber M, Maurer T, Souvatzoglou M, Beer AJ, Ruffani A, Haller B, Graner FP, Kübler H, Haberhorn U, Eisenhut M, Wester HJ, Gschwend JE, Schwaiger M.

19.03.2015 [Original Artikel]

The expression of prostate-specific membrane antigen (PSMA) is increased in prostate cancer. Recently, (68)Ga-PSMA (Glu-NH-CO-NH-Lys-(Ahx)-[(68)Ga(HBED-CC)]) was developed as a PSMA ligand. The aim of this study was to investigate the detection rate of (68)Ga-PSMA PET/CT in patients with biochemical recurrence after radical prostatectomy. Two hundred forty-eight of 393 patients were evaluable for a retrospective analysis. Median prostate-specific antigen (PSA) level was 1.99 ng/mL (range, 0.2-59.4 ng/mL). All patients underwent contrast-enhanced PET/CT after injection of 155 ± 27 MBq of (68)Ga-PSMA ligand. The detection rates were correlated with PSA level and PSA kinetics. The influence of antihormonal treatment, primary Gleason score, and contribution of PET and morphologic imaging to the final diagnosis were assessed. Two hundred twenty-two (89.5%) patients showed pathologic findings in (68)Ga-PSMA ligand PET/CT. The detection rates were 96.8%, 93.0%, 72.7%, and 57.9% for PSA levels of ≥2, 1 to <2, 0.5 to <1, and 0.2 to <0.5 ng/mL, respectively. Whereas detection rates increased with a higher PSA velocity (81.8%, 82.4%, 92.1%, and 100% in <1, 1 to <2, 2 to <5, and ≥5 ng/mL/y, respectively), no significant association could be found for PSA doubling time (82.7%, 96.2%, and 90.7% in >6, 4-6, and <4 mo, respectively). (68)Ga-PSMA ligand PET (as compared with CT) exclusively provided pathologic findings in 81 (32.7%) patients. In 61 (24.6%) patients, it exclusively identified additional involved regions. In higher Gleason score (≤7 vs. ≥8), detection efficacy was significantly increased (P = 0.0190). No significant difference in detection efficacy was present regarding antiandrogen therapy (P = 0.0783). Hybrid (68)Ga-PSMA ligand PET/CT shows substantially higher detection rates than reported for other imaging modalities. Most importantly, it reveals a high number of positive findings in the clinically important range of low PSA values (<0.5 ng/mL), which in many cases can substantially influence the further clinical management.