Detection rate of PET/CT in patients with biochemical relapse of prostate cancer using [68Ga]PSMA I&T and comparison with published data of [68Ga]PSMA HBED-CC

Berliner C, Tienken M, Frenzel T, Kobayashi Y, Helberg A, Kirchner U, Klutmann S, Beyersdorff D, Budäus L, Wester HJ, Mester J, Bannas P

2016 Nov 28 [Original Artikel]

To determine the detection rate of PET/CT in biochemical relapse of prostate cancer using [68Ga]PSMA I&T and to compare it with published detection rates of [68Ga]PSMA HBED-CC. We performed a retrospective analysis in 83 consecutive patients with documented biochemical relapse after prostatectomy. All patients underwent whole body [68Ga]PSMA I&T PET/CT. PET/CT images were evaluated for presence of local recurrence, lymph node metastases, and distant metastases. Proportions of positive PET/CT results were calculated for six subgroups with increasing prostate specific antigen (PSA) levels (<0.5 ng/mL, 0.5 to <1.0 ng/mL, 1.0 to <2.0 ng/mL, 2.0 to <5.0 ng/mL, 5.0 to <10.0, ≥10.0 ng/mL). Detection rates of [68Ga]PSMA I&T were statistically compared with published detection rates of [68Ga]PSMA HBED-CC using exact Fisher’s test. Median PSA was 0.81 (range: 0.01 – 128) ng/mL. In 58/83 patients (70 %) at least one [68Ga]PSMA I&T positive lesion was detected. Local recurrent cancer was present in 18 patients (22 %), lymph node metastases in 29 patients (35 %), and distant metastases in 15 patients (18 %). The tumor detection rate was positively correlated with PSA levels, resulting in detection rates of 52 % (<0.5 ng/mL), 55 % (0.5 to <1.0 ng/mL), 70 % (1.0 to <2.0 ng/mL), 93 % (2.0 to <5.0 ng/mL), 100 % (5.0 to <10.0 ng/mL), and 100 % (≥10.0 ng/mL). There was no significant difference between the detection rate of [68Ga]PSMA I&T and published detection rates of [68Ga]PSMA HBED-CC (all p>0.05). [68Ga]PSMA I&T PET/CT has high detection rates of recurrent prostate cancer that are comparable to [68Ga]PSMA HBED-CC.

Value of 111 In-prostate-specific membrane antigen (PSMA)-radioguided surgery for salvage lymphadenectomy in recurrent prostate cancer: correlation with histopathology and clinical follow-up

Rauscher I, Düwel C, Wirtz M, Schottelius M, Wester HJ, Schwamborn K, Haller B, Schwaiger M, Gschwend JE, Eiber M, Maurer T.

2016 Nov 10 [Original Artikel]

To evaluate the use of 111In-labelled prostate-specific membrane antigen (PSMA)-I&T-based radioguided surgery (111In-PSMA-RGS) for salvage surgery in recurrent prostate cancer (PCa) using comparison of intra-operative gamma probe measurements with histopathological results of dissected specimens. In addition, to determine the success of 111In-PSMA-RGS with regard to postoperative prostate-specific antigen (PSA) responses, PCa-specific treatment-free survival rates and postoperative complication rates. A total of 31 consecutive patients with localized recurrent PCa undergoing salvage surgery with PSMA-targeted radioguided surgery using a 111In-labelled PSMA ligand between April 2014 and July 2015 were retrospectively included in this study. The preoperative (interquartile range; range) median PSA level was 1.3 (0.57–2.53 ng/mL; 0.2–13.9 ng/mL). Results of ex vivo radioactivity rating (positive vs negative) of resected tissue specimens were compared with findings of postoperative histological analysis. Best PSA response without additional treatment was determined after 111In-PSMA-RGS, and salvage-surgery-related postoperative complications and PCa-specific additional treatments were recorded. In 30/31 patients, 111In-PSMA-RGS allowed intra-operative identification of metastatic lesions. In total, 145 surgical specimens were removed and 51 showed metastatic involvement at histological analysis. According to 111In-PSMA-RGS ex vivo measurements, 48 specimens were correctly classified as metastatic and 87 as cancer-free, four were false-negative and six were false-positive compared with histological evaluation. Follow-up information was available for 30/31 patients. PSA declines of >50% and >90% were observed in 23/30 patients and in 16/30 patients, respectively. In 18/30 patients, a PSA decline to <0.2 ng/mL was observed. In 10/30 patients further PCa-specific treatment was given after a median (range) of 125 (48–454) days post-111In-PSMA-RGS. The remaining 20 patients remained treatment-free at a median (range) follow-up of 337 (81–591) days. Of 30 patients, 10 presented with surgery-related complications (Clavien–Dindo grade 1, n = 6, Clavien–Dindo grade 3b, n = 4). 111In-PSMA-RGS proved to be of high value for intra-operative detection of even small metastatic lesions in patients with PCa scheduled for salvage lymphadenectomy. It allows the exact localization and resection of metastatic tissue during 111In-PSMA-RGS and is therefore anticipated to have a beneficial influence on further disease progression; however, identification of suitable patients on the basis of PSMA-positron-emission tomography imaging as well as clinical variables is essential for satisfactory results to be obtained.


Impact of 68Ga-PSMA PET/CT on salvage radiotherapy planning in patients with prostate cancer and persisting PSA values or biochemical relapse after prostatectomy

Bluemel C, Linke F, Herrmann K, Simunovic I, Eiber M, Kestler C, Buck AK, Schirbel A, Bley TA, Wester HJ, Vergho D, Becker A.

26.10.2016 [Original Artikel]

Salvage radiotherapy (SRT) is clinically established in prostate cancer (PC) patients with PSA persistence or biochemical relapse (BCR) after prior radical surgery. PET/CT imaging prior to SRT may be performed to localize disease recurrence. The recently introduced 68Ga-PSMA outperforms other PET tracers for detection of recurrence and is therefore expected also to impact radiation planning. Forty-five patients with PSA persistence (16 pts) or BCR (29 pts) after prior prostatectomy, scheduled to undergo SRT of the prostate bed, underwent 68Ga-PSMA PET/CT. The median PSA level was 0.67 ng/ml. The impact of 68Ga-PSMA PET/CT on the treatment decision was assessed. Patients with oligometastatic (≤5 lesions) PC underwent radiotherapy (RT), with the extent of the RT area and dose escalation being based on PET positivity. Suspicious lesions were detected in 24/45 (53.3 %) patients. In 62.5 % of patients, lesions were only detected by 68Ga-PSMA PET. Treatment was changed in 19/45 (42.2 %) patients, e.g., extending SRT to metastases (9/19), administering dose escalation in patients with morphological local recurrence (6/19), or replacing SRT by systemic therapy (2/19). 38/45 (84.4 %) followed the treatment recommendation, with data on clinical follow-up being available in 21 patients treated with SRT. All but one showed biochemical response (mean PSA decline 78 ± 19 %) within a mean follow-up of 8.12 ± 5.23 months. 68Ga-PSMA PET/CT impacts treatment planning in more than 40 % of patients scheduled to undergo SRT. Future prospective studies are needed to confirm this significant therapeutic impact on patients prior to SRT.

Evaluation of 68Ga-Glutamate Carboxypeptidase II Ligand Positron Emission Tomography for Clinical Molecular Imaging of Atherosclerotic Plaque Neovascularization

Derlin T, Thiele J, Weiberg D, Thackeray JT, Püschel K, Wester HJ, Aguirre Dávila L, Larena-Avellaneda A, Daum G, Bengel FM, Schumacher U.

8.9.2016 [Original Artikel]

Intraplaque neovascularization contributes to the progression and rupture of atherosclerotic lesions. Glutamate carboxypeptidase II (GCPII) is strongly expressed by endothelial cells of tumor neovasculature and plays a major role in hypoxia-induced neovascularization in rodent models of benign diseases. We hypothesized that GCPII expression may play a role in intraplaque neovascularization and may represent a target for imaging of atherosclerotic lesions. The aim of this study was to determine frequency, pattern, and clinical correlates of vessel wall uptake of a 68Ga-GCPII ligand for positron emission tomographic imaging. Data from 150 patients undergoing 68Ga-GCPII ligand positron emission tomography were evaluated. Tracer uptake in various arterial segments was analyzed and was compared with calcified plaque burden, cardiovascular risk factors, and immunohistochemistry of carotid specimens. Focal arterial uptake of 68Ga-GCPII ligand was identified at 5776 sites in 99.3% of patients. The prevalence of uptake sites was highest in the thoracic aorta; 18.4% of lesions with tracer uptake were colocalized with calcified plaque. High injected dose (P=0.0005) and obesity (P=0.007) were significantly associated with 68Ga-GCPII ligand accumulation, but other cardiovascular risk factors showed no association. The number of 68Ga-GCPII ligand uptake sites was significantly associated with overweight condition (P=0.0154). Immunohistochemistry did not show GCPII expression. Autoradiographic blocking studies indicated nonspecific tracer binding. 68Ga-GCPII ligand positron emission tomography does not identify vascular lesions associated with atherosclerotic risk. Foci of tracer accumulation are likely caused by nonspecific tracer binding and are in part noise-related. Taken together, GCPII may not be a priority target for imaging of atherosclerotic lesions.

PSMA-Based Radioligand Therapy for Metastatic Castration-Resistant Prostate Cancer: The Bad Berka Experience Since 2013

Kulkarni HR, Singh A, Schuchardt C, Niepsch K, Sayeg M, Leshch Y, Wester HJ, Baum RP.

1.10.2016 [Original Artikel]

A potential milestone in personalized nuclear medicine is theranostics of metastatic castration-resistant prostate cancer (mCRPC) based on molecular imaging using PET/CT with 68Ga-labeled prostate-specific membrane antigen (PSMA) ligands and molecular radiotherapy using PSMA-targeted radioligand therapy (PRLT) with 177Lu-PSMA ligands. 68Ga-PSMA PET/CT enables accurate detection of mCRPC lesions with high diagnostic sensitivity and specificity and provides quantitative and reproducible data that can be used to select patients for PRLT and therapeutic monitoring. Our comprehensive experience over the last 3 years using different radioligands indicates that PRLT is highly effective for the treatment of mCRPC, even in advanced cases, and potentially lends a significant benefit to overall and progression-free survival. Additionally, significant improvement in clinical symptoms and excellent palliation of pain can be achieved.

Radiation dosimetry for 177Lu-PSMA-I&T in metastatic castration-resistant prostate cancer: Absorbed dose in normal organs and tumor lesions

Okamoto S, Thieme A, Allmann J, D'Alessandria C, Maurer T, Retz M, Tauber R, Heck MM, Wester HJ, Tamaki N, Fendlder WP, Herrmann K, Pfob CH, Scheidhauer K, Schwaiger M, Ziegler S, Eiber M.

22.09.2016 [Original Artikel]

Prostate-specific membrane antigen (PSMA) targeted radioligand therapy (RLT) is increasingly used in metastatic castration-resistant prostate cancer (mCRPC). We aimed to estimate the absorbed doses for normal organs and tumor lesions using 177Lu-PSMA-I&T in patients undergoing up to four cycles RLT. Results were compared to pre-therapeutic 68Ga-PSMA-HBED-CC positron-emission-tomography (PET). A total of 34 cycles in 18 patients were analyzed retrospectively. In 15 patients the first, in 9 the second, in 5 the third and in 5 the fourth cycle was analyzed, respectively. Whole-body scintigraphy was performed at least between 30-120 minutes, 24 hours and 6-8 days after administration. Regions of interest (ROIs) covering the whole body, organs and up to 4 tumor lesions were drawn. Organ and tumor masses were derived from pre-therapeutic 68Ga-PSMA-HBED-CC PET/Computed tomography (CT). Absorbed doses for individual cycles were calculated using OLINDA/EXM. Standardized-uptake-values (SUV) from pre-therapeutic PET were compared to absorbed doses and to change of SUV. Mean whole body effective dose for all cycles was 0.06±0.03 Sv/GBq. The mean absorbed organ doses were 0.72±0.21 Gy/GBq for the kidneys, 0.12±0.06 Gy/GBq for liver, 0.55±0.14 Gy/GBq for parotid, 0.64±0.40 Gy/GBq for the submandibular and 3.8±1.4 Gy/GBq for lacrimal glands. Absorbed organ doses were relatively constant when among the four different cycles. Tumor lesions received a mean absorbed dose per cycle of 3.2±2.6 Gy/GBq (range 0.22-12 Gy/GBq). Doses to tumor lesions gradually decreased with 3.5±2.9 Gy/GBq for the first, 3.3±2.5 Gy/GBq for the second, 2.7±2.3 Gy/GBq for the third and 2.4±2.2 Gy/GBq for the fourth cycle. SUVs of pre-therapeutic PET moderately correlated with absorbed dose (r=0.44, p<0.001 for SUVmax, r=0.43, p<0.001 for SUVmean) and moderately correlated with the change of SUV (ΔSUV; r=0.478, p<0.001 for SUVmax, r=0.50, p<0.001 for SUVmean). Organ and tumor absorbed doses for 177Lu-PSMA-I&T are comparable to recent reports and complement these with information on an excellent correlation between the four therapy cycles. With the kidneys representing the critical organ, a cumulative activity of 40 GBq 177Lu-PSMA-I&T appears to be safe and justifiable. The correlation between pre-therapeutic SUV and absorbed tumor dose emphasizes the need for PSMA-ligand PET-imaging for patient selection.

Preclinical evaluation and first patient application of [99mTc]PSMA-I&S for SPECT imaging and radioguided surgery in prostate cancer.

Robu S, Schottelius M, Eiber M, Maurer T, Gschwend J, Schwaiger M, Wester HJ

15.09.2016 [Original Artikel]

Initial studies in patients have demonstrated the suitability of 111In-PSMA-I&T (111In-DOTAGA-(3-iodo-y)-f-k-Sub(KuE)) for radioguided surgery (RGS) of small metastatic prostate cancer (PCa) soft tissue lesions. To meet the clinical need for a more cost-effective alternative, the PSMA-I&T-based tracer concept was adapted to 99mTc-labeling chemistry. Two PSMA-I&T-derived inhibitors with all-L-serine- (MAS3) and all-D-serine- (mas3) chelating moieties were evaluated in parallel, and a kit procedure for routine 99mTc-labeling was developed. PSMA-affinities (IC50) and internalization kinetics of 99mTc-MAS3-y-nal-k(Sub-KuE) and 99mTc-mas3-y-nal-k(Sub-KuE) ("99mTc-PSMA-I&S" for Imaging and Surgery) were determined using LNCaP cells and (125I-BA)KuE as radioligand and reference standard. In vivo metabolite analyses and biodistribution studies were carried out using CD-1 nu/nu and LNCaP-tumor bearing CB-17-SCID mice. Pharmacokinetics of 99mTc-PSMA-I&S in humans were investigated in a patient with advanced metastatic PCa via sequential planar whole-body SPECT imaging at 1, 3, 5 and 21h p.i. Additionally, preoperative SPECT/CT (12h p.i.) and 99mTc-PSMA-I&S-supported RGS (16h p.i.) were performed in one PCa patient with proven iliac and inguinal lymph node metastases. A robust and reliable kit-labeling procedure was established, allowing the preparation of 99mTc-MAS3-y-nal-k(Sub-KuE) and 99mTc-PSMA-I&S in consistently high radiochemical yield and purity (≥98%, n>50 preparations). Because of its improved internalization efficiency and superior in vivo stability, 99mTc-PSMA-I&S was selected for further in vivo evaluation. Compared to 111In-PSMA-I&T, 99mTc-PSMA-I&S showed delayed clearance kinetics, but identical uptake in PSMA+ tissues in the LNCaP xenograft model (1h p.i.). In exemplary PCa patients, relatively slow whole-body clearance of 99mTc-PSMA-I&S was also observed due to high plasma protein binding (94%) of the tracer. This, however, promoted efficient tracer uptake in PCa lesions over time, and lead to steadily increasing lesion-to-background ratios up to 21h p.i.. Preoperative SPECT/CT showed high 99mTc-PSMA-I&S uptake in all suspect lesions identified in previous 68Ga-HBED-CC-PSMA PET/CT, allowing for their successfully intraoperative detection and resection during first-in-man RGS. Due to a straightforward and reliable kit-production, 99mTc-PSMA-I&S represents a cost-effective, readily available alternative to 111In-PSMA-I&T. Initial patient data indicate its comparable or even superior performance as a probe for PSMA-targeted RGS and also hint towards the unexpected potential of 99mTc-PSMA-I&S as a SPECT imaging agent.

Intrapatient Comparison of 111In-PSMA I&T SPECT/CT and Hybrid 68Ga-HBED-CC PSMA PET in Patients With Early Recurrent Prostate Cancer.

Rauscher I, Maurer T, Souvatzoglou M, Beer AJ, Vag T, Wirtz M, Weirich G, Wester HJ, Gschwend JE, Schwaiger M, Schottelius M, Eiber M.

01.09.2016 [Original Artikel]

The aim of this study was to evaluate the detection efficiency of 111In-PSMA-I&T SPECT/CT in comparison to hybrid 68Ga-PSMA HBED-CC PET in patients with early recurrent prostate cancer. Twenty-two patients (mean age, 68.2 ± 6.8 years; range, 52-76 years) with rising prostate-specific antigen (PSA; median, 1.03 ng/mL; range, 0.2-7.2ng/mL) and known positive lesions in hybrid Ga-PSMA HBED-CC PET scheduled for salvage surgery were included. Whole-body scintigraphy and SPECT/CT were performed 4 hours after application of 147.0 ± 24.8 MBq (range, 90-183 MBq) In-PSMA I&T. Images were evaluated for suspected lesions, and conspicuity of all lesions was rated using a 4-point-scale (0 = not seen, 1 = retrospectively seen in knowledge of Ga-PSMA HBED-CC PET, 2 = low signal, 3 = high signal). Tumor-to-background ratios were determined for SPECT and PET and compared. Tumor-to-background ratio of SPECT was correlated with lesion size as well as patients' Gleason score and PSA level. In-PSMA I&T SPECT/CT detected 14 of 29 PET-positive lesions (48.3%) with no additional lesions identified with In-PSMA I&T SPECT/CT. There was a significant weak to moderate correlation of PSA level with tumor-to-background ratio of In-PSMA I&T SPECT/CT (correlation coefficient r = 0.6406; 95% confidence interval, 0.1667-0.8741; P = 0.0136). There was no significant difference (P > 0.05), but a weak trend toward a higher detectability in In-PSMA I&T SPECT/CT regarding lesion size and initial PSA level. In a preselected collective of recurrent prostate cancer patients with low PSA values, In-PSMA I&T SPECT/CT showed lower detection rates than hybrid Ga-HBED-CC PSMA PET. However, In-PSMA I&T SPECT/CT showed a patient based detection rate of 59%, making it a potentially valuable imaging tool where PET is not available apart from its proven value as a PSMA-targeted probe for radioguided surgery.

68Ga-PSMA-PET/CT in Patients With Biochemical Prostate Cancer Recurrence and Negative 18F-Choline-PET/CT

Bluemel C, Krebs M, Polat B, Linke F, Eiber M, Samnick S, Lapa C, Lassmann M, Riedmiller H, Czernin J, Rubello D, Bley T, Kropf S, Wester HJ, Buck AK, Herrmann K.

01.07.2016 [Original Artikel]

Investigating the value of Ga-PSMA-PET/CT in biochemically recurring prostate cancer patients with negative F-choline-PET/CT. One hundred thirty-nine consecutive patients with biochemical recurrence after curative (surgery and/or radiotherapy) therapy were offered participation in this sequential clinical imaging approach. Patients first underwent an F-choline-PET/CT. If negative, an additional Ga-PSMA-PET/CT was offered. One hundred twenty-five of 139 eligible patients were included in the study; 32 patients underwent additional Ga-PSMA-PET/CT. Patients with equivocal findings (n = 5) on F-choline-PET/CT and those who declined the additional Ga-PSMA-PET/CT (n = 9) were excluded. Images were analyzed visually for the presence of suspicious lesions. Findings on PET/CT were correlated with PSA level, PSA doubling time (dt), and PSA velocity (vel). The overall detection rates were 85.6% (107/125) for the sequential imaging approach and 74.4% (93/125) for F-choline-PET/CT alone. Ga-PSMA-PET/CT detected sites of recurrence in 43.8% (14/32) of the choline-negative patients. Detection rates of the sequential imaging approach and F-choline-PET/CT alone increased with higher serum PSA levels and PSA vel. Subgroup analysis of Ga-PSMA-PET/CT in F-choline negative patients revealed detection rates of 28.6%, 45.5%, and 71.4% for PSA levels of 0.2 or greater to less than 1 ng/mL, 1 to 2 ng/mL, and greater than 2 ng/mL, respectively. The sequential imaging approach designed to limit Ga-PSMA imaging to patients with negative choline scans resulted in high detection rates. Ga-PSMA-PET/CT identified sites of recurrent disease in 43.8% of the patients with negative F-choline PET/CT scans.

[68Ga]PSMA ligand PET/CT-based radiotherapy in locally recurrent and recurrent oligometastatic prostate cancer : Early efficacy after primary therapy

Henkenberens C, von Klot CA, Ross TL, Bengel FM, Wester HJ, Merseburger AS, Vogel-Claussen J, Christiansen H, Derlin T.

01.06.2016 [Original Artikel]

The goal of this work was to evaluate the early efficacy of (68)Ga-PSMA ligand PET/CT imaging for radiotherapy of locally recurrent and/or oligometastatic prostate cancer. A total of 29 patients with biochemical recurrence received a (68)Ga-PSMA ligand PET/CT for restaging of disease, followed by 3D conformal radiotherapy of metastases or intensity-modulated radiation therapy of the prostate bed. Prostate-specific antigen (PSA) levels and imaging procedures served as the reference standard to assess the treatment efficacy. PET/CT was positive in 96.6% of patients and revealed that 13.8% of patients had locally recurrent disease, 58.6% had isolated lymph node metastases, 20.7% had isolated bone metastases, and 3.4% showed lymph node metastases and a vertebral metastasis. The median follow-up was 8.3 months (range 3.0-17.3 months). The median PSA prior to radiotherapy was 1.47 ng/ml (range 0.52-32.01 ng/ml) and showed a statistically significant decrease to 0.58 ng/ml (range < 0.07 to 6.33 ng/ml, p < 0.001). Two patients (6.8%) developed progressive disease outside the radiation field after 12.0 and 12.7 months, yielding a local control rate of 100% at the median follow-up. No grade III acute toxicity or late toxicity grade II was observed. Only 2 patients (6.8%) reported persisting grade I diarrhoea according to the LENT-SOMA criteria 3 months after radiotherapy. Deterioration of the urinary or faecal continence was not observed. Preliminary results in the presented cohort suggest that radiotherapy based on (68)Ga-PSMA ligand PET/CT yields effective local control and significant treatment response in terms of PSA levels in the absence of clinically important side effects. Furthermore, this approach delayed the necessity of androgen deprivation therapy or systemic therapy.

Biodistribution and radiation dosimetry of (68)Ga-PSMA HBED CC-a PSMA specific probe for PET imaging of prostate cancer

Pfob CH, Ziegler S, Graner FP, Köhner M, Schachoff S, Blechert B, Wester HJ, Scheidhauer K, Schwaiger M, Maurer T, Eiber M.

20.05.2016 [Original Artikel]

Positron emission tomography (PET) agents targeting the prostate-specific membrane antigen (PSMA) are currently under broad clinical and scientific investigation. (68)Ga-PSMA HBED-CC constitutes the first (68)Ga-labelled PSMA-inhibitor and has evolved as a promising agent for imaging PSMA expression in vivo. The aim of this study was to evaluate the whole-body distribution and radiation dosimetry of this new probe. Five patients with a history or high suspicion of prostate cancer were injected intravenously with a mean of 139.8 ± 13.7 MBq of (68)Ga-PSMA HBED-CC (range 120-158 MBq). Four static skull to mid-thigh scans using a whole-body fully integrated PET/MR-system were performed 10 min, 60 min, 130 min, and 175 min after the tracer injection. Time-dependent changes of the injected activity per organ were determined. Mean organ-absorbed doses and effective doses (ED) were calculated using OLINDA/EXM. Injection of a standard activity of 150 MBq (68)Ga-PSMA HBED-CC resulted in a median effective dose of 2.37 mSv (Range 1.08E-02 - 2.46E-02 mSv/MBq). The urinary bladder wall (median absorbed dose 1.64E-01 mGv/MBq; range 8.76E-02 - 2.91E-01 mGv/MBq) was the critical organ, followed by the kidneys (median absorbed dose 1.21E-01 mGv/MBq; range 7.16E-02 - 1.75E-01), spleen (median absorbed dose 4.13E-02 mGv/MBq; range 1.57E-02 - 7.32E-02 mGv/MBq) and liver (median absorbed dose 2.07E-02 mGv/MBq; range 1.80E-02 - 2.57E-02 mGv/MBq). No drug-related pharmacological effects occurred. The use of (68)Ga-PSMA HBED-CC results in a relatively low radiation exposure, delivering organ doses that are comparable to those of other (68)Ga-labelled PSMA-inhibitors used for PET-imaging. Total effective dose is lower than for other PET-agents used for prostate cancer imaging (e.g. (11)C- and (18)F-Choline).

Towards Personalized Treatment of Prostate Cancer: PSMA I&T, a Promising Prostate-Specific Membrane Antigen-Targeted Theranostic Agent

Chatalic KL, Heskamp S, Konijnenberg M, Molkenboer-Kuenen JD, Franssen GM, Clahsen-van Groningen MC, Schottelius M, Wester HJ, van Weerden WM, Boerman OC, de Jong M.

12.04.2016 [Original Artikel]

Prostate-specific membrane antigen (PSMA) is a well-established target for nuclear imaging and therapy of prostate cancer (PCa). Radiolabeled small-molecule PSMA inhibitors are excellent candidates for PCa theranostics—they rapidly and efficiently localize in tumor lesions. However, high tracer uptake in kidneys and salivary glands are major concerns for therapeutic applications. Here, we present the preclinical application of PSMA I&T, a DOTAGA-chelated urea-based PSMA inhibitor, for SPECT/CT imaging and radionuclide therapy of PCa. 111In-PSMA I&T showed dose-dependent uptake in PSMA-expressing tumors, kidneys, spleen, adrenals, lungs and salivary glands. Coadministration of 2-(phosphonomethyl)pentane-1,5-dioic acid (2-PMPA) efficiently reduced PSMA-mediated renal uptake of 111In-PSMA I&T, with the highest tumor/kidney radioactivity ratios being obtained using a dose of 50 nmol 2-PMPA. SPECT/CT clearly visualized subcutaneous tumors and sub-millimeter intraperitoneal metastases; however, high renal and spleen uptake in control mice (no 2-PMPA) interfered with visualization of metastases in the vicinity of those organs. Coadministration of 2-PMPA increased the tumor-to-kidney absorbed dose ratio during 177Lu-PSMA I&T radionuclide therapy. Hence, at equivalent absorbed dose to the tumor (36 Gy), coinjection of 2-PMPA decreased absorbed dose to the kidneys from 30 Gy to 12 Gy. Mice injected with 177Lu-PSMA I&T only, showed signs of nephrotoxicity at 3 months after therapy, whereas mice injected with 177Lu-PSMA I&T + 2-PMPA did not. These data indicate that PSMA I&T is a promising theranostic tool for PCa. PSMA-specific uptake in kidneys can be successfully tackled using blocking agents such as 2-PMPA.

68Ga-PSMA I&T PET/CT for assessment of prostate cancer: evaluation of image quality after forced diuresis and delayed imaging

Derlin T, Weiberg D, von Klot C, Wester HJ, Henkenberens C, Ross TL, Christiansen H, Merseburger AS, Bengel FM.

24.03.2016 [Original Artikel]

Urinary radiotracer excretion of 68Ga-Labelled prostate-specific membrane antigen (PSMA) ligands may complicate the assessment of the prostate region and differentiation of lymph nodes from ureteral activity. The aim of this study was to assess the value of delayed imaging after forced diuresis. Sixty-six patients underwent 68Ga-PSMA I&T PET/CT for evaluation of prostate cancer at 60 min post-injection. In subgroups of patients, this was amended by delayed imaging after 180 min post-injection, preceded by furosemide and oral hydration early, at the time of tracer injection, or delayed, at 100 min post-injection. Urinary tracer activity within the bladder and focal ureteral activity was analyzed. After forced diuresis, linear and focal visualization of ureters was significantly reduced. After delayed furosemide, mean and peak bladder activity decreased (p < 0.001), and image quality of the prostate region improved on delayed images (p < 0.001). Early furosemide co-injection with tracer resulted in increased mean and peak bladder activity (p < 0.001) and in deteriorated image quality of the prostate region on delayed images (p = 0.008). Ga-PSMA I&T PET/CT delayed imaging after forced diuresis can improve the assessment of prostate region and pelvic lymph nodes by removing excreted tracer from the lower urinary tract. Forced diuresis can improve image quality in 68Ga-PSMA I&T. After forced diuresis, linear and focal visualization of ureters was reduced. Timing of diuresis relative to 68Ga-PSMA I&T injection is important. Early furosemide co-injection with tracer resulted in deteriorated image quality on delayed images. After delayed furosemide, image quality improved on delayed images.

Systemic Radioligand Therapy with (177)Lu Labeled Prostate Specific Membrane Antigen Ligand for Imaging and Therapy in Patients with Metastatic Castration Resistant Prostate Cancer

Heck MM, Retz M, D'Alessandria C, Rauscher I, Scheidhauer K, Maurer T, Storz E, Janssen F, Schottelius M, Wester HJ, Gschwend JE, Schwaiger M, Tauber R, Eiber M.

08.03.2016 [Original Artikel]

We report our initial clinical experience with β -emitting (177)Lu-PSMA-I&T ((177)Lu labeled prostate specific membrane antigen ligand for imaging and therapy) for systemic treatment of metastatic castration resistant prostate cancer. Patients with metastatic castration resistant prostate cancer who experienced treatment failure with chemotherapy and novel androgen receptor targeted therapy were treated for 8 weeks with up to 4 cycles of (177)Lu-PSMA-I&T. We report safety data, the antitumor response with prostate specific antigen decreases and the radiographic tumor response as well as the clinical outcome with changes in ECOG (Eastern Cooperative Oncology Group) performance status and pain severity. The first 3 patients were treated with a lower activity of 3.7 GBq in cycle 1. Due to a favorable safety profile the activity was increased to 7.4 GBq in 19 subsequent patients who completed a total of 40 cycles. With the higher activity no grade 3/4 toxicities were observed. The main nonhematological and hematological grade 1/2 toxicities were dry mouth in 7 patients (37%), anemia in 6 (32%) and thrombopenia in 5 (25%). The proportion of patients who achieved a maximum prostate specific antigen decrease of 30% or greater, 50% or greater and 90% or greater was 56%, 33% and 11%, respectively. Combined assessment of bone and soft tissue metastases showed complete remission in 5% of patients, stable disease in 63% and progressive disease in 32%. ECOG performance status improved or was stable in 74% of patients. Of men with bone pain 58% achieved complete resolution or reduced pain. Radioligand therapy with (177)Lu-PSMA-I&T appears to be safe and active in heavily pretreated patients with metastatic castration resistant prostate cancer.

177Lu-Labeled Prostate-Specific Membrane Antigen Radioligand Therapy of Metastatic Castration-Resistant Prostate Cancer: Safety and Efficacy

Baum RP, Kulkarni HR, Schuchardt C, Singh A, Wirtz M, Wiessalla S, Schottelius M, Mueller D, Klette I, Wester HJ.

21.10.2016 [Original Artikel]

The objective of this study was to analyze the safety and efficacy of the (177)Lu-labeled DOTAGA-based prostate-specific membrane antigen (PSMA) ligand (177)Lu-DOTAGA-(I-y)fk(Sub-KuE) ((177)Lu-PSMA) in patients with metastatic castration-resistant prostate cancer (mCRPC). Fifty-six mCRPC patients underwent PSMA radioligand therapy (RLT) with (177)Lu-PSMA. (68)Ga-PSMA-(N,N'-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid) ((68)Ga-PSMA) PET/CT was used for patient selection and follow-up after PSMA RLT. Hematologic status, renal function, and serum prostate-specific antigen levels were documented before and after therapy. Dosimetry was performed in 30 patients. (177)Lu-PSMA demonstrated high absorbed tumor doses (median, 3.3 mGy/MBq) compared with the levels in normal organs. Parotid glands received higher doses (1.3 mGy/MBq) than kidneys (0.8 mGy/MBq). All patients tolerated the therapy without any acute adverse effects. Except for mild reversible xerostomia in 2 patients, no long-term side effects were observed. There was a small but statistically significant reduction in erythrocyte and leukocyte counts; only the reduction in erythrocyte counts decreased slightly below the reference range. No thrombocytopenia occurred. The severity of pain was significantly reduced in 2 of 6 patients (33.3%). A decrease in prostate-specific antigen levels was noted in 45 of 56 patients (80.4%). Of 25 patients monitored for at least 6 mo after 2 or more PSMA RLT cycles, a molecular response evaluation ((68)Ga-PSMA PET/CT) revealed partial remission in 14, stable disease in 2, and progressive disease in 9 patients. Contrast-enhanced CT revealed partial remission in 5, stable disease in 13, and progressive disease in 7 patients. The median progression-free survival was 13.7 mo, and the median overall survival was not reached during follow-up for 28 mo. PSMA RLT with (177)Lu-PSMA is feasible, safe, and effective in end-stage progressive mCRPC with appropriate selection and follow-up of patients by (68)Ga-PSMA PET/CT through application of the concept of theranostics.

Simultaneous 68Ga-PSMA HBED-CC PET/MRI Improves the Localization of Primary Prostate Cancer

Eiber M, Weirich G, Holzapfel K, Souvatzoglou M, Haller B, Rauscher I, Beer AJ, Wester HJ, Gschwend J, Schwaiger M, Maurer T.

18.01.2016 [Original Artikel]

Ligands of the prostate-specific membrane antigen (PSMA) show promising results in positron emission tomography (PET) imaging of prostate cancer (PCa). To compare the diagnostic performance of simultaneous gallium 68 (68Ga)-PSMA HBED-CC PET/magnetic resonance imaging (MRI) for localization of primary PCa with multiparametric magnetic resonance imaging (mpMRI) and PET alone. We performed 68Ga-PSMA HBED-CC PET/MRI in 66 men with biopsy-proven PCa. PET, mpMRI, and combined 68Ga-PSMA HBED-CC PET/MRI were independently evaluated using Prostate Imaging Reporting and Data System criteria or a 5-point Likert scale. The prostate was divided into sextants for histopathology and coregistered with imaging. Diagnostic performance for localization of malignancy was calculated based on receiver operating characteristics analysis for each modality. Regional quantitative PET tracer uptake was recorded; uptake ratio was defined as the ratio of malignant to nonmalignant prostate tissue. A total of 53 of 66 patients were eligible for analysis. mpMRI, PET, and PET/MRI detected cancer in 66% (35 of 53), 92% (49 of 53), and 98% (52 of 53) of the patients, respectively. Overall, 202 of 318 sextants (63.5%) contained cancer at pathologic examination. Simultaneous PET/MRI statistically outperformed mpMRI (area under the curve [AUC]: 0.88 vs 0.73; p<0.001) and PET imaging (AUC: 0.88 vs 0.83; p=0.002) for localization of PCa. Compared with mpMRI, PET imaging was more accurate (AUC: 0.83 vs 0.73; p=0.003). PET provided a high uptake ratio between malignant versus nonmalignant tissue (5.02 [range: 0.89-29.8]), but no significant correlation was observed between quantitative PET parameters and Gleason score or prostate-specific antigen value. Simultaneous 68Ga-PSMA HBED-CC PET/MRI improves diagnostic accuracy for PCa localization both compared with mpMRI and with PET imaging alone. Further prospective studies are warranted to evaluate its potential (eg, for biopsy guidance). We examined gallium 68 (68Ga)-prostate-specific membrane antigen (PSMA) HBED-CC positron emission tomography/magnetic resonance imaging (PET/MRI) for primary prostate cancer (PCa) and compared it with multiparametric MRI and PET alone. Our results indicate a higher diagnostic accuracy for 68Ga-PSMA HBED-CC PET/MRI that may help localize PCa.