Prostate-Specific Membrane Antigen-Targeted Radioguided Pelvic Lymph Node Dissection in Newly Diagnosed Prostate Cancer Patients with a Suspicion of Locoregional Lymph Node Metastases: The DETECT Trial.

Prostate-specific membrane antigen (PSMA)-targeted radioguided surgery (RGS) aims to optimize the peroperative detection and removal of PSMA-avid lymph node (LN) metastases (LNMs) and has been described in patients with recurrent prostate cancer (PCa). In newly diagnosed PCa patients undergoing pelvic LN dissections, PSMA RGS could guide the urologist toward PSMA-expressing LNMs as identified on preoperative 18F-PSMA PET/CT imaging. The objective was to evaluate the safety and feasibility of 111In-PSMA RGS in primary PCa patients with one or more suggestive LNs on preoperative 18F-PSMA PET/CT. Methods: This prospective, phase I/II study included 20 newly diagnosed PCa patients with at least 1 suggestive LN on preoperative 18F-PSMA PET/CT. PSMA RGS was performed 24 h after 111In-PSMA-I&T administration, and postoperative 18F-PSMA PET/CT was performed to verify successful removal of the suggestive lesions. The primary endpoint was determination of the safety and feasibility of 111In-PSMA RGS. Safety was assessed by monitoring adverse events. Feasibility was described as the possibility to peroperatively detect suggestive LNs as identified on preoperative imaging. Secondary outcomes included the accuracy of 111In-PSMA RGS compared with histopathology, tumor- and lesion-to-background ratios, and biochemical recurrence. Results: No tracer-related adverse events were reported. In 20 patients, 43 of 49 (88%) 18F-PSMA PET-suggestive lesions were successfully removed. 111In-PSMA RGS facilitated peroperative identification and resection of 29 of 49 (59%) RGS-target lesions, of which 28 (97%) contained LNMs. Another 14 of 49 (29%) resected LNs were not detected with 111In-PSMA RGS, of which 2 contained metastases. Conclusion: 111In-PSMA RGS is a safe and feasible procedure that allows peroperative detection of 18F-PSMA PET/CT-suggestive lesions in newly diagnosed PCa patients. The use of a radioactive PSMA tracer and a detection device (γ-probe) during surgery helps in identifying LNs that were suggestive of PCa metastases on the 18F-PSMA PET/CT before surgery and thus may improve the peroperative identification and removal of these LNs.

Subnodal Correspondence of PSMA Expression and USPIO-MRI in Metastatic Pelvic Lymph Nodes in Prostate Cancer.

OBJECTIVES: Two advanced imaging modalities used to detect lymph node (LN) metastases in prostate cancer patients are prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography and ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI). As these modalities use different targets, a subnodal comparison is needed to interpret both their correspondence and their differences. The aim of this explorative study was to compare ex vivo 111In-PSMA µSPECT images with high-resolution 7 T USPIO µMR images and histopathology of resected LN specimens from prostate cancer patients to assess the degree of correspondence at subnodal level. MATERIALS AND METHODS: Twenty primary prostate cancer patients who underwent pelvic LN dissection were included and received USPIO contrast and 111In-PSMA. A total of 41 LNs of interest (LNOIs) were selected for ex vivo imaging based on γ-probe detection or palpation. µSPECT and µMRI acquisition were performed immediately after resection. Overlay of µSPECT images on MR images was performed, and the level of correspondence (LoC) between µSPECT and µMR findings was assessed according to a 4-point Likert classification scheme. RESULTS: Forty-one LNOIs could be matched to an LN on ex vivo µMRI. Coregistration of µSPECT and USPIO-enhanced water-selective multigradient echo MR images was successful for all 41 LNOIs. Ninety percent of the lesions showed excellent correspondence regarding the presence of metastatic tissue and affected subnodal site (LoC 4; 37/41). In only 1 of 41 LNOIs, a small metastasis was misclassified by both techniques. Three LNOIs were classified as LoC 3 (7%) and 1 LNOI as LoC 2. All LoC 2 and LoC 3 lesions had PSMA-expressing metastases on final histopathology. CONCLUSIONS: Coregistration of µSPECT and USPIO-µMRI showed excellent subnodal correspondence in the majority (90%) of LNs. Ex vivo imaging may thus help localize small cancer deposits within resected LNs and could contribute to improved interpretation of in vivo imaging of LNs.

Imaging and photodynamic therapy of prostate cancer using a theranostic PSMA-targeting ligand.

PURPOSE: Incomplete resection of prostate cancer (PCa) results in increased risk of disease recurrence. Combined fluorescence-guided surgery with tumor-targeted photodynamic therapy (tPDT) may help to achieve complete tumor eradication. We developed a prostate-specific membrane antigen (PSMA) ligand consisting of a DOTA chelator for 111In labeling and a fluorophore/photosensitizer IRDye700DX (PSMA-N064). We evaluated the efficacy of PSMA-tPDT using PSMA-N064 in cell viability assays, a mouse xenograft model and in an ex vivo incubation study on fresh human PCa tissue. METHODS: In vitro, therapeutic efficacy of PSMA-N064 was evaluated using PSMA-positive LS174T cells and LS174T wild-type cells. In vivo, PSMA-N064-mediated tPDT was tested in immunodeficient BALB/c mice-bearing PSMA-positive LS174T xenografts. Tumor growth and survival were compared to control mice that received either NIR light or ligand injection only. Ex vivo tPDT efficacy was evaluated in excised fresh human PCa tissue incubated with PSMA-N064. RESULTS: In vitro, tPDT led to a PSMA-specific light- and ligand dose-dependent loss in cell viability. In vivo, tPDT-induced tumor cell apoptosis, delayed tumor growth, and significantly improved survival (p = 0.004) of the treated PSMA-positive tumor-bearing mice compared with the controls. In fresh ex vivo human PCa tissue, apoptosis was significantly increased in PSMA-tPDT-treated samples compared to non-treated control samples (p = 0.037). CONCLUSION: This study showed the feasibility of PSMA-N064-mediated tPDT in cell assays, a xenograft model and excised fresh human PCa tissue. This paves the way to investigate the impact of in vivo PSMA-tPDT on surgical outcome in PCa patients.

How Advanced Imaging Will Guide Therapeutic Strategies for Patients with Newly Diagnosed Prostate Cancer in the Years to Come.

In recent years, clinical use of novel advanced imaging modalities in prostate cancer detection, staging, and therapy has intensified and is currently reforming clinical guidelines. In the future, advanced imaging technologies will continue to develop and become even more accurate, which will offer new opportunities for improving patient selection, surgical treatment, and radiotherapy, with the potential to guide prostate cancer therapy.

An Explorative Study of the Incidental High Renal Excretion of [18F]PSMA-1007 for Prostate Cancer PET/CT Imaging.

Positron emission tomography (PET) of prostate-specific membrane antigen (PSMA) allows for accurate diagnosis and staging of prostate cancer (PCa). Compared to other PSMA PET tracers available, [18F]PSMA-1007 is predominantly excreted via the hepatobiliary tract resulting in low renal excretion which improves evaluation of the pelvic area. However, some patients do show high urinary uptake of [18F]PSMA-1007. The present study aimed to investigate this sudden high urinary uptake of [18F]PSMA-1007 by evaluating [18F]PSMA-1007 PET scans from PCa patients. In this single-center retrospective study, patients that underwent [18F]PSMA-1007 PET imaging between July 2018 and January 2021 were included. Data regarding the individual patient characteristics, scan acquisition and batch production were analyzed. To determine the urinary excretion of [18F]PSMA-1007, a region of interest was drawn in the bladder, and standardized uptake values (SUVs) were calculated and compared to SUVs in the prostate. An SUVmax of >10 was considered high urinary excretion, an SUVmax 7.5−10 intermediate and an SUVmax < 7.5 low urinary excretion. A total of 344 patients underwent [18F]PSMA-1007 PET/CT imaging, with 37 patients receiving three or more [18F]PSMA-1007 PET/CT scans. The mean SUVmean and SUVmax of the bladder were 3.9 (SD 2.9) and 5.9 (SD 4.2), respectively. Fourteen percent of patients showed high urinary uptake of [18F]PSMA-1007. Twelve of the thirty-seven patients (32.4%) that had multiple scans showed a varying urinary uptake of [18F]PSMA-1007 per PSMA PET/CT scan. In terms of patient characteristics, risk factors, medication and blood laboratory results, no significant influencing variables were found. Nor was there a difference observed in the batch size and the mean radiochemical purity of PSMA-1007 for high- and low-excreting patients. However, the bladder volume affected the mean SUVmax in the bladder significantly, with higher SUVs in lower bladder volumes. In this study, we observed that a higher SUV in the urinary tract seemed to occur in patients with low bladder volume. A prospective study is needed to corroborate this hypothesis.

How Image-Guided Pathology Can Improve the Detection of Lymph Node Metastases in Prostate Cancer.

ABSTRACT: Detection of lymph node (LN) metastases in prostate cancer (PCa) is pivotal for accurate staging and determining treatment options. To date, the reference standard for nodal staging is histopathological examination of all harvested surgical specimens from extended pelvic LN dissections. However, this is a labor-intensive process, and small metastatic foci can be missed due to sampling effects. With current research expanding toward using radiolabeled prostate-specific membrane antigen ligands for image-guided surgery, new opportunities arise for image-guided pathological assessment of surgical specimens. Here, we illustrate how molecular imaging can complement histopathology and improve accurate detection of LN metastases.

Lutetium-177-PSMA-617 in Low-Volume Hormone-Sensitive Metastatic Prostate Cancer: A Prospective Pilot Study.

PURPOSE: [177Lu]Lu-PSMA-617 radioligand therapy (177Lu-PSMA) is a novel treatment for metastatic castration-resistant prostate cancer (mCRPC), which could also be applied to patients with metastatic hormone-sensitive prostate cancer (mHSPC) with PSMA expression. In this prospective study (NCT03828838), we analyzed toxicity, radiation doses, and treatment effect of 177Lu-PSMA in pateints with low-volume mHSPC. PATIENTS AND METHODS: Ten progressive patients with mHSPC following local treatment, with a maximum of ten metastatic lesions on [68Ga]Ga-PSMA-11 PET/diagnostic-CT imaging (PSMA-PET) and serum PSA doubling time <6 months received two cycles of 177Lu-PSMA. Whole-body single-photon emission CT/CT (SPECT/CT) and blood dosimetry was performed to calculate doses to the tumors and organs at risk (OAR). Adverse events (AE), laboratory values (monitoring response and toxicity), and quality of life were monitored until week 24 after cycle 2, the end of study (EOS). All patients underwent PSMA-PET at screening, 8 weeks after cycle 1, 12 weeks after cycle 2, and at EOS. RESULTS: All patients received two cycles of 177Lu-PSMA without complications. No treatment-related grade III-IV adverse events were observed. According to dosimetry, none of the OAR reached threshold doses for radiation-related toxicity. Moreover, all target lesions received a higher radiation dose than the OAR. All 10 patients showed altered PSA kinetics, postponed androgen deprivation therapy, and maintained good quality of life. Half of the patients showed a PSA response of more than 50%. One patient had a complete response on PSMA-PET imaging until EOS and two others had only minimal residual disease. CONCLUSIONS: 177Lu-PSMA appeared to be a feasible and safe treatment modality in patients with low-volume mHSPC.

Head-to-Head Comparison of 68Ga-Prostate-Specific Membrane Antigen PET/CT and Ferumoxtran-10-Enhanced MRI for the Diagnosis of Lymph Node Metastases in Prostate Cancer Patients.

Accurate assessment of lymph node (LN) metastases in prostate cancer (PCa) patients is critical for prognosis and patient management. Both prostate-specific membrane antigen (PSMA) PET/CT and ferumoxtran-10 nanoparticle-enhanced MRI (nano-MRI) are imaging modalities with high potential to identify LN metastases in PCa patients. The aim of this study was to compare the results of these imaging technologies in terms of characteristics and anatomic localization of suspicious LNs in order to assess the feasibility of their complementary use for imaging in PCa patients. Methods: In total, 45 patients with either primary PCa (n = 8) or recurrence (n = 36) were included in this retrospective study. All patients underwent both 68Ga-PSMA PET/CT and nano-MRI between October 2015 and July 2017 within 3 wk. Both scans were performed at the same institution according to local clinical protocols. All scans were analyzed independently by experienced nuclear medicine physicians and radiologists. The size, anatomic location, and level of suspicion were determined for all visible LNs. Subsequently, the findings from 68Ga-PSMA PET/CT and nano-MRI were compared without respect to a reference standard. Results: In total, 179 suspicious LNs were identified. Significantly more suspicious LNs per patient were detected by nano-MRI (P < 0.001): 160 were identified in 33 patients by nano-MRI, versus 71 in 25 patients by 68Ga-PSMA PET/CT. Of all suspicious LNs, 108 were identified only by nano-MRI (60%), 19 (11%) only by 68Ga-PSMA PET/CT, and 52 (29%) by both methods. The mean size of the suspicious LNs as identified by nano-MRI was significantly smaller (5.3 mm) than that by 68Ga-PSMA PET/CT (6.0 mm; P = 0.006). The median level of suspicion did not differ significantly. Both modalities identified suspicious LNs in all anatomic regions of the pelvis. Conclusion: Both modalities identified suspicious LNs that were missed by the other. Both modalities identified suspicious LNs in all anatomic regions of the pelvis; however, nano-MRI appeared to be superior in detecting smaller suspicious LNs. These findings suggest that nano-MRI has a potential role as a complement to PSMA PET/CT. However, since the clinical implications of the different results are not well established yet, further investigation of this complementary use is encouraged.

Evaluating F-18-PSMA-1007-PET in primary prostate cancer and comparing it to multi-parametric MRI and histopathology.

BACKGROUND: PSMA-PET is a novel imaging modality for the staging of prostate cancer (PCa). While there are several PSMA ligands available, F-18-PSMA-1007 is particularly of interest as it is not renally excreted and therefore does not impair the imaging of the pelvic area. Hence, this study aimed to investigate the F-18-PSMA-1007-PET for the primary staging of PCa and compared it to multi-parametric (mp) MRI and histopathology. METHODS: A retrospective study was performed of men with intermediate and high-risk PCa patients that underwent a F-18-PSMA-1007-PET after mpMRI with subsequent MR-guided target biopsy (MRGB). Suspicious mpMRI lesions and F-18-PSMA-1007-PET were simultaneously reviewed on both a per patient and per-lesion basis. Results were subsequently evaluated with histopathological outcome of MRGB, and if performed, the radical prostatectomy specimen. RESULTS: A total of 66 suspicious mpMRI lesions were identified in 53 patients and underwent MRGB. Two lesions had a maximum standardized uptake value (SUVmax) less than the mean SUVmax of healthy prostate tissue and were considered as non-PSMA-expressing. All PSMA avid tumors had higher SUVmax than the mean SUVmean of the bladder/urine, therefore all lesions were clearly distinguishable in the pelvic area. Twenty-three patients received a radical prostatectomy of which the histopathology specimens were evaluated. F-18-PSMA-1007-PET/CT correctly staged seminal vesicle invasion (i.e. pT3b) more often than mpMRI (90 vs. 76%), whereas mpMRI more accurately detected extracapsular extension (i.e. pT3a) compared to F-18-PSMA-1007-PET (90% vs 57%). CONCLUSIONS: The present study of a selected cohort suggest that dual imaging with mpMRI and F-18-PSMA-1007-PET may improve staging of primary PCa. F-18-PSMA-1007-PET/CT had low renal clearance, which could assist the evaluation of tumors in proximity of the bladder.

Comparison of risk-calculator and MRI and consecutive pathways as upfront stratification for prostate biopsy.

PURPOSE: In biopsy naïve men suspected for prostate cancer (PCa), it is uncertain how a risk-calculator and bi-parametric (bp) MRI should be combined to decide on prostate biopsy, balancing cancer detection rates and diagnostic burden. METHODS: Prospective, single centre cohort study (August 2018-April 2019). All patients referred with serum PSA ≥ 3 ng/ml or abnormal digital rectal examination received bpMRI and risk for PCa was calculated using the ERSPC risk-calculator. Men with either PI-RADS ≥ 3 or calculator risk-score > 20% were recommended to undergo systematic biopsy (SB) and targeted biopsy (TB) of any visible lesion (reference pathway). Eight different derived diagnostic pathways were compared to the reference pathway regarding cancer detection, number of biopsies and bpMRIs performed. RESULTS: Of 496 patients; 233 (47%) had a risk-calculator score of > 20%; 201 (41%) had PI-RADS score ≥ 3. The reference pathway detected PCa in 32.1%, clinically significant (cs) PCa in 19.4%, with 41% avoided biopsies, but 0% avoided bpMRI. Stratification with only risk-calculator: 76% csPCa diagnosed, 53% avoided biopsies and 100% avoided bpMRI. Stratification with only bpMRI: 97% csPCa diagnosed, 59% avoided biopsies, but 0% avoided bpMRI. A pathway with risk-calculator first, followed only with bpMRI when high-risk: 81% csPCa diagnosed, 72% avoided biopsies and 53% avoided bpMRI. CONCLUSION: Upfront bpMRI as a risk stratification tool outperforms risk-calculator in detecting significant disease. Applying the risk-calculator first to decide on performing an MRI, avoids 1 out of 2 MRIs, but up to 1 out of 5 significant cancers are missed.