Intra-therapeutic dosimetry of [177Lu]Lu-PSMA-617 in low-volume hormone-sensitive metastatic prostate cancer patients and correlation with treatment outcome.

INTRODUCTION: While [177Lu]Lu-PSMA radioligand therapy is currently only applied in end-stage metastatic castrate-resistant prostate cancer (mCRPC) patients, also low-volume hormone-sensitive metastatic prostate cancer (mHSPC) patients can benefit from it. However, there are toxicity concerns related to the sink effect in low-volume disease. This prospective study aims to determine the kinetics of [177Lu]Lu-PSMA in mHSPC patients, analyzing the doses to organs at risk (salivary glands, kidneys, liver, and bone marrow) and tumor lesions < 1 cm diameter. METHODS: Ten mHSPC patients underwent two cycles of [177Lu]Lu-PSMA therapy. Three-bed position SPECT/CT was performed at 5 time points after each therapy. Organ dosimetry and lesion dosimetry were performed using commercial software and a manual approach, respectively. Correlation between absorbed index lesion dose and treatment response (PSA drop of > 50% at the end of the study) was calculated and given as Spearman's r and p-values. RESULTS: Kinetics of [177Lu]Lu-PSMA in mHSPC patients are comparable to those in mCRPC patients. Lesion absorbed dose was high (3.25 ± 3.19 Gy/GBq) compared to organ absorbed dose (salivary glands: 0.39 ± 0.17 Gy/GBq, kidneys: 0.49 ± 0.11 Gy/GBq, liver: 0.09 ± 0.01 Gy/GBq, bone marrow: 0.017 ± 0.008 Gy/GBq). A statistically significant correlation was found between treatment response and absorbed index lesion dose (p = 0.047). CONCLUSIONS: We successfully performed small lesion dosimetry and showed that the tumor sink effect in mHSPC patients is of less concern than was expected. Tumor-to-organ ratio of absorbed dose was high and tumor uptake correlates with PSA response. Additional treatment cycles are legitimate in terms of organ toxicity and could lead to better tumor response.

The effect of primary urological cancers on survival in men with secondary prostate cancer.

BACKGROUND: To test the effect of urological primary cancers (bladder, kidney, testis, upper tract, penile, urethral) on overall mortality (OM) after secondary prostate cancer (PCa). METHODS: Within the Surveillance, Epidemiology and End Results (SEER) database, patients with urological primary cancers and concomitant secondary PCa (diagnosed 2004-2016) were identified and were matched in 1:4 fashion with primary PCa controls. OM was compared between secondary and primary PCa patients and stratified according to primary urological cancer type, as well as to time interval between primary urological cancer versus secondary PCa diagnoses. RESULTS: We identified 5,987 patients with primary urological and secondary PCa (bladder, n = 3,287; kidney, n = 2,127; testis, n = 391; upper tract, n = 125; penile, n = 47; urethral, n = 10) versus 531,732 primary PCa patients. Except for small proportions of Gleason grade group and age at diagnosis, PCa characteristics between secondary and primary PCa were comparable. Conversely, proportions of secondary PCa patients which received radical prostatectomy were smaller (29.0 vs. 33.5%), while no local treatment rates were higher (34.2 vs. 26.3%). After 1:4 matching, secondary PCa patients exhibited worse OM than primary PCa patients, except for primary testis cancer. Here, no OM differences were recorded. Finally, subgroup analyses showed that the survival disadvantage of secondary PCa patients decreased with longer time interval since primary cancer diagnosis. CONCLUSIONS: After detailed matching for PCa characteristics, secondary PCa patients exhibit worse survival, except for testis cancer patients. The survival disadvantage is attenuated, when secondary PCa diagnosis is made after longer time interval, since primary urological cancer diagnosis.

Upfront metastasis-directed therapy in oligorecurrent prostate cancer does not decrease the time from initiation of androgen deprivation therapy to castration resistance.

The aim of the present study was to explore the potential impact of upfront metastases-directed therapy (MDT) in terms of prolongation of castration-sensitive phase in a series of oligorecurrent castration-sensitive prostate cancer (PC) patients. The present article is a multicenter retrospective study. The population of interest was castrate-sensitive oligorecurrent PC, defined as the presence of 1-3 uptakes in non-visceral sites such as bones or nodes detected by means of 18F-Choline PET/CT or 68-Gallium PSMA PET/CT. Primary endpoint was the time to castration resistance. Secondary endpoints were ADT-free survival, local progression-free survival, and overall survival. Eighty-two patients and 118 lesions were analyzed. The median time to castration resistance for the entire population of the study was 49 months (95% CI 43.6-54.4 months). The 1- and 2-year TTCR-free survival rates were 94% and 82%, respectively. At the time of analysis, 52 patients were still in the castration-sensitive phase of the disease. In this cohort of patients, the median ADT-free survival was 20 months (range 3-69 months). On the other hand, during follow-up 30 patients switched to the castration-resistant phase of disease. In this last group of patients, the median ADT-free survival was 20 months (range 4-50 months). After the ADT administration, the median castration-sensitive phase was 29 months (range 5-71 months). Castration resistance generally occurs at a median follow-up of 24-36 months following ADT. In the current study, upfront MDT does not decrease the time from initiation of ADT to castration resistance.

Overall Survival of Men with Metachronous Metastatic Hormone-sensitive Prostate Cancer Treated with Enzalutamide and Androgen Deprivation Therapy.

Men who initially present with localized prostate cancer and later develop metachronous metastases have a better prognosis than men with de novo metastatic disease and often have a low burden of disease on conventional imaging. Some have disease amenable to metastasis-directed therapy for lymph node or bone metastases, a strategy used by some because no documented overall survival (OS) benefit of combination systemic therapy in this setting. We report data for patients prospectively classified as "M0" at initial diagnosis from the interim analysis of the ENZAMET trial, with 34 mo of median follow-up for survivors. A total of 312 (28%) of the 1125 enrolled patients were classified as M0 at diagnosis, and 205 (66%) of the 312 patients had low-volume disease at study entry as per the CHAARTED criteria. The hazard ratio for OS, that is, HR(OS), was 0.56 (95% confidence interval [CI]: 0.29-1.06) with the addition of enzalutamide for all patients with metachronous metastatic hormone-sensitive prostate cancer, and for the low-volume subset the HR(OS) was 0.40 (95% CI: 0.16-0.97). The 3-yr OS was 83% without and 89% with enzalutamide for all patients with metachronous metastases, and 83% and 92%, respectively, for the low-volume subset. Intensification of hormonal therapy should strongly be considered for these men. PATIENT SUMMARY: Many men present with prostate cancer that has spread to distant sites beyond the prostate gland years after their initial diagnosis and treatment, while others have distant spread at the time the cancer is diagnosed. On average, men whose cancer comes back years after the initial diagnosis often survive much longer than men whose cancer has been found to spread to distant sites when it is first diagnosed. In this report, we demonstrate strong evidence for the first time that the survival of men whose cancer comes back years later is improved when drugs such as enzalutamide or apalutamide are added to testosterone suppression in this setting.

Inhibition of glypican-1 expression induces an activated fibroblast phenotype in a human bone marrow-derived stromal cell-line.

Cancer-associated fibroblasts (CAFs) are the most abundant stromal cell type in the tumor microenvironment. CAFs orchestrate tumor-stromal interactions, and contribute to cancer cell growth, metastasis, extracellular matrix (ECM) remodeling, angiogenesis, immunomodulation, and chemoresistance. However, CAFs have not been successfully targeted for the treatment of cancer. The current study elucidates the significance of glypican-1 (GPC-1), a heparan sulfate proteoglycan, in regulating the activation of human bone marrow-derived stromal cells (BSCs) of fibroblast lineage (HS-5). GPC-1 inhibition changed HS-5 cellular and nuclear morphology, and increased cell migration and contractility. GPC-1 inhibition also increased pro-inflammatory signaling and CAF marker expression. GPC-1 induced an activated fibroblast phenotype when HS-5 cells were exposed to prostate cancer cell conditioned media (CCM). Further, treatment of human bone-derived prostate cancer cells (PC-3) with CCM from HS-5 cells exhibiting GPC-1 loss increased prostate cancer cell aggressiveness. Finally, GPC-1 was expressed in mouse tibia bone cells and present during bone loss induced by mouse prostate cancer cells in a murine prostate cancer bone model. These data demonstrate that GPC-1 partially regulates the intrinsic and extrinsic phenotype of human BSCs and transformation into activated fibroblasts, identify novel functions of GPC-1, and suggest that GPC-1 expression in BSCs exerts inhibitory paracrine effects on the prostate cancer cells. This supports the hypothesis that GPC-1 may be a novel pharmacological target for developing anti-CAF therapeutics to control cancer.

Vinculin orchestrates prostate cancer progression by regulating tumor cell invasion, migration, and proliferation.

BACKGROUND: Prostate cancer (PCa) is a leading cause of death in men, and effective treatment of PCa requires further development. Our study aimed to investigate the potential role of vinculin (VCL) in PCa progression in vitro and in vivo. METHODS: We investigated the methylation level of the VCL promoter based on the TCGA database. The knockdown efficacy of VCL gene expression was confirmed by quantitative polymerase chain reaction, Western blot analysis, and immunofluorescence. Furthermore, morphological changes in PCa cells were detected using phalloidin staining. The mobility of PCa cells was measured using transwell assays and high-content analysis. Moreover, cell growth and viability were determined using the colony formation and cell counting kit-8 assays. The role of VCL in tumor growth in vivo was investigated using a subcutaneous xenograft model generated by injecting tumor cells into the right flank of BALB/c nude mice. RESULTS: The methylation level of the VCL promoter in PCa was significantly downregulated concomitant with age and the progression of nodal metastasis. VCL expression was markedly decreased by shRNA. Importantly, VCL knockdown significantly changed the cell morphology; inhibited the migration, invasion, and movement; and repressed colony formation and viability of PCa cells in vitro. Furthermore, downregulation of VCL suppressed tumor growth in vivo. CONCLUSIONS: Our study comprehensively evaluated the role of VCL in PCa progression in vivo and in vitro. The findings of the present study suggest that VCL can be a potential target for PCa prognosis and treatment.

Ephrin-A2 promotes prostate cancer metastasis by enhancing angiogenesis and promoting EMT.

BACKGROUND: Ephrin-A2, a member of the Eph receptor subgroup, is used in diagnosing and determining the prognosis of prostate cancer. However, the role of ephrin-A2 in prostate cancer is remains elusive. METHODS: We established stable clones overexpressing or silencing ephrin-A2 from prostate cancer cells. Then, CCK-8 was used in analyzing the proliferation ability of cells. CD31 staining was used in evaluating angiogenesis. Migration and invasion assay were conducted in vivo and in vitro. The expression of EMT-related markers was evaluated in prostate cancer cells through Western blotting. RESULTS: We revealed that the ectopic expression of ephrin-A2 in prostate cancer cells facilitated cell migration and invasion in vitro and promoted tumor metastasis and angiogenesis in vivo and that the silencing of ephrin-A2 completely reversed this effect. Although ephrin-A2 did not affect tumor cell proliferation in vitro, ephrin-A2 significantly promoted primary tumor growth in vivo. Furthermore, to determine the biological function of ephrin-A2, we assayed the expression of EMT-related markers in stable-established cell lines. Results showed that the overexpression of ephrin-A2 in prostate cancer cells down-regulated the expression of epithelial markers (ZO-1, E-cadherin, and claudin-1) and up-regulated the expression of mesenchymal markers (N-cadherin, ß-catenin, vimentin, Slug, and Snail), but the knocking out of ephrin-A2 opposed the effects on the expression of EMT markers. CONCLUSIONS: These findings indicate that ephrin-A2 promotes prostate cancer metastasis by enhancing angiogenesis and promoting EMT and may be a potentially therapeutic target in metastatic prostate cancer.

External beam radiation therapy improves survival in low-volume metastatic prostate cancer patients: a North American population-based study.

BACKGROUND: We hypothesized that the survival benefit of external beam radiation therapy (EBRT) recorded in European low-volume metastatic prostate cancer (mPCA) patients, will apply to similar North American patients. METHODS: Newly diagnosed mPCa patients with M1a/b substages, treated with EBRT or no EBRT were abstracted from the Surveillance, Epidemiology, and End Results database (2004-2016). Kaplan-Meier plots and Cox-regression models targeted overall mortality (OM) and cancer specific-mortality (CSM) according to EBRT administration. M1 substages and PSA stratified analyses were performed. Internal validation relied on 2000 bootstrap resamples. RESULTS: Of 15,494 patients, 1156 (7.5%) were M1a vs 14,338 (92.5%) were M1b. PSA at diagnosis ≤10.0 ng/ml was recorded in 1463 (9.4%) patients. In all 15,494 patients, EBRT did not affect OM (hazard ratio [HR] 1.0; p = 0.5). However, in M1a patients and M1b patients with PSA ≤ 10.0 ng/ml EBRT was associated with lower OM (HR 0.73, CI 0.62-0.86; p < 0.001) but not in M1b patients with PSA > 10.0 ng/ml. The PSA cut-off of ≤ 10.0 ng/ml represented the most statistically significant cut-off for OM prediction in M1b patients. Moreover, internal validation with 2000 bootstrap resamples confirmed these findings. Finally, all results were virtually the same, when CSM represented the endpoint of interest. CONCLUSIONS: We validated the OM reduction associated with EBRT in M1a and M1b patients with PSA ≤ 10.0 ng/ml but not in M1b patients with PSA > 10.0 ng/ml. In consequence, it appears that a smaller subset of North American mPCa patients benefit of EBRT than originally reported in European patients. Further North American validation studies are essential.

Survival following upfront chemotherapy for treatment-naïve metastatic prostate cancer: a real-world retrospective cohort study.

BACKGROUND: Upfront chemotherapy prolongs overall survival for men with metastatic, hormone-sensitive prostate cancer (mHSPC) based on data from clinical trials. We sought to assess the association between upfront chemotherapy and overall survival in men with mHSPC in a real-world cohort. METHODS: We performed a retrospective cohort study of men with de novo, treatment-naïve metastatic prostate cancer from a large, national cancer database in the United States (2014-2015). Men in the upfront chemotherapy group received chemotherapy within 4 months of diagnosis (n = 1033, 28%) versus no chemotherapy or chemotherapy later than 12 months after diagnosis (controls; n = 2704, 72%). Overall survival was assessed using Kaplan-Meier estimates and compared using multivariable Cox regression analysis. RESULTS: After a median follow-up of 23 months, median overall survival was 35.7 months in the upfront chemotherapy group and 32.5 months for controls (log-rank p < 0.001). After adjusting for patient and clinical variables, upfront chemotherapy was associated with longer overall survival (hazard ratio 0.78, 95% confidence interval 0.68-0.89, p < 0.001). In exploratory analyses, the association between upfront chemotherapy and overall survival did not differ by age groups, race, or number of comorbidities (all interaction p > 0.2). CONCLUSIONS: In this real-world cohort, upfront chemotherapy for mHSPC was associated with longer overall survival. These data support the continued use of chemotherapy for men with mHSPC regardless of race or age if they are fit for chemotherapy and underscore the importance of evaluating cancer therapeutics outside of clinical trials to demonstrate treatment efficacy in populations that may be underrepresented in clinical trials.

Clinical outcomes of definitive whole pelvic radiotherapy for clinical lymph node metastatic prostate cancer.

BACKGROUND: In this study, we aim to present the clinical outcomes of radiotherapy (RT) in clinical pelvic lymph node-positive prostate cancer (cN1) patients. We also analyze the prognostic factors with focus on RT dose escalation to metastatic lymph nodes (LN). METHODS: We retrospectively analyzed the data from cN1 patients who were treated with definitive RT and androgen deprivation therapy (ADT) between June 2004 and February 2016. All patients received localized irradiation to the prostate region and whole pelvis irradiation. Some patients received intensity-modulated radiation therapy with RT dose escalation to metastatic LN. Univariate analyses using log-rank test were performed to find prognostic factors between patient subgroups. RESULTS: Fifty-one consecutive patients were identified. The median follow-up period for all patients was 88 (range 20-157) months. Primary Gleason pattern and LN RT dose were statistically significant prognostic factors for relapse-free survival (RFS) and distant metastasis-free survival (DMFS). Especially, RT dose escalation (60 Gy or more) to metastatic LN significantly improved RFS and DMFS compared with standard dose RT (4-year RFS 90.6% vs 82.1%, 7-year RFS 90.6% vs 58.0%, P = .015; 4-year DMFS 90.6% vs 82.1%, 7-year DMFS 90.6% vs 62.8%, P = .023). The following factors were all statistically significant for biochemical relapse-free survival (BRFS): T stage, LN RT dose, local RT dose, and ADT duration period. Any significantly different toxicity was not seen for each LN or local RT dose except for the incident rate of grade 2 or more acute urinary retention, which was significantly higher in the higher LN RT dose (60 Gy or more) group by the Chi-square test. CONCLUSIONS: RT dose escalation to metastatic LN in cN1 patients improves BRFS, RFS, and DMFS at 4 and 7 years, without increasing severe adverse events.

PEACE V - Salvage Treatment of OligoRecurrent nodal prostate cancer Metastases (STORM): a study protocol for a randomized controlled phase II trial.

BACKGROUND: Pelvic nodal recurrences are being increasingly diagnosed with the introduction of new molecular imaging techniques, like choline and PSMA PET-CT, in the restaging of recurrent prostate cancer (PCa). At this moment, there are no specific treatment recommendations for patients with limited nodal recurrences and different locoregional treatment approaches are currently being used, mostly by means of metastasis-directed therapies (MDT): salvage lymph node dissection (sLND) or stereotactic body radiotherapy (SBRT). Since the majority of patients treated with MDT relapse within 2 years in adjacent lymph node regions, with an estimated median time to progression of 12-18 months, combining MDT with whole pelvic radiotherapy (WPRT) may improve oncological outcomes in these patients. The aim of this prospective multicentre randomized controlled phase II trial is to assess the impact of the addition of WPRT to MDT and short-term androgen deprivation therapy (ADT) on metastasis-free survival (MFS) in the setting of oligorecurrent pelvic nodal recurrence. METHODS & DESIGN: Patients diagnosed with PET-detected pelvic nodal oligorecurrence (≤5 nodes) following radical local treatment for PCa, will be randomized in a 1:1 ratio between arm A: MDT and 6 months of ADT, or arm B: WPRT added to MDT and 6 months of ADT. Patients will be stratified by type of PET-tracer (choline, FACBC or PSMA) and by type of MDT (sLND or SBRT). The primary endpoint is MFS and the secondary endpoints include clinical and biochemical progression-free survival (PFS), prostate cancer specific survival, quality of life (QoL), toxicity and time to castration-resistant prostate cancer (CRPC) and to palliative ADT. Estimated study completion: December 31, 2023. DISCUSSION: This is the first prospective multicentre randomized phase II trial assessing the potential of combined WPRT and MDT as compared to MDT alone on MFS for patients with nodal oligorecurrent PCa. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03569241, registered June 14, 2018, ; Identifier on Swiss National Clinical Trials Portal (SNCTP): SNCTP000002947, registered June 14, 2018.

Independent external validation of nomogram to predict extracapsular extension in patients with prostate cancer.

INTRODUCTION: The objective of this study was to perform an independent external validation of the Giganti-Coppola nomogram (GCN), which uses clinical and radiological parameters to predict prostate extracapsular extension (ECE) on the final pathology of patients undergoing radical prostatectomy (RP). MATERIAL AND METHODS: Seventy-two patients diagnosed with prostate cancer (PCa), who were RP candidates from two institutions, were prospectively included. All patients underwent preoperative multi-parametric magnetic resonance imaging (mpMRI) at 1.5 T, without the use of an endorectal coil, with multiplanar images in T1WI, T2WI, DWI, and DCE. The AUC and a calibration graph were used to validate the nomogram, using the regression coefficients of the Giganti-Coppola study. RESULTS: The original nomogram had an AUC of 0.90 (p = 0.001), with a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 100%, 5.1%, 47.1%, 100%, and 48%, respectively. The calibration graph showed an overestimation of the nomogram for ECE. CONCLUSION: The GCN has an adequate ability in predicting ECE; however, in our sample, it showed limited accuracy and overestimated likelihood of ECE in the final pathology of patients with PCa submitted to RP. KEY POINTS: • Knowledge of preoperative local staging of prostate cancer is essential for surgical treatment. Extracapsular extension increases the chance of positive surgical margins. • Imaging modalities such as mpMRI alone does not have suitable accuracy in local staging. • Giganti-Coppola's nomogram achieved an adequate ability in predicting ECE.

[Treatment concepts for primary oligometastatic prostate cancer]. / Therapiekonzepte beim primär oligometastasierten Prostatakarzinom.

BACKGROUND: About 5% of prostate cancer patients have distant metastases at diagnosis. In these metastatic hormone-sensitive prostate cancers (mHSPC), systemic therapy is recommended, according to the guidelines. Moreover, metastasis-directed therapy (MDT) is discussed to prolong survival. OBJECTIVES: The contemporary literature concerning local therapy and MDT in patients with mHSPC is summarized. METHODS: Selective literature search. RESULTS: In 2018, randomized controlled data on local therapy in mHSPC patients were published by the authors of the STAMPEDE study. Here, patients were randomized between standard of care (SOC) ± radiotherapy to the prostate (RT). Within the overall cohort, no difference regarding 3­year overall survival (OS) was observed. Within a prespecified subgroup of patients with low metastatic burden. Similar results were observed in numerous retrospective studies analyzing radical prostatectomy; prospective randomized studies are pending. For MDT, there are no sufficient data in mHSPC patients yet. CONCLUSIONS: In the current guidelines, systematic therapy is standard of care in mHSPC patients. In patients with low metastatic burden, a survival benefit was observed when adding percutaneous RT to the prostate. Retrospective studies also suggest a benefit when adding RP. However, whether MDT prolongs survival is still unknown.

Single-port robot-assisted radical prostatectomy: a systematic review and pooled analysis of the preliminary experiences.

OBJECTIVE: To summarize the clinical experiences with single-port (SP) robot-assisted radical prostatectomy (RARP) reported in the literature and to describe the peri-operative and short-term outcomes of this procedure. MATERIAL AND METHODS: A systematic review of the literature was performed in December 2019 using Medline (via PubMed), Embase (via Ovid), Cochrane databases, Scopus and Web of Science (PROSPERO registry number 164129). All studies that reported intra- and peri-operative data on SP-RARP were included. Cadaveric series and perineal or partial prostatectomy series were excluded. RESULTS: The pooled mean operating time, estimated blood loss, length of hospital stay and catheterization time were 190.55 min, 198.4 mL, 1.86 days and 8.21 days, respectively. The pooled mean number of lymph nodes removed was 8.33, and the pooled rate of positive surgical margins was 33%. The pooled minor complication rate was 15%. Only one urinary leakage and one major complication (transient ischaemic attack) were recorded. Regarding functional outcomes, pooled continence and potency rates at 12 weeks were 55% and 42%, respectively. CONCLUSIONS: The present analysis confirms that SP-RARP is safe and feasible. This novel robotic platform resulted in similar intra-operative and peri-operative outcomes to those obtained with the standard multiport da Vinci system. The advantages of single incision can be translated into a preservation of the patient's body image and self-esteem and cosmesis, which have a great impact on a patient's quality of life.